MXPA06000514A - Method of diagnosis and treatment for asthma based on haplotype association. - Google Patents

Abstract

Methods for diagnosis of asthma or a susceptibility to asthma based on detection of at-risk haplotypes associated with MAP3K9 are disclosed. Also methods for treatment of asthma or a susceptibility to asthma based on detection of at-risk haplotypes associated with MAP3K9 are disclosed. In particular, pathway targeting for treating individuals who are at-risk of developing asmtha are described. In certain aspects, MLK1 inhibitors are used in treatment methods.

Description

METHODS OF DIAGNOSIS AND TREATMENT OF ASTHMA AND OTHERS RESPIRATORY DISEASES BASED ON THE ASSOCIATION OF HAPLOTIPOS BACKGROUND OF THE INVENTION Bronchial asthma [morbidity index (MIM) 600807], the most common chronic disease affecting children and young adults, is a complex genetic disorder with several superimposed phenotypes (Cookson and Moffatt 2000; Weiss 2001). There are strong indications of a genetic component in asthma (Bleecker et al., 1997 Kauffmann et al., 2002). It is also known that multiple environmental factors modulate the clinical expression of asthma, as well as the phenotypes associated with asthma: bronchial hyperresponsiveness, atopy and elevated levels of IgE (Koppelman et al., 1999, Cookson 1999, Holloway et al., 1999) . It is a commonly held opinion that asthma is produced by multiple interacting genes, some having a protective effect and others contributing to the pathogenesis of the disease, with each gene having its own tendency to be influenced by the environment (Koppelman et al., And Postma, 1999, Cookson, 1999, Holloway et al., 1999). In this way, the complex nature of the asthma phenotype, together with the substantial heterogeneity of the loci and the environmental influence, have made it difficult to discover the genetic factors underlying asthma. It has been reported that numerous loci and candidate genes show connection and association to asthma and atopy. Although some studies presenting these observations are convincing, no asthma gene conferring high risk has been located in the genetic map in such a way that it meets the rigorous criteria for meaning at the genome level.

SUMMARY OF THE INVENTION As described herein, a gene has been identified on chromosome 14g24 that plays an important role in asthma. The gene of ??? 3? 9 (the asthma gene) encodes a kinase that is part of the family of mixed lineage kinases (MLK). The protein encoded by the MAP3K9 gene is termed MAP3K9 (herein) or, more commonly, LK-1. This locus has been termed the locus of asthma one (hereinafter referred to as "ASI"). The present invention relates to methods of treatment using inhibitors of gene products of asthma. The invention relates to methods of treatment (prophylactic and / or therapeutic) for certain diseases and conditions (eg, asthma and other respiratory diseases) associated with MAP3 9 or with other members of the JNK pathway, for example, 'members of the MLK family of kinases (eg. Example MLK1, MLK2, MLK3 (SPRK, PTK1) MLK4, LZK, DLK, (ZPK, MUK) and MLK6), in particular, MLK1; and / or with other members of the JNK pathway (as shown in FIG.1), receptors and / or binding agents of the enzymes; the transcription factor AP-1 and its individual components, c-jun and v-fos, and receptors for the kinases of the MLK family. The methods include the following: methods of treating asthma or asthma susceptibility; and methods of treating respiratory diseases associated with MAP3K9 or with other members of the MLK family. In the methods of the invention, an inhibitor of the MLK kinase family is administered to an individual in a therapeutically effective amount. The MLK kinase family inhibitor can be an agent that inhibits or antagonizes a member of the JNK pathway, in particular the pathway of the MLK family of kinases (eg, MLK1, MLK2, MLK3) that are members of the MLK family. a subseries of the JK pathway, and the transcription factor AP-1 and its individual components, c-jun and v-fos. For example, the MLK kinase family inhibitor synthesis inhibitor can be an agent that inhibits or antagonizes MAP3K9 polypeptide (MLK1) activity (e.g., a? 3? 9 inhibitor, e.g. compound (1), CEP-1347, or a compound of formula IV) and / or the expression of the MAP3K9 nucleic acid, as described herein (e.g., a nucleic acid antagonist of ??? 3? 9). In one aspect, the agent alters the activity and / or the expression of the MAP3K9 nucleic acid. In another aspect, the agents used in the methods are those represented by formula I and described further in Tables A and B, and their optically pure stereoisomers, mixtures of stereoisomers, salts, chemical derivatives and the like. In other aspects, the agent used in the methods is CEP-1347 as shown in formula III, its optically pure stereoisomers, mixtures of stereoisomers, salts, chemical derivatives and the like, or a compound of structural formula IV, its stereoisomers optically pure, mixtures of stereoisomers, salts, chemical derivatives and the like. In another aspect, the agent alters the metabolism or inhibits the activity of a MLK1 protein (e.g., the MILK1 kinase) or a member of the MLK kinase family.

In certain aspects of the invention, the individual is an individual who has at least one risk factor, such as a haplotype of risk for asthma; a haplotype of risk in the gene of ??? 3? 9; a polymorphism in a MAP3K9 nucleic acid; dysregulation of MAP3K9 mRNA expression; deregulation of an MAP3K9 mRNA isoform; increased expression of the MLK1 protein; increased biochemical activity of MLK1; and greater expression of an isoform of the MKL1 protein.

The invention further relates to methods for evaluating the response to treatment with a protein of the MLK family of kinases, e.g. MLK1, by evaluating the protein level of the MLK kinase family in the individual prior to treatment, and comparing the level with a protein level of the MLK kinase family evaluated during or after treatment. A level that is significantly lower during or after treatment than before treatment indicates efficacy of treatment with the protein of the MKL family of kinases. The protein level of the MLK kinase family can be measured using a biochemical assay of enzymatic activity or using methods that allow direct quantification of the amount of MLK protein kinase, for example, by immunosorbent assay with bound enzyme (EIA). The invention furthermore relates to methods for evaluating the response to treatment with a protein from the MLK kinase family, by stimulating the production of a protein from the MLK kinase family or a protein from the MLK kinase family in a first test sample. of the individual (e.g., a sample comprising leukocytes) before treatment, and comparing the protein level of the MLK kinase family with a production level of the MLK kinase family protein in a second test sample from of the individual, during or after treatment. A production level of the protein from the MLK kinase family or protein from the MLK kinase family in the second test sample that is significantly lower than the level in the first test sample indicates efficacy of the treatment. Similarly, the invention includes methods for evaluating the response to treatment with an inhibitor of the MLK kinase family, evaluating the level of an inflammatory marker (e.g., 11-2 and TNFa) in the individual prior to treatment, and during or after the treatment. A level of inflammatory protein marker during or after treatment that is significantly less than the level of inflammatory marker before treatment indicates efficacy of the treatment. The first sample may also be a "control level" of the protein from the MLK kinase family that has been determined by extensive sampling of the individual with no incidence of asthma. The present invention also relates to isolated nucleic acid molecules comprising the asthma gene located within the ASI locus. It has also been discovered that certain particular combinations of genetic markers ("haplotypes") are present at a higher frequency than expected in patients with phenotypes associated with asthma and a susceptibility to asthma. The markers that are included in the haplotypes described in this document are associated with the genomic region that directs kinase expression? 3? 9. In one embodiment, the invention relates to a method for diagnosing asthma or an asthma susceptibility in an individual, comprising detecting the presence or absence of a risk haplotype, comprising a haplotype selected from the group consisting of: haplotype 1 , haplotype 2, haplotype 3, haplotype 4, haplotype 5, haplotype 6, haplotype 7 and combinations thereof; where the presence of the haplotype indicates asthma or susceptibility to asthma. In one embodiment, the invention relates to testing the presence of a first nucleic acid molecule in a sample, which comprises contacting said sample with a second nucleic acid molecule comprising one or more haplotypes described herein. In a particular embodiment, the determination of the presence or absence of the haplotype comprises the enzymatic amplification of a nucleic acid of the individual. In a particular embodiment, the determination of the presence or absence of the haplotype further comprises an electrophoretic analysis. For example, in one embodiment, the determination of the presence or absence of the haplotype comprises the analysis of restriction fragment length polymorphisms. In another embodiment, the determination of the presence or absence of the haplotype comprises a sequence analysis. In another embodiment, the invention relates to a method for diagnosing asthma or an asthma susceptibility in an individual, comprising detecting the presence or absence of a risk haplotype comprising haplotype 6 (shown in Table 1), wherein the presence of the haplotype indicates asthma or a susceptibility to asthma. In a particular embodiment, the determination of the presence or absence of the haplotype comprises enzymatic amplification of an individual's nucleic acid. In a particular embodiment, the determination of the presence or absence of the haplotype further comprises an electrophoretic analysis. For example, in one embodiment, the determination of the presence or absence of the haplotype comprises an analysis of restriction fragment length polymorphisms. In another embodiment, the determination of the presence or absence of the haplotype comprises sequence analysis. In another embodiment, the invention relates to a method for diagnosing asthma or an asthma susceptibility in an individual, comprising detecting the presence or absence of a risk haplotype comprising haplotype 7 (shown in table 1), where the presence of the haplotype indicates asthma or a susceptibility to asthma. In a particular embodiment, the determination of the presence or absence of the haplotype comprises the enzymatic amplification of the nucleic acid of the individual. In a particular embodiment, the determination of the presence or absence of the haplotype further comprises an electrophoretic analysis. For example, in one embodiment, the determination of the presence or absence of the haplotype comprises an analysis of restriction fragment length polymorphisms. In another embodiment, the determination of the presence or absence of the haplotype comprises the analysis of the sequence. In another embodiment, the invention relates to a kit for testing in a sample the presence of a haplotype associated with asthma, where the haplotype comprises two or more specific alleles and where the kit comprises one or more nucleic acids capable of detecting the presence or absence of two or more of the specific alleles, thus indicating the presence or absence of the haplotype in the sample. In a particular embodiment, the nucleic acid comprises a contiguous nucleotide sequence that is completely complementary to a region comprising a specific allele of the haplotype. In another embodiment, the invention relates to a kit of reagents for testing in a sample the presence of a haplotype associated with asthma, wherein the haplotype comprises two or more specific alleles, comprising, in separate containers: a) one or more labeled nucleic acids capable of detecting one or more specific alleles of the haplotype; and b) reagents for the detection of said marker. In a particular embodiment, the labeled nucleic acid comprises a contiguous nucleotide sequence that is completely complementary to a region comprising a specific allele of the haplotype. In another embodiment, the invention relates to a kit of reagents for testing in a sample the presence of a haplotype associated with asthma, wherein the haplotype comprises two or more specific alleles, wherein the kit comprises one or more nucleic acids comprising a nucleotide sequence that is at least partially complementary to a part of the nucleotide sequence of the.? 3? 9 gene, and where the nucleic acid can act as a primer for a primer extension reaction capable of detecting one or more of the specific alleles of the haplotype. In another embodiment, the invention relates to a method for the diagnosis and identification of asthma susceptibility in an individual, comprising: investigating in a sample of the individual in which it is desired to make the diagnosis a risk haplotype associated with ??? 3? 9 that is present more frequently in an individual susceptible to asthma than in an individual who is not susceptible to asthma, where the risk haplotype significantly increases the risk. In a particular embodiment, the significant increase is at least about 20%. In another embodiment, the significant increase is identified as a prevalence ratio (odds ratio) of at least about 1.2. The invention also relates to a method for diagnosing asthma or. a susceptibility to asthma in an individual, comprising detecting in a sample of the individual in which it is desired to make the diagnosis the presence or absence of at least one marker of a risk haplotype associated with the selected gene of ??? 3? 9 between the group consisting of: DG14S202, DG14S428, D14S1002, DG14S4399, DG14S404, D14S251, DG14S1300, DG14S266, DG14S462, DG14S448 and DG14S406, where the presence of one or more markers indicates asthma or a susceptibility to asthma. In another embodiment, the invention relates to a method for diagnosing an asthma susceptibility in an individual, comprising determining in a sample of the individual in which it is desired to make the diagnosis the presence or absence in the individual of a haplotype, comprising two or more alleles selected from the group consisting of one or a combination of the markers comprising the haplotypes indicated in Table 1, where the presence of the haplotype indicates susceptibility to asthma. In a particular embodiment, the determination of the presence or absence of the haplotxpo further comprises an electrophoretic analysis. For example, in one embodiment, the determination of the presence or absence of the haplotxpo comprises an analysis of restriction fragment length polymorphisms. In another embodiment, the determination of the presence or absence of the haplotype comprises a sequence analysis. In another embodiment, the invention relates to a method for diagnosing an asthma susceptibility in an individual, comprising obtaining a nucleic acid sample from the individual; and analyzing in the nucleic acid sample the presence or absence of a haplotype comprising two or more alleles selected from the group consisting of one or a combination of the markers comprising the haplotypes indicated in Table 1, where the presence of the haplotype indicates susceptibility to asthma. The present invention relates to isolated nucleic acid molecules comprising the asthma gene located within the ASI locus. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence of SEQ ID NO: 1 or the complement thereof, wherein the nucleic acid molecule optionally may comprise one or more of the SNPs indicated in the examples. The invention further relates to a nucleic acid molecule that hybridizes under stringent conditions to a nucleotide sequence of SEQ ID NO: 1 and its complement. The invention furthermore relates to isolated nucleic acid molecules (e.g., cDNA molecules) that encode a γ3β9 polypeptide (e.g., which encodes a polypeptide of SEQ ID NO: 2).

The invention also contemplates a method for testing the presence of a first nucleic acid molecule in a sample, comprising contacting said sample with a second nucleic acid molecule, wherein the second nucleic acid molecule comprises at least one (or more) nucleic acid sequences selected from the sequences described herein, wherein the nucleic acid sequence hybridizes with the first nucleic acid under conditions of high stringency. In certain embodiments, the second nucleic acid molecule contains one or more polymorphisms described herein. The invention also relates to a vector comprising an isolated nucleic acid molecule of the invention, optionally including one or more of the polymorphisms described herein, operably linked to a regulatory sequence, as well as to a recombinant host cell comprising the vector The invention also provides a method for producing a polypeptide encoded by an isolated nucleic acid molecule having a polymorphism, which comprises culturing the recombinant host cell under conditions suitable for the expression of the nucleic acid molecule. The invention also contemplates a method of assaying for the presence of a polypeptide encoded by an isolated nucleic acid molecule of the invention in a sample, the method comprising contacting the sample with an antibody that specifically binds to the encoded polypeptide. The invention further relates to a method for identifying an agent that alters the expression of a MA.P3K9 nucleic acid, comprising: contacting a solution containing a nucleic acid comprising the promoter region of the MAP3 gene 9 operatively linked to a reporter gene, with an agent to be tested; evaluate the level of expression of the reporter gene in the presence of the agent, and compare the level of expression of the reporter gene in the presence of the agent with a level of expression of the reporter gene in the absence of the agent; where if the level of expression of the reporter gene in the presence of the agent differs by an amount that is statistically significant from the level of expression in the absence of the agent, then the agent is an agent that alters the expression of the MAP3K9 gene or nucleic acid. An agent identified by this method is also contemplated.

The invention further comprises a method for identifying an agent that alters the expression of a MA.P3K9 nucleic acid, comprising contacting a solution containing a nucleic acid of the invention or a derivative or fragment thereof with an agent to be tested.; comparing the expression of the nucleic acid, derivative or fragment in the presence of the agent with the expression of the nucleic acid, derivative or fragment in the absence of the agent; where if the expression of the nucleic acid, derivative or fragment in the presence of the agent differs by an amount that is statistically significant from expression in the absence of the agent, then the agent is an agent that alters the expression of the nucleic acid of ??? 3? 9. In certain embodiments, the expression of the nucleic acid, derivative or fragment in the presence of the agent comprises expression of one or more splice variants that differ in type or amount of expression of one or more splice variants in the absence from the people. The agents identified by this method are also contemplated. Representative agents that alter the expression of a ??? 3? 9 nucleic acid contemplated by the invention include, for example, antisense nucleic acids against a gene or MAP3K9 nucleic acid; a gene or MAP3 9 nucleic acid; a MAP3K9 polypeptide; a receptor for the gene or nucleic acid of ??.? 3? 9 or another receptor; a MAP3K9 binding agent; a peptidomimetic; a fusion protein; a prodrug thereof; an antibody; and a ribozyme. A method is also contemplated for altering the expression of a nucleic acid of ??? 3? 9, which comprises contacting a cell containing a nucleic acid with such an agent. The invention further relates to a method for identifying a polypeptide that interacts with a MAP3K9 polypeptide (e.g., a γ3? 9 polypeptide encoded by a nucleic acid of the invention, such as a nucleic acid comprising one or more polymorphisms described herein), which comprises employing a yeast double hybrid system using a first vector comprising a nucleic acid encoding a DNA binding domain and a MAP3K9 polypeptide, a splice variant or a fragment or derivative thereof, and a second vector comprising a nucleic acid encoding a transcriptional activation and nucleic acid domain encoding a test polypeptide. If the activation of the transcription is performed in the yeast double hybrid system, the test polypeptide is a polypeptide that interacts with a polypeptide of ?? 3? 9. In certain methods of the invention, a therapeutic agent against asthma is used. The therapeutic agent against asthma may be an agent that alters (e.g., increases or inhibits) the MAP3K9 polypeptide activity and / or the expression of the MAP3K9 nucleic acid, as described herein (e.g., an agonist or nucleic acid antagonist). Therapeutic agents against asthma may alter the activity of the polypeptide or the expression of the nucleic acid of an AP3K9 nucleic acid by a variety of means such as, for example, by providing an additional polypeptide or by positively regulating the transcription or translation of the nucleic acid which encodes the MAP3K9 polypeptide; altering the posttranslational processing of the MAP3K9 polypeptide; altering the transcription of the splice variants; or by interfering with the activity of the polypeptide (eg, by binding to the ??? 3? 9 polypeptide, or by binding to another polypeptide that interacts with?.? 3? 9, such as a binding agent? 3? 9 as described herein), altering (e.g., downregulating) the expression, transcription or translation of a nucleic acid encoding MA.P3K9; or by altering the interaction between MAP3K9 and a binding agent of ??? 3? 9. In another embodiment, the invention relates to a therapeutic agent against asthma, such as an agent selected from the group consisting of: a MA.P3K9 nucleic acid or a fragment or derivative thereof; a polypeptide encoded by a ??? 3 9 nucleic acid (eg, encoded by a MAP3K9 nucleic acid having one or more polymorphisms such as those described herein); a MAP3K9 receptor; a ??? 3? 9 binding agent; a peptidomimetic; a fusion protein; a prodrug; an antibody; an agent that alters the expression of the gene or nucleic acid of MA.P3K9; an agent that alters the activity of a polypeptide encoded by a gene or nucleic acid of ??? 3? 9; an agent that alters the post-transcriptional processing of a polypeptide encoded by a MA.P3K9 gene or nucleic acid; an agent that alters the interaction of a MAP3 polypeptide 9 with a ??? 3? 9 receptor or binding agent; an agent that alters the transcription of splice variants encoded by a gene or MAP3K9 nucleic acid; and ribozymes. The invention also relates to pharmaceutical compositions comprising at least one therapeutic agent against asthma as described herein. The present invention relates to methods for diagnosing an asthma susceptibility in an individual, comprising detecting a polymorphism in a MAP3K9 nucleic acid, where the presence of the polymorphism in the nucleic acid indicates a susceptibility to asthma. The invention further relates to methods for diagnosing asthma in an individual, which comprises detecting a polymorphism in a nucleic acid of ??? 3? 9, where the presence of the polymorphism in the nucleic acid indicates asthma. In one embodiment, to diagnose asthma or asthma susceptibility by the 'detection of the presence of a polymorphism in a nucleic acid of ??? 3? 9, the presence of the polymorphism in the nucleic acid of ??? 3? 9 it can be indicated, for example, by the presence of one or more of the polymorphisms indicated in the examples section. In other embodiments, the invention relates to methods for diagnosing asthma susceptibility in an individual, which comprises detecting an alteration in the expression or composition of a polypeptide encoded by a? 3? 9 nucleic acid in a test sample. , compared to the expression or composition of a polypeptide encoded by a? 9 9 nucleic acid in a control sample, where the presence of an alteration in the expression or composition of the polypeptide in the test sample indicates a susceptibility to asthma. The invention further relates to a method for diagnosing asthma in an individual, which comprises detecting an alteration in the expression or composition of a polypeptide encoded by a MAP3K9 nucleic acid in a test sample, as compared to the expression or composition of a polypeptide encoded by a MAP3K9 nucleic acid in a control sample, where the presence of an alteration in the expression or composition of the polypeptide in the test sample indicates asthma. The invention also relates to a method for treating a disease or condition associated with a MAP3K9 polypeptide (eg, asthma) in an individual, comprising administering a therapeutic agent against asthma to the individual, in a therapeutically effective amount. In certain embodiments, the therapeutic agent against asthma is a MAP3K9 agonist; In other embodiments, the therapeutic agent against asthma is an MAP3K9 antagonist. The invention also contemplates a transgenic animal comprising a nucleic acid selected from the group consisting of: an exogenous MAP3K9 gene or nucleic acid and a nucleic acid encoding a ??? 3? 9 polypeptide.

In another embodiment, the invention relates to a method for testing in a sample the presence of a MAP3K9 nucleic acid, which comprises contacting the sample with a nucleic acid comprising a contiguous nucleotide sequence that is at least partially complementary to a part of the sequence of said nucleic acid of? 3? 9 under conditions suitable for hybridization, and evaluating whether hybridization has occurred between a ??? 3.9 nucleic acid and said nucleic acid comprising a sequence of contiguous nucleotides that is at least partially complementary to a part of the sequence of said MAP3K9 nucleic acid; where if hybridization has occurred, a nucleic acid of MA.P3K9 is present in the sample. In certain embodiments, the contiguous nucleotide sequence is completely complementary to a part of the sequence of said ??? 3? 9 nucleic acid. If desired, amplification of at least part of said ??? 3? 9 nucleic acid can be performed. In certain different embodiments, the contiguous nucleotide sequence has a length of 100 or less nucleotides and has an identity of at least 80% with a contiguous nucleotide sequence, an identity of at least 80% with the complement of a sequence of contiguous nucleotides; or is capable of selectively hybridizing with said MAP3K9 nucleic acid. In other embodiments, the invention relates to a reagent for testing in a sample the presence of a MAP3K9 gene or nucleic acid, the reagent comprising a contiguous nucleotide sequence that is at least partially complementary to a part of the nucleic acid sequence. of said gene or nucleic acid of ??? 3? 9; or comprising a contiguous nucleotide sequence that is completely complementary to a part of the nucleic acid sequence of said gene or MA.P3K9 nucleic acid. The invention also contemplates a kit of reagents, for example, for testing in a sample the presence of a MAP3K9 nucleic acid, comprising (eg, in separate containers) one or more labeled nucleic acids comprising a contiguous nucleotide sequence that is at least partially complementary to a part of the nucleic acid sequence of ??? 3? 9, and reagents- for the detection of said marker. In certain embodiments, the labeled nucleic acid comprises a contiguous nucleotide sequence that is completely complementary to a part of the nucleotide sequence of said MAP3K9 gene or nucleic acid. In other embodiments, the labeled nucleic acid may comprise a contiguous nucleotide sequence that is at least partially complementary to a part of the nucleotide sequence of said gene or nucleic acid of ??? 3? 9, and that is capable of acting as primer for said Δ3 9 nucleic acid when maintained in conditions for the extension of primers. The invention also provides the use of a nucleic acid having a length of 100 or less nucleotides and which is: a) at least 80% identical to a contiguous nucleotide sequence; b) at least 80% identical to the complement of an adjacent nucleotide sequence; or c) capable of selectively hybridizing with said MA.P3K9 nucleic acid, to test in a sample the presence of a ??? 3? 9 nucleic acid.

In another embodiment, there is provided the use of a first nucleic acid having a length of 100 or less nucleotides and which is: a) at least 80% identical to a contiguous nucleotide sequence; b) identical by at least 80% to the complement of an adjacent nucleotide sequence; or c) capable of selectively hybridizing with said MAP3K9 nucleic acid; for testing in a sample the presence of a MAP3K9 gene or nucleic acid having at least one nucleotide difference from the first nucleic acid (eg, a SNP as indicated herein), such as to diagnose a susceptibility to a disease or condition associated with ??? 3? 9. The invention also relates to the use of a kinasase inhibitor of the MLK family for the manufacture of a medicament for the treatment of asthma in an individual, wherein the individual has at least one risk factor selected from the group consisting of: a haplotype of risk for asthma; a haplotype of risk in the gene of ??? 3? 9; a polymorphism in a nucleic acid of ??? 3? 9; dysregulation of the expression of ??.? 3? 9 mRNA, deregulation of an isoform of ??? 3? 9 mRNA; an increase in the expression of the MLK1 protein; an increase in the biochemical activity of MLK1; and an increase in the expression of an isoform of the MLK1 protein. In certain embodiments, the kinase inhibitor of the MLK family is an inhibitor of MLK1, for example CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts or an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts. The present invention also contemplates the use of a first nucleic acid molecule for diagnosing asthma or a susceptibility to asthma in a sample of an individual in which it is desired to diagnose the disease, which comprises detecting in the sample the presence or absence of a second nucleic acid molecule of at least one marker of a risk haplotype associated with the gene of ??? 3? 9 selected from the group consisting of: haplotype 1, 2, 3, 4, 5, 6 or 7 of Table 1 and combinations thereof, by contact with the first nucleic acid, where the presence of one or more markers indicates asthma or a susceptibility to asthma. The presence or absence of the label can be performed by enzymatic amplification of nucleic acids, electrophoretic analysis, analysis of restriction fragment length polymorphisms or sequence analysis. BRIEF DESCRIPTION OF THE DRAWINGS The above objects and other objects, features and advantages of the invention will be apparent after the most particular description of preferred aspects of the invention provided below, as illustrated in the accompanying drawings. The file of the patent or application contains at least one drawing made in color. The office will provide copies of this patent or patent application publication with color drawings when requested and after payment of the necessary cost. FIG. 1 is an illustration of the JNK signaling cascade. FIG. 2 shows examples of asthma lineages used in linkage analysis. The unaffected siblings of the patients are not shown and sex indicators have been shuffled for some individuals in the two upper generations to protect privacy. The darkened squares and circles represent affected men and women, respectively. Oblique symbols represent dead individuals. FIG. 3 shows the multipuntual lod score of shared alleles of chromosome 14. A flanking genome scan is shown by a dotted line. A fine mapping lod score of 4.00 was detected within the peak region after the addition of 34 microsatellite type markers to obtain a marker density less than 0.2 cM, using the deCODE high density genetic map. to determine the genetic distances. The multi-point lod score is on the y-axis and the distance in centimorgans from the p-end of the chromosome is on the x-axis. FIG. 4 shows the mean age, gender, history of smoking habit,% of patients with positive skin tests, the total mean level of IgE, the severity level of asthma and lung function values expressed as% of volume of forced expiration predicted in one second (% FEV1), the forced expiratory volume ratio in one second / forced vital capacity (FEV1 / FVC) and% of patients requiring < 2.0 mg / ml and < 8 mg / ml methacholine, respectively, to produce a 20% reduction in FEV1 (PC2o) for the asthma study population. FIG. 5 shows a map of the MAP3K9 gene with SPN and microsatellites. FIG. 6.1 and 6.2 show the linkage disequilibrium (LD) plot for "the chr! 4q4,2-3 region with all the markers present." The location on the chromosomal map of the linkage disequilibrium blocks using multiple microsatellite-type markers and SNP (x and y axis), covering the lod reduction on chromosome 14q24.2-3 (FIG.1.1) and the three LD blocks (FIG.2.2) that show the greatest association with asthma and include the gene of ??? 3? 9. The graph of the d dimer is shown above the transverse line (ie, LD of any two markers close to each other) and the corresponding p values are shown below the line. The meaning of the d dimer and the p values is reflected in the difference in black and white intensities (vertical axis to the right). FIG. 6.2 shows a narrowly centered section of the linkage disequilibrium graphic of FIG. 6.1 in the region where the markers comprising the haplotypes reside. FIG. 7.1 to 7.19 show the nucleic acid sequence of MA.P3K9 with coding regions (SEQ ID NO: 1). The uppercase letters indicate the coding regions (exons). FIG. 8 is the amino acid sequence of MAP3K9 (SEQ ID NO: 2). FIG. 9 is a graph showing the expression of ??? 3? 9 in airway tissue with asthma using RT-PCR. OLD: Surgical resection of a non-cancerous tissue of individuals; OLD-1 and OLD-2, with obstructive pulmonary disease. CO: Control lung (surgical resection of non-cancerous tissue from two individuals, CO-1 and CO-2). The results show a marked increase in the expression of Map3K9 in airway tissue with asthma compared to the weave of the control airway. FIG. 10 is a graph showing the expression of MAP3K9 in PBM cells from patients with asthma versus control subjects. The results indicate a significant increase in the expression in PBM cells of patients with asthma for variant b comparable to the lung data. FIG. 11.1-11.17 show the mRNA and amino acid sequences for the a-e splice variants. FIG. 12.1 to 12.430 are a table of microsatellite and SNP markers with forward and inverse sequence primers. The amplimer sequences and the initial and final positions of the nucleic acid are also provided. DETAILED DESCRIPTION OF THE INVENTION Extensive genealogical information of a population has been combined with a population-based list of patients with powerful shared genome methods to locate the first major locus in asthma with genomic significance. A genomic exploration of patients, related in 6 meiotic events, diagnosed with asthma and their unaffected family members, has been completed. By means of linkage studies it has been identified that the ASI locus of chromosome 14q24 is associated with asthma. This locus does not correspond to known susceptibility loci for asthma and represents the first location of a gene for asthma on chromosome 14q24. Until now there were no known linkage studies of asthma in humans that showed connection to this region of the chromosome. Based on the linkage studies conducted, the applicants have discovered a direct relationship between the ASI locus significant at the genomic level (GWS) and asthma. Linkage and association studies have identified a ??? 3? 9 gene that is located at 14q24.2-3 and is in the middle of a region in which there is a significant three-marker haplotype that overlaps the gene of AP3K9 and is present in up to 14% of patients and in 5% of controls (relative risk 2,784). This haplotype is the most common of seven overlapping haplotypes that extend over a 286 kb region that covers the total and a part of two other LD blocks. See Tables 1 and 2 of the examples section. All patients studied have asthma diagnosed by a physician (2/3 of them also have atopy as determined by positive skin tests and / or an elevation of IgE levels). The seven genetic marker haplotypes are shown in Table 1 and their p (p-val) values and their relative risk relationships (r) are shown in Table 2. Initially the MA.P3K9 gene was isolated from a human epithelial tumor cell line. The expression of MA.P3K9 has been found in lung tumor cells and in different cell lines of the immune system, as well as in smooth muscle cells. MAP3K9 is a part of the signal transduction pathways of mitogen-activated protein kinase (MAPK), which are among the most widespread mechanisms of regulation in eukaryotic cells. In all eukaryotic cells there are multiple pathways of ??. ???, each reacting to different stimuli. The regulation of MAP3K represents an entry point in the routes of MA.PK and, therefore, is complementary. Several kinases have been the therapeutic target in various diseases and it has been shown that their function is modulated efficiently using small molecules. One example is the development of new small molecule inhibitors of p38 kinase that are being considered a potential new therapy for asthma. The AP3K9 kinase is a gene that covers the center of a haplotype that is almost three times more common in patients than in controls (ie RR 2.8); Currently, no asthma gene that carries a greater risk than this gene has been isolated. The gene is in the cell signaling pathway that involves mitogenic and second messenger activities (including regulation of IP3). In this way, this gene is a strong candidate as a therapeutic target for the development of a new therapy of small molecules for patients with asthma. ??? 3? 9 is a member of the family of mixed lineage kinases (MLK). The kinase domain of the kinases of the MLK family has similarity in the sequence of amino acids both with the specific tyrosine kinase class and with the serine / threonine specific kinase class, although ??? 3? 9 is a serine kinase. / threonine. Known substrates of serine / threonine phosphorylation of members of the MLK family are the MKK7 or MKK4 kinases. The MLK family kinases MKK7 and MKK4 are known members of the JNK signaling cascade (see FIG 1). Within the JNK signaling cascade there are three levels of kinases that bind stimuli such as cell stress, lesions or cytokines through the JNK to transcriptional regulation by means of phosphorylation of c-Jun and related transcription factors (JunB & JunD). The JNK and a substrate of the JNK, c-Jun, have been implicated in the positive regulatory control of cell death or a'poptosis. This could be related to asthma through two fundamental processes: 1) dysregulation of immune function through inappropriate cell death or absence; and 2) inappropriate hyperplasia of smooth muscle cells of the respiratory tract and vascular tissue and the consequent increase in thickness of the airways increasing the risk or severity of asthma. Although the MAP3K9 gene itself has never been associated with asthma, the JNK pathway has been implicated in the following processes that relate to various aspects of asthma: 1. Activation of AP-l induced by nitric oxide in bronchial epithelial cells human. Differentiation of adjuvant T cells of type 2 and production of proinflammatory cytokines IFN-gamma and TGF-beta; 2. Inflammation of the airways induced by allergen in mice (this is reduced in mice with deficiency in Jun-B), - 3. Production of IL-10 and IL-13 induced by LPS by mast cells in relation to the inflammation of the Respiratory tract in asthma. It has been shown that MLK-1 and the JNK pathway regulate the secretion of TNFa and IL-lb, both molecules being important cytokines in asthma. In addition, the TH2, IL10, IL13, and IL5 type cytokines, all of which are effective modulators of smooth muscle contractility and relaxation of the airways (ASM), exert their effects on airway hyperresponsiveness, at least in part, by means of the induction of expression and the autocrine action of ILlbeta (Hakonarson and Grunstein, Respir Physiol Nurobiol, Sep 16,137 (2 -3): 263-76 (2003), Nakae S et al., Int Immunol. Apr. 15 (4): 483-90 (2003)). Apart from regulating the secretion of IL-lb and TNFa, the signaling pathway of MLK1, through JNK and c-Jun, is involved in the regulation of several other proinflammatory cytokines, including IL6, IL8, as well as various chemokines and TH1-type cytokines (IL2, IL12, IFNg) by their regulation of the activity of the transcription factor AP-1. It has been shown that IL-lb and TNFa are critically involved in the local regulation of airway inflammation (Wuyts et al., Respir Med Jul; 97 (7): 811-7 (2003)). In addition, IL-lb and to a lesser extent TNFa are key regulators of contractility and relaxation of ASM, two of the cardinal phenotype characteristics of asthma (Hakonarson et al., Mechanism of cytokine-induced modulation of beta-adrenoceptor responsiveness in airway smooth muscle. (Hakonarson et al., J Clin Invest., Jun. 197 (11): 2593-300 (1996)); Autocrine role of interleukin lbeta in altered responsiveness of atopic asthmatic sensitized airway smooth muscle (J Clin Invest Jan 1; 99 (1): 117-24 (1997)). Both IL1b and TNFa are potent mitogens in ASM and in mucous glands (Page et al., Front Biosci, 5: 258-267, (2000), Stylianou et al., Int. J. Bioche Cell Biol. Oct; 30 (10). : 1075-9 (1998)) and, therefore, respond, at least in part, to the greater muscle mass of ASM and mucosal hypersecretion, the other main characteristics of the asthma phenotype. Therefore, it would be expected that an MLK1 inhibitor such as compound CEP-1347, which has been shown to potently inhibit the release of TNF secretion and IL-1 in various cellular systems, will block asthma. Chemical inhibitors of 'kinases' of the MLK family have been described (Maroney et al., JBC, 276 (27): 25302-25308 (2001)). For example, CEP-1347 (formula III) directly inhibits the kinases of the MLK family including MLK1, MLK2 and MLK3. The inhibitory potency defined as the concentration of CEP-1347 necessary to inhibit the kinase activity of MLK in a standardized biochemical assay is 38 nM ± 17 nM, 51 nM i 9 nM and 23 nM + 0.1 nM for MLK1, MLK2 and MLK3 respectively. CEP-1347 also effectively inhibits the activity of MLK kinases within intact cells with inhibitory potencies of 61 nM ± 11 nM, 82 nM ± 10 nM and 39 nM for MLK1, MLK2 and MLK3 respectively. The kinetics of the inhibition by CEP-1347 of MLK kinases is consistent with a competitive mode of action with the binding of adenosine triphosphate at the active site of MLK. In addition, it has been demonstrated that CEP-1347 inhibits the production of TNFα and IL- ββ by cells grown in conventional in vitro pharmacological assay procedures (see O 97/49406). Also in animals, CEP-1347 reduces the production of TNFa and IL-? Β by mice after exposure to lipopolysaccharide (LPS) and provides protection from LPS-induced death. As IL1b and TNFa are key regulators of ASM contractility (ie, bronchial hyperresponsiveness) and relaxation, two of the cardinal phenotypic characteristics of asthma, and are the main cytokines responsible for the hypertrophy and hyperplasia of ASM and the glands In addition to having deep autocrine effects that promote local inflammation of the airways, it would be expected that the inhibition of IL-lb and TNFa would be beneficial for asthma. In this way, CEP-1347 possesses pharmaceutical properties that indicate its potential beneficial effect for the treatment of human diseases including asthma due to deregulation of the MAP3K9 gene and the consequent deregulation of MLK1 production. TARGETED POPULATIONS WITH RISK The target populations for the methods described in this document include individuals that have a risk factor in a haplotype of the gene of ??? 3? 9 or a polymorphism in the MAP3K9 gene. These individuals at risk with the DNA risk haplotype of MAP3K9 are a subset of all patients with asthma. At-risk populations also include individuals with deregulation of the? 3? 9 gene transcript and dysregulation of an MAP3K9 mRNA isoform, eg, an increase in RNA transcripts of the MLKI protein or an isoform of the protein. At-risk populations may have a higher biochemical activity of MLKl, higher levels of MLKl protein or the level of a particular isoform of the MLKl protein may be increased. In this way, at-risk populations with asthma associated with the MAP3K9 gene may have differences with DNA sequences, RNA regulation and protein expression. These underlying genetic and protein differences can be manipulated in the type and extent of the treatment provided. The isolation and identification of target populations for the treatment of individuals are advantageous for many reasons. For example, it is possible to identify individuals in a specific risk population who respond to a specific treatment, such as treatment with one of the compounds described in this document. Samples of individuals with asthma can be tested in a diagnostic assay such as those described herein to help identify the underlying genetic cause of the disease. Effective direct treatment of the subset of the population with an underlying genetic cause of asthma is possible using the diagnosis and treatments described in the present application. Knowledge of the underlying cause is useful to identify an individual who is likely to be a responder to a particular treatment designed for the underlying cause of an individual who does not respond to this treatment. For example, if an asthmatic individual is diagnosed as a carrier of a haplotype based on DNA or a variant of the isoform of the MAP3K9 protein, this individual would have more likelihood to respond to one of the compounds described in this document that interferes with the route of of JTSTK disturbed. In this way, an individual identified by diagnosis as a target population at risk may have a treatment adapted to the specific diagnosis, thus reducing the possible side effects or other harmful reactions that the individual could have with a conventional treatment. In general, conventional treatments typically correct only the symptoms associated with the disease and do not prevent, delay or stop the progression of the disease. Therefore, the specific diagnosis of the target population at risk and the subsequent treatments described in this document allow the patient to be treated not only to reduce the symptoms associated with the disease, but also to stop the progression of the disease by remodeling the problem underlying genetic THERAPEUTIC TS OF NUCLEIC ACID In another aspect, a nucleic acid of the invention can be used; a nucleic acid complementary to a nucleic acid of the invention; or a portion of said nucleic acid (e.g., an oligonucleotide as described below); or a nucleic acid encoding a member of the MLK pathway (eg,? 3? 9), in an "antisense" therapy, wherein a nucleic acid (e.g., an oligonucleotide) that specifically hybridizes with the MRNA and / or genomic DNA of a nucleic acid is administered or generated in yourself. The antisense nucleic acid that hybridizes specifically to the mRNA and / or DNA inhibits the expression of the polypeptide encoded by that mRNA and / or DNA, for example, by inhibiting translation and / or transcription. The binding of the antisense nucleic acid can be carried out by conventional base pair complementarity or, for example, in the case of DNA duplex binding, by means of a specific interaction in the main groove of the double helix. An antisense construct can be administered, for example, as an expression plasmid as described above. When the plasmid is transcribed in the cell, it produces RNA that is complementary to a portion of the mRNA and / or DNA encoding the polypeptide for the MKL pathway member (eg, MAP3K9). Alternatively, the antisense construct can be an oligonucleotide probe that is generated ex vivo and introduced into the cells; then it inhibits expression by hybridization with the mRNA and / or genomic DNA of the polypeptide. In one aspect, oligonucleotide probes are modified oligonucleotides that are resistant to endogenous nucleases, for example, exonucleases and / or endonucleases, thereby making them stable in vivo. Examples of nucleic acid molecules for use as antisense oligonucleotides are phosphoramidate, phosphorothioate and DNA methylphosphonate analogues (see also U.S. Patent Nos. 5,176,996, 5,264,564 and 5,256,775). In addition, general strategies for constructing oligomers useful in antisense therapy are also described, for example, by Van der Krol et al. (Biotechniques 6: 958-976 (1998)); and Stein et al. (Cancer Res. 48: 2659-2668 (1998)). With respect to antisense DNA, oligodeoxyribonucleotides derived from the translation start site are preferred. To perform antisense therapy, oligonucleotides (mRNA, cDNA or DNA) are designed that are complementary to the mRNA encoding the polypeptide. Antisense oligonucleotides bind to mRNA transcripts and prevent translation. Absolute complementarity is not required, although it is preferred. A "sequence complementarity" with a portion of an RNA, as referred to herein, indicates that a sequence has sufficient complementarity to be able to hybridize with the RNA, forming a stable duplex; in the case of double-stranded antisense nucleic acids, in this way a single strand of the duplex DNA can be tested, or the formation of a triplex can be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid, as described in detail above. In general, the greater the length of the hybridizing nucleic acid, the more uncoupling of bases with an RNA can contain and can form a stable duplex (or triplex) if it is the case. A person skilled in the art can find out a tolerable degree of decoupling through the use of conventional methods. The oligonucleotides used in the antisense therapy may be DNA, RNA or chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotides can be modified in the base moiety, in the sugar moiety or in the phosphate backbone, for example, to improve the stability of the molecule, hybridization, etc. Oligonucleotides can include other pendant groups such as peptides (for example, to target host cell receptors in vivo) or agents that facilitate transport across the cell membrane (see, for example, Letsinger et al., Proc. Nati. Acad Sci. USA 86: 6553-6556 (1989); Lemaitre et al., Proc. Nati Acad. Sic USA 84: 648-652 (1987)); PCT International Publication No. WO 88/09810 or the blood-brain barrier (see, for example, PCT International Publication No. WO 89/10134), or hybridization-induced cleavage agents (see, for example, Krol et al., BioTechniqru .es 6: 958-976 (1988)) or intercalating agents. (See, for example, Zon, Pharm, Res. 5: 539-549 (1988)). For this purpose, the oligonucleotide can be conjugated with another molecule (for example, a peptide, crosslinking agent induced by hybridization, transport agent, hybridization-induced cleavage agent). Antisense molecules are delivered to cells expressing the MLK route member in vivo. Several methods can be used to deliver antisense DNA or RNA to cells; for example, antisense molecules can be injected directly into the tissue site, or modified antisense molecules, engineered to target the desired cells (eg, the antisense molecule bound to peptides or antibodies that specifically bind to expressed receptors or antigens can be administered systematically). on the surface of the target cell). Alternatively, in a preferred aspect, a recombinant DNA construct is used in which the antisense oligonucleotide is placed under the control of a strong promoter (eg, pol III or pol II). The use of said construct to transfect target cells in the patient produces the transcription of sufficient amounts of nonocatenary RNA that will form base pairs complementary to the endogenous transcripts and thus prevent the translation of the mRNA. For example, an in vivo vector can be introduced in such a way that it is absorbed by the cell and directs the transcription of an antisense RNA. Such a vector can remain episomal or be integrated chromosomally, as long as it can be transcribed to produce the desired antisense RNA. These vectors can be constructed by recombinant DNA technology methods conventional in the art and described above. For example, a plasmid, cosmid, YAC or viral vector can be used to prepare the recombinant DNA construct that can be introduced directly into the tissue site. Alternatively, viral vectors that selectively infect the desired tissue may be used, in which case administration may be by other route (eg, systemic). In another aspect of the invention, double-stranded interfering RNA (interfering RNA (AR i)) can be used. RNAi is a posttranscription process in which double-stranded RNA is introduced and sequence-specific gene silencing is obtained by means of catalytic degradation of the target mRNA. See, for example, Elbashir. S M et al., Nature 411: 454-498 (2001); Lee, N. S., Nature Biotech. 19: 500-505 (2002); Lee, S-K et al., Nature Medicine 8 (7): 681-686 (2002); The complete teachings of this reference are incorporated herein by reference. RNAi is routinely used to investigate gene function in high performance or to modulate gene expression in human diseases (Chi et al., PNAS, 100 (11): 6343-6346 (2003)). The introduction of long double-stranded RNA leads to a specific degradation of the transcript sequence of homologous genes. Long double-stranded RNA is metabolized into small siRNAs of 21-23 nucleotides (small interfering RNA). The siRNA then binds to a protein complex RISC (RNA-induced silencing complex) with double-function helicase. The helicase has RNase activity and can unwind the RNA. The uncoiled siRNA allows an antisense strand to bind to a target. This results in a sequence-dependent degradation of the affine mRNA. Apart from the endogenous RNAi, exogenous, chemically synthesized or recombinantly produced RNAi can also be used.

Using non-intronic portions of the MAP3K9 gene such as corresponding portions of the mRNA of SEQ ID NO: 1, target regions of the MAP3K9 gene that are accessible to RNAi are reached and silenced. With this technique it is possible to carry an RNAi gene of the MAP3K9 nucleic acids and determine the amount of inhibition of the protein product. In this way, it is possible to design specific gene therapies by direct targeting of the MAP3K9 gene mRNA related to asthma. The endogenous expression of a member of the MLK route (eg MAP3K9) can also be reduced by inactivating or "knocking out" the gene or its promoter using homologous directed recombination (see, eg, Smithies et al., Nature 317: 230-234 (1985); Thomas &Capecchi, Cell 51: 503-512 (1987): Thompson et al., Cell 5: 313-321 (1989).) For example, a non-functional gene altered from a member of the MLK pathway (or a completely unrelated DNA sequence). flanked by DNA homologous to the endogenous gene (the coding regions or regulatory regions of the gene) can be used with or without a selective marker and / or a negative selective label, to transfect cells expressing the gene in vivo. , through directed homologous recombination, produces the inactivation of the gene.The recombinant DNA constructs can be administered directly or directed to the required site in vivo using appropriate vectors as described above. unaltered can be increased using a similar method: homologous directed recombination can be used to insert a DNA construct comprising an unaltered functional gene, or its complement, or a portion thereof, in place of a gene in the cell as previously described. In another aspect, homologous directed recombination can be used to insert a DNA construct comprising a nucleic acid encoding a polypeptide variant that differs from that present in the cell. Alternatively, the endogenous expression of a member of the MLK pathway can be reduced by targeting deoxyribonucleotide sequences complementary to the regulatory region of the MKL pathway member (i.e., the promoter and / or enhancers) to form triple helical structures that prevent the transcription of the gene in target cells in the body. (See generally, Helene, C, Anticancer Drug Des., 6 (6) 569-84 (1991): Helene, C. et al., Ann., NY Acad. Sci. 660: 27-36 (1992); Maher, LJ Bioassays 14 (12): 807-15 (1992)). Similarly, the antisense constructs described herein, by antagonizing the normal biological activity of one of the members of the MLK pathway, can be used in the manipulation of theses, for example differentiation of theids, both in vivo and for culture. of tissues ex vivo. In addition, antisense techniques (e.g., microinjection of antisense molecules or transfection with plasmids whose transcripts are antisense to a nucleic acid AR or nucleic acid sequence) can be used to investigate the role of one or more members of the pathway. MLK in the development of disease-related states. These techniques can be used in cell culture, but they can also be used in the creation of transgenic animals. The therapeutic agents described herein may be delivered in a composition, as described above, or by themselves. They can be administered systemically or can be targeted to a particular tissue. The therapeutic agents can be produced by a variety of media, including chemical family kinase; recombinant production; production in vivo (eg, a transgenic animal, such as in U.S. Patent No. 4,873,316 to Meade et al.), for example, and can be isolated using conventional means such as those described herein. In addition, a combination of any of the above methods of treatment (eg, administration of a non-altered polypeptide together with antisense therapy targeting the altered mRNA for a member of the ML route can also be used.; administration of a first variant of splicing together with antisense therapy that is directed to a second variant of splicing). The invention further relates to the use of these therapeutic agents, as described herein, for the manufacture of a medicament for the treatment of asthma and other respiratory diseases associated with the MAPK39 gene, for example, using the methods described herein. document METHODS OF THERAPY As a result of these findings, methods are now available for the treatment of asthma and other respiratory diseases including, but not limited to: chronic obstructive pulmonary disease, chronic bronchitis and other respiratory diseases associated with the ??? 3 gene? 9 and potentially also other inflammatory diseases (such as rheumatoid arthritis, psoriasis, multiple sclerosis and inflammatory bowel disease) with the use of MLK1 inhibitors, such as agents that inhibit the kinase activity of MLKl and thus reduce the cellular production of cytokines and other inflammatory mediators as a result of cell stimulation. The term "treatment", as used herein, refers not only to improving the symptoms associated with the disease or condition, but also to preventing or delaying the onset of the disease or condition; prevent or delay the onset of a second episode of the disease or condition; reduce the "severity or frequency of the symptoms of the disease or condition, and / or reduce the need for concomitant therapy with other drugs that improve the symptoms associated with the disease or condition, for example, corticosteroids. for assessing an individual's risk of developmental and / or other respiratory diseases In one aspect, the individual to be treated is an individual who is susceptible (at an increased risk) to asthma, or for whom the severity of the disease or condition is associated with haplotypes of DNA risk in the gene of ??? 3? 9, deregulation of the mRNA expression of ??? 3? 9 or increase in the amount of protein and / or biochemical activity of the MLKl protein and / or increase in the amount of a particular isoform of the MLK1 protein TREATMENT METHODS The present invention includes treatment methods (prophylactic and / or therapeutic, as described above) for asthma and other respiratory diseases in individuals, such as individuals in the target populations described above, as well as for other diseases and conditions associated with MAP3K9 or with other members of the MLK family of kinases. Members of the "JNK pathway", in particular members of the kinases of the MLK family as used herein, include other polypeptides (e.g., enzymes, receptors) and other molecules that are associated with route signaling. of JNK, including transcription factors c-jun, v-fos and AP-1 or the production of an MLK protein, such as the transcription of the MAP3K9 gene and the production of the MLK-1 protein and / or the stability of the MLK-1 protein. In particular, the invention relates to methods of treating asthma or asthma susceptibility using a therapeutic agent against asthma. A "therapeutic agent against asthma" is an agent that alters (e.g., increases or inhibits) the activity of the polypeptide of ??? 3? 9 and / or the expression of the ??? 3? 9 nucleic acid as described in this document (for example, an antagonist of the nucleic acid of asthma). In certain aspects, the therapeutic agent against asthma alters the activity and / or expression of the MAP3K9 nucleic acid. Therapeutic agents against asthma may alter the MAP3K9 polypeptide activity or the expression of the nucleic acid with a variety of means, such as, for example, by reducing the polypeptide of ??? 3? 9 or by negatively regulating the transcription or translation of the MAP3K9 nucleic acid; altering the posttranslational processing of the MAP3K9 polypeptide; altering the transcription of splicing variants of ??? 3? 9; or by interfering with MAP3K9 polypeptide activity (eg, by binding to a ??? 3? 9 polypeptide) or by binding to another polypeptide that interacts with ??? 3? 9, altering (e.g., negatively regulating) the expression, transcription or translation of a MAP3 9 nucleic acid or altering (e.g. agonizing or antagonizing) the activity. In particular, the invention relates to methods of treating asthma or susceptibility to asthma, for example: for individuals in a population at risk such as those described; as well as treatment methods for asthma or other respiratory diseases; methods to reduce the risk of asthma; and / or to reduce cellular cytokines through the use of agents that inhibit the kinase activity of MLK, for example, CEP-1347, or compounds such as those included by formula I and Tables A and B. The invention furthermore relates to use of one or more ML inhibitors, as described herein, for the manufacture of a medicament for the treatment of asthma and other respiratory diseases, for example, using the methods described herein. In the methods of the invention, the "therapeutic agent against asthma" is an "inhibitor of the MLK family". In one aspect, an "inhibitor of the MLK family" is an agent that inhibits the activity of the MAP3K9 polypeptide and / or the expression of the? 3? 9 nucleic acid, as described herein (e.g. nucleic acid antagonist). In another aspect, an inhibitor of the MLK family is an agent that inhibits the activity of the polypeptide and / or the expression of the nucleic acid of multiple members of the kinases of the MLK family in the JNK pathway. In another aspect, an inhibitor of the MLK family is an agent that alters the activity or metabolism of an MLK kinase (eg, an MLK kinase antagonist, an MLK kinase activator antagonist). In certain aspects, the MLK inhibitor alters the activity and / or expression of the MAP3K9 nucleic acid. Inhibitors of kinases of the MLK family can alter the activity of the polypeptide or the expression of the nucleic acid of a member of the JNK pathway, in a variety of means such as, for example, by catalytic degradation, negative regulation or interference with the expression, transcription or translation of a nucleic acid encoding the member of the JKN pathway; altering the post-translational processing of the polypeptide; altering the transcription of splice variants; or by interfering with the activity of the polypeptide (for example by binding to the polypeptide or by binding to another polypeptide that interacts with that member of the JNK pathway, such as a ??? 3? 9 binding agent or MLK1 as described in this document or some other binding agent of a route member), by altering the interaction between two or more members of the MLK family kinases on the JNK route, or by antagonizing the activity of a member of the route of JNK. Inhibitors of representative MLK family kinases include the following: agents that inhibit the activity of a member of the MLK signaling pathway (e.g., proteins ??? 3? 9, MLK1) eg CEP-1347, and compounds represented by formula I and Tables A and B; agents that inhibit the activation of activators of MLK pathway members, such as MKL1 activators, MLK2 activators and MLK3 activators or agents that bind to MLK family kinases or that otherwise affect the activity of the MLK family. MLK signaling pathway (eg RACI / Cdc42 inhibitors KK4 and MKK7), other agents that alter (eg, inhibit or antagonize) the expression of a member of the JNK pathway, such as the expression of a nucleic acid or the activity of the polypeptide of ??? 3? 9 or of a kinase of the MLK family, or that regulate the transcription of splice variants of ??? 3? 9 or (for example, agents that affect the expression of the splice variants, or that affect the amount of each variant of splicing that is expressed); polypeptides described herein and / or splice variants encoded by the MAP3K9 nucleic acid or fragments or derivatives thereof; other polypeptides (e.g., MAP3K9 activators); MAP3K9 binding agents; or agents that affect (e.g., increase) activity or reduce the stability of the? 3? 9 polypeptide; antibodies against MLK, such as an antibody against an altered MAP3K9 polypeptide, or an antibody against a non-altered ??? 3? 9 polypeptide, or an antibody against a particular splice variant encoded by a MAP3K9 nucleic acid as it has been described above; for example MLK3 (A-20): SC 15068, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) which can be administered intracellularly to reduce the activity or amount of MLK1; antisense nucleic acids or small double-stranded interfering RNA against nucleic acids encoding MAP3K9 or a kinase of the MLK family or another member of the JNK pathway, or fragments or derivatives thereof, including antisense nucleic acids against nucleic acids encoding the MAP3K9 or other kinase polypeptides of the MLK family and vectors comprising said antisense nucleic acids (e.g., nucleic acid, cDNA and / or mRNA, double stranded interferential AR or a nucleic acid encoding an active fragment or derivative thereof, or a oligonucleotide, for example, the complement of one of SEQ ID NOs: 1 or 3, or a nucleic acid complementary to the nucleic acid encoding SEQ ID NO: 2, or fragments or derivatives thereof); other agents that alter (e.g., inhibit or antagonize) the expression of a member of the JNK pathway, such as the expression of the nucleic acid or the activity of the polypeptide of ??? 3? 9 or of the kinase of the MLK family , or that regulate the transcription of splicing variants of ??? 3? 9 or (for example, agents that affect the type of splicing variant that is expressed or that affect the amount of each variant cut and splice that is expressed). If desired, more than one kinase inhibitor of the MLK family can be used together. The therapy is designed to alter the activity of a MAP3K9 polypeptide, a kinase of the MLK family or another member of the JNK pathway in an individual, such as by means of inhibition or antagonist activity. For example, a kinase inhibitor of the MLK family can be administered to reduce the kinase of the MLK family within the individual or to down-regulate or reduce the expression or availability of the MAP3K9 nucleic acid or specific splice variants of the nucleic acid of the MLK family. ??? 3? 9. Negative regulation or reduction of the expression or availability of a native γ 3 κ nucleic acid or of a particular splice variant could minimize the expression or activity of a defective nucleic acid or the variant of cut and particular splice and thus minimize the impact of the defective nucleic acid or the particular splice variant. Inhibitors of kinases of the MLK family are administered in a therapeutically effective amount, ie, an amount that is sufficient to treat the disease or condition, such as by improving the symptoms associated with the disease or condition, by preventing or delaying the onset of the disease. disease or condition and / or also reducing the severity or frequency of symptoms of the disease or condition. The amount that will be therapeutically effective in the treatment of a disease or condition of a particular individual will depend on the symptoms and severity of the disease and can be determined by conventional clinical techniques. In addition, in vitro or in vivo assays can optionally be used to help identify optimal dosage ranges. The precise dose to be used in the formulation will also depend on the route of administration and the severity of the disease or disorder, and should be decided according to the criteria of a physician and the circumstances of each patient. Effective doses can be extrapolated from dose-response curves derived from test systems in animal or in vitro models. In certain aspects of the invention, the kinase inhibitory agent of the MLK family is an agent that inhibits the activity of MAP3K9. In certain methods of the invention, the agents indicated in Formula I, Tables A and B and Formula III (CEP-1347) can be used for the prophylactic and / or therapeutic treatment of diseases and conditions associated with MAP3K9 or with other members. of kinases of the MLK family or other members of the JK pathway, or with increased activity of the kinase of the MLK family. In particular, they can be used for the treatment of asthma or asthma susceptibility, such as in individuals in a population at risk as described above (for example, based on identified risk factors) and the individual treatment required. In one aspect of the invention, the kinase inhibitor of the MLK family is an inhibitor of MLK1 such as CEP-1347 (also known as KT7515, Cephalon, Inc. W. Chester, PA), its optically pure stereoisomers, mixtures of stereoisomers, salts, chemical derivatives, analogues or other compounds that inhibit MAP3K9 that effectively reduce kinases of the MLK family when administered to humans. The compounds contemplated as inhibitors of kinases of the MLK family in the methods described herein can be represented by the following formula: Formula I. or a pharmaceutically acceptable salt thereof, wherein: one of R1 and R2 is selected from the group consisting of: a) -CO (CH2) jR4, where j is from 1 to 6 and R4 is selected from the group consisting of: 1) hydrogen and a halogen; 2) -NR5 Rs, wherein R5 and Rs are independently hydrogen, substituted lower alkyl, unsubstituted lower alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted aralkyl, unsubstituted aralkyl, lower alkylaminocarbonyl or lower alkoxycarbonyl; or R5 and R6 are combined with a nitrogen atom to form a heterocyclic group; 3) N3; 4) -SR27, wherein R27 is selected from the group consisting of: i) hydrogen; ii) substituted lower alkyl; iii) unsubstituted lower alkyl; iv) substituted aryl; v) unsubstituted aryl; vi) substituted heteroaryl; vii) unsubstituted heteroaryl; viii) substituted aralkyl; ix) unsubstituted aralkyl; x) thiazolinyl; xi) - (CH2) aC02R28, where a is 1 or 2, and R28 is selected from the group consisting of: hydrogen and lower alkyl; and xii) - (CH2) aCONR5 R6; and 5) 0R2g (wherein R29 is hydrogen, substituted lower alkyl, unsubstituted lower alkyl, or COR30 (wherein R30 is hydrogen, lower alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl)); b) -CH (OH) (CH2) bR4A, where b is from 1 to 6 and RA is hydrogen or the same as R4; c) - (C¾) dCHR31C02R32 where d is from 0 to 5, R31 is hydrogen, -CONR5 R6 or -C02R33 (where R33 is hydrogen or lower alkyl) and R32 is hydrogen or lower alkyl; d) - (C¾) dCHR31CONR5R6; e) - (CH2) kR7 wherein k is from 2 to 6 and R7 is halogen, C02R8 (where R8 is hydrogen, lower alkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl), CONR5R6, substituted aryl, aryl unsubstituted, substituted heteroaryl, unsubstituted heteroaryl, OR9 (where R9 is hydrogen, substituted lower alkyl, unsubstituted lower alkyl, acyl, substituted aryl, or unsubstituted aryl), SR27B (where R27B is the same as R27), NR10 Rn ( where R10 and R11 are the same as R5 and Rs) or N3; f) -CH = CH (CH2) mR12 where m is from 0 to 4, and R12 is hydrogen, lower alkyl, C02R8A (where R8A is the same as R8), -CO R5 R6, substituted aryl, unsubstituted aryl, substituted heteroaryl , unsubstituted heteroaryl, 0R9A (where R9A is the same as R5), or NR10A R11A (where R10A and R11A are the same as R5 and R6); g) -CH = C (C02R33A) 2l where R33A is the same as R33; h) -C / C (CH2) nR13, where n is 0 to 4 and R13 is the same as R12; i) -CH2-OR44, wherein R44 is substituted lower alkyl; and the balance of R1 or R2 is selected from the group consisting of: j) hydrogen, lower alkyl, halogen, acyl, nitro, NR14 R15 (where R14 or R15 is hydrogen or lower alkyl, and the other is hydrogen, lower alkyl, acyl, carbamoyl, lower alkylaminocarbonyl, substituted arylaminocarbonyl or unsubstituted arylaminocarbonyl); k) -CH (SR34) 2, wherein R34 is lower alkyl or alkylene; 1) -CH2R35, where R3S is OR36 (where R36 is tri-lower alkylsilyl where the three lower alkyl groups are the same or different, or is the same as R29), or SR37 (where R37 is the same as R27); m) -CO (CH2) qR16, where q is from 1 to 6, and R16 is the same as R4; n) -CH (OH) (CH2) e R, where e is from 1 to 6, and R3B is the same as R; o) - (CH2) fCHR39C02R40, where f is from 0 to 5, R39 is the same as R31 and R40 is the same as R32; p) - (CH2) rR17, where r is from 2 to 6, and R17 is the same as R7; q) -CH = CH (CH2) tR18, where t is from 0 to 4 and R18 is the same as R12; r) -CH = C (C02R33B) 2; where R33B is the same as R33; s) -C / C (CH2) UR19, where u is from 0 to 4 and R19 is the same as R13; R3 is hydrogen, acyl or lower alkyl; X is selected from the group consisting of: a) hydrogen; b) formyl; c) lower alkoxycarbonyl; d) -CONR20 R21, where: R20 and R21 are independently: hydrogen; lower alkyl; -CH2R22, where R22 is hydroxy, or -NR23 R24 (where R23 or R24 is hydrogen or lower alkyl, and the other is hydrogen, lower alkyl or the residue of a D-amino acid in which the hydroxy group of the carboxyl group is excluded , or R23 and R24 combine with a nitrogen atom to form a heterocyclic group); and e) -CH = N-R25, wherein R25 is hydroxy, lower alkoxy, amino, guanidino or imidazolylamino; Y is hydroxy, lower alkoxy, aralkyloxy or acyloxy; or X and Y combined represent -XY-, = 0, -CH20 (C = 0) O-, -CH20C (= S) 0-, -CH2NR26C (= 0) - (where R26 is hydrogen or lower alkyl), - C¾NHC (= S) O-, -CH20S (= 0) 0- or -CH20C (C¾) 20-; and W1 and W2 are hydrogen, or W1 and W2 together represent oxygen. The compounds represented by the formula (I) will be referred to below as Compound (I), and the same applies to the compounds of other formula numbers. In the definitions of the groups of the formulas, lower alkyl means a straight or branched chain alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tere -butyl, pentyl, isomeric, neopentyl, 1-ethylpropyl and hexyl. The lower alyl residue of lower alkoxy, lower alkoxycarbonyl, lower alkylaminocarbonyl and tri-lower alkylsilyl has the same meaning as the lower alkyl defined above. The acyl moiety of the acyl and acyloxy groups means a straight or branched chain alkanoyl group having from 1 to 6 carbon atoms, such as formyl, acetyl, propanoyl, butyryl, valeryl, pivaloyl and hexanoyl, an arylcarbonyl group described below or a heteroarylcarbonyl group described below. The aryl moiety of the aryl, arylcarbonyl and arylaminocarbonyl groups means a group having from 6 to 12 carbon atoms, such as phenyl, biphenyl and naphthyl. The heteroaryl moiety of the heteroaryl and heteroarylcarbonyl groups contains at least one heteroatom selected from O, S, and N, and includes pyridyl, pyrimidyl, pyrrolyl, furylthienyl, imidazolyltriazolyl, tetrazolyl, quinolyl, isoquinolyl, benzoimidazolyl, thiazolyl, and benzothiazolyl. The aralkyl moiety of the aralkyl and aralkyloxy groups means an aralkyl group having from 7 to 15 carbon atoms, such as benzyl, phenethyl, benzhydryl and naphthylmethyl. The substituted lower alkyl group has from 1 to 3 independently selected substituents, such as hydroxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, dioxolane, dioxane, dithiolane and dithione. The lower alkyl moiety of the substituted lower alkyl group, and the lower alyl moiety of the lower alkoxy, lower alkoxycarbonyl and mono- or di-lower alkylamino group in the substituents of the substituted lower alkyl group has the same meaning as lower alkyl defined above. Each of the substituted aryl, substituted heteroaryl and substituted aralkyl groups have from 1 to 3 independently selected substituents, such as lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino and halogen . The lower alkyl moiety of the lower alkyl, lower alkoxy, lower alkoxycarbonyl and mono- or di-lower alkylamino groups between the substituents have the same meaning as lower alkyl defined above. The heterocyclic group formed with a nitrogen atom includes pyrrolidinyl, piperidinyl, piperidino, morpholinyl, morpholino, thiomorpholino, -methylpiperazinyl, indolyl and isoindolyl. The alpha-amino acid groups include glycine, alanine, proline, glutamic acid and lysine, which may be in the L form, in the D form or in the form of a racemate. A halogen includes fluorine, chlorine, bromine and iodine. Preferably, one of R1 and R2 is selected from the group consisting of - (CH2) kR7, -CH = CH (CH2) mR12, -C / C (CH2) nR13, -CO (CH2) jSR27 and -CH2 OR44 where R is methoxymethyl, ethoxymethyl or methoxyethyl; and the other of R1 and R2 is selected from the group consisting of - (CH2) rR17, -CH = CH (CH2) R18, - C / C (CH2) UR19, NR14R15, hydrogen, halogen, nitro, -C¾0- ( substituted or unsubstituted) lower alkyl, -C0 (CH2) qSR27, -CH2R3S, -CH2OH and -CH2SR37, where R37 is selected from the group consisting of lower alkyl, pyridyl and benzimidazole. Preferably, R35 is OR36 where R36, preferably, is selected from the group consisting of methoxymethyl, ethoxymethyl and methoxyethyl. Preferably, R27 is selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, thiazole and tetrazole. Preferably, each of kyr, independently, is 2, 3 or 4. Preferably, j and q, independently, are 1 or 2. Preferably, R7 and R17, independently, are selected from the group consisting of (1) C02R8 and C02R8A, where R8 and R8A, independently, are hydrogen, methyl, ethyl, or phenyl; (2) phenyl, pyridyl, imidazolyl, thiazolyl, or tetrazolyl; (3) OR9 and OR9A, where R9 and R9A, independently, are hydrogen, methyl, ethyl, phenyl or acyl; (4) SR27B wherein R27B is selected from the group consisting of unsubstituted lower alkyl, 2-thiazoline and pyridyl; and (5) WR ^ R11 and NR14R15, where R10, R11, R14 and R15, independently, are selected from the group consisting of hydrogen, methyl, ethyl, phenyl, carbamoyl and lower alkylaminocarbonyl. Preferably, m, n, t and u, independently, are 0 or 1.

Preferably, R, R, R and R, independently, are selected from the group consisting of hydrogen, methyl, ethyl, phenyl, pyridyl, imidazole, thiazole, tetrazole, C02R8, OR9, and NR10R11 where R8, R9, R10, and R11 they have the preferred values shown above. Preferably, R3 is hydrogen or acetyl, more preferably hydrogen. Preferably, X is hydroxymethyl or lower alkoxycarbonyl, with methoxycarbonyl being particularly preferred. Preferably, Y is hydroxy or acetyloxy, more preferably hydroxy. Preferably, each of W1 and W2 is hydrogen. The values of the most preferred real substituents are shown in the compounds of Table 1, with Compounds 1-157 being especially preferred. The Examples of Compound (I) are shown in Table A and the intermediates are shown in Table B. TABLE A Compound R1 R2 R3 Y 1 CH = CHC02Me CH = CHC02Me H OH 2 CH = CHC02Et H H OH 3 CH = CHC02Et CH = CHC02Et H OH 4 CH = CHC02Me H H OH 5 CH = CH-C5H5 H OH 6 CH = CH-CSH 5 CH = CH-CgH 5 H OH 7 CH = CH-2-Pir H H OH 8 CH = CH-2-Pir CH = CH-2-Pir H OH 9 CH2CH2-C5H5 CH2CH2-CgHs H OH 10 CH2CH2-CsH5 H OH 11 CH2CH2-2-Pir CH2CH2-2-Pir H OH H CH = CHC02Et H OH H CH = CH-2-Pir H OH H CH2CH2-2-Pir H OH N02 CH = CH-2-Pir Ac OAc N02 CH = CH-2-Pir H OH H2 C¾CH2-2-Pir Ac OAc ¾ CH2CH2-2-Pir H OH NHCONHEt CH2CH2-2-Pir H OH C / CCH2 Me2 C / CCH2NMe2 H OH C / CCH2OMe I H OH C / CCH2OMe C / CCH20Me H OH C / CCH2OH C / CCH2OH H OH C0C¾C1 COCH2Cl Ac OAc COCH2-l-Pip COCH2-l-Pip H OH COC¾CH2Cl H Ac OAC C0CH2CH2C1 C0C¾CH2C1 Ac OAc COCH2CH2-l-Pip H H OH COCH2CH2-l-Pip COCH2CH2-l-Pip H OH COCH2C¾-1-Morf COCH2C¾-1-Morf H OH COCH2-1-Morf COCH2-1-Morf H OH COCH2NMe2 COCH2NMe2 H OH a COCH2Cl H Ac OAc b H C0CH2C1 Ac OAc COCH2 Me2 H H OH COCH2-l-THP HH OH to COCH2-1-Morf H Ac OAc b H COCH2-1-Morph Ac OAc to COCH2-1-Morf HH OH b H COCH2-1-Morph H OH COCH2-l-THP COCH-l -THP H OH COCH2-l-Pipz (4- COCH2-l-Pipz (4- Ac OAc Me) Me) COC¾-l-Pipz (4- COCH2-l-Pipz (4- H OH Me) Me) H COC¾SEt H OH at COCH2S -4-Pir HH OH b H COCH 2 S-4-Pir H OH COCH2SMe COCH2SMe H OH COC¾SEt COCH2SEt H OH COCH2SCH2Et COC¾SC¾ Et H OH COCH2S (C¾) 2 OH COC¾S (CH2) 2 OH H OH COCH2S-4-Pir COCH2S-4-Pir H OH COCH2S-2-Pir COCH2S-2-Pir H OH COCH2S-2-Pirm COC¾S-2-Pirm H OH COCH2S-C6H4 (4-OH) COC¾S-C6H4 (4-OH). H OH COC¾S-2-Tiazl COC¾S-2-Tiazl H OH COCH2S-5-Tet (1- COCH2S-5-Tet (1- H OH Me) Me) CO (CH2) 2SMe CO (CH2) 2SMe H OH CO (CH 2) 20Me CO (C¾) 2OMe H OH Br CO (CH2) 3H OH CO (CH2) 4H CO (CH2) 4H Ac OAc COC¾Br COCH2Br AC OAc CH (OH) Me H Ac OAc CH (OH) (C¾) 2 C 1 CH (OH) (CH 2) 2 C 1 H OH CH (OH) CH2-1- CH (0H) CH2-1 H OH Pipz (4-Me) Pipz (4-Me) C / CCH2NMe2 H H OH Br C / CCH2NMeBn H OH CH = CHCH2NMe2 CH = CHCH2NMe2 AC OAc CH = CHC¾NMe2 CH = CHCH 2 Me 2 H OH CH = CHEt H Ac OAc CH = CHEt H H OH CH = CHEt I Ac OAc CH = CHEt CH = CHEt H OH (CH2) 2C1 (C¾) 2 C 1 H OH a (CH 2) 2 I (C 2) 2 I OH OH (CH 2) 2 OCOH (CH 2) 2 OCOH H OH c (CH 2) 2 OH (CH 2) 2 OH H OH (CH2) 2OCO-4-Pir (CH2) 2OCO-4-Pir H OH to CH2C02 and HH OH b CH2C02Me C¾C02Me H OH a (C¾) 3I (CH2) 3I H OH b (CH2) 3OCOH (CH2) 3OCOH H OH c (CH2) 30H (CH2) 3 OH OH (CH2) 3OMe (CH2) 3OMe H OH (CH2) 2-1-Pip (CH2) 2-1-Pip H OH (CH2) 2-l- orf (C¾) 2-l-Morf H OH (CH2) 2NEt2 (CH2) 2NEt2H OH (CH2) 2NMe (CH2) 20H (CH2) 2 Me (CH2) 2 OH OH (CH2) 2 HMe (CH2) 2NHMe H OH (CH2) 2NHCH2C6H4 (4- (CH2) 2 HCH2C6H4 (4- H OH MeO) MeO) (C¾) 2N3 (CH2) 2N3 H OH (CH2) 3-1-Pip (CH2) 3-1-Pip H OH (C¾) 3-l-Morph (CH 2) 3-1-Morph H OH (CH2) 3NEt2 (CH2) 3NEt2 H OH 85 (C¾) 3NHCONHEt (CH2) 3NHCONHEt H OH 86 (CH2) 3NHC02t-Bu CH2) 3 HC02t-Bu H OH 87 (CH2) 2SMe (C¾) 2SMe H OH 88 (CH2) 2SEt (CH2) 2SEt H OH 89 (CH2) 2SCH2C02Me (CH2) 2SCH2C02Me H OH 90 (CH2) 2S (C¾) 2C02Et (CH2) 2S (CH2) 2 C02H OH Et 91 (CH2) 2S-CSH4 (4- (CH2) 2S-CSH4 (4H OH OH) OH) 92 (C¾ ) 2S-2-Tiazl (C¾) 2S-2-Tiazl H OH 93 (CH2) 2S-4-Pir (CH2) 2S-4-Pir H OH 94 (CH2) 2S-2-Pir (CH2) 2S-2-Pir H OH 95 (C¾) 3SMe (C¾) 3SMe H OH 96 (C¾) 3S-2- (CH 2) 3 S-2 H OH (Benz) iazole (Benz) iazole 97 CH = CH-2-Pyr CHO Ac OAc 98 CH = CH-2-Pir CH2OH Ac OAc 99 CH = CH-2-Pir CH2OH H OH 100 CH = CH-2-Pir CH2OSiMe2t-Bu Ac OAc 101 CH = CH-2-Pir CH2OSiMe2t-Bu H OH 102 CH = CH-2-Pir CH2OMe H OH 103 CH = CH-2-Pir CH2OEt H OH 104 CH = CH-2-Pyr CH20 (C¾) 2NMe2 H OH 105 CH = CH-2-Pir CH2SEt H OH 106 CH = CH-2-Pyr CH2S (C¾) 2 Me 2 H OH 107 CH = CH-2-Pyr CH 2 S-2-OH (Benz) Imid 108 CH = CH-2-Pyr CH 2 S-2-Pyr H OH 109 CH = CH-2-Pir CH (SEt) 2 Ac OAc 110 CH = CH-2-Pir CH (SEt) 2 H OH 111 CHO CH = CH-2-Pir Ac OAc 112 CH20H CH = CH-2-Pir Ac OAc 113 CH2OH CH = CH-2-Pir H OH 114 CH2OSiMe2t-Bu CH = CH-2-Pir Ac OAc 115 CH2OSiMe2t-Bu CH = CH-2-Pir H OH 116 CH2OMe CH = CH-2-Pir H OH 117 CH20Et CH = CH-2-Pir H OH 118 CH2SEt CH = CH-2-Pir H OH 119 CH2S-2-Pir CH = CH-2-Pir H OH 120 CH2S-2- CH-CH-2-Pir H OH (Benz) Imid 121 CH = CHEt CH-CH-2-Pir Ac OAc 122 CH = CHEt CH = CH-2-Pir H OH 123 (CH2) 2-2-Pir CH2OSiMe2t-Bu Ac OAc 124 (CH2) 2-2-Pir CH2OSiMe2t-Bu H OH 125a (CH2) 2-2-Pir CH2OMe Ac OAc 125b (CH2) 2-2-Pir CH2OMe H OAc 126 (CH2) 2-2-Pir CH2OMe H OH 127a (CH2) 2-2-Pir CH2OEt H OH 127b (CH2) 2-2-Pir C¾OH H OH 128 (CH2) 2-2-Pir CH2S-2-Pir Ac OAc 129 (CH2) 2-2-Pir CH2S-2-Pir H OH 130 CH2OSiMe2t-Bu (CH2) 2-2-Pir Ac OAc 131 CH2OSiMe2t-Bu (CH2) 2-2-Pir H OH 132 CH2OMe (CH2) 2-2-Pir H OH 133 CH20Et (C¾) 2-2-Pir H OH 134 CH 2 SEt (CH 2) 2-2-Pir H OH 135 CH2S (CH2) 2 Me2 (CH2) 2-2-Pir H OH 136 CH2S-2-Pir (CH2) 2-2-Pir Ac OAc 137 CH2S-2-Pir (CH2) 2-2-Pir H OH * 138 C / CCH2OMe C / CCH2O and H OH 139 CH2CH2C02Me CH2CH2C02Me H OH 140 CH2CH2C02Et CH2CH2C02Et H OH 141 Br CH = CH-2-Pir Ac OAc 142 Br CH = CH-2-Pir H OH 143 Br CH2CH2-2-Pir H OH 144 CH = CH-4-Pir CH = CH-4-Pir Ac OAc 145 CH = CH-4-Pir CH = CH-4-Pir H OH 146 CH2CH2-4-Pir CH2CH2-4-Pir H OH 147 CH = CH-2-Imid H Ac OAc 148 CH = CH-2-Imid H H OH 149 CH2CH2-2-Imid H H OH 150 CH = C (C02Me) 2 CH = C (C02Me) 2 Ac OAc 151 CH2CH (C02Me) 2 CH2CH (C02Me) 2 Ac OAc 152 CH2CH (C02Me) 2 CH2CH (C02Me) 2 H OH 153 12 ~ C4H9 (CH2) 2-2-Pir H OH 154 C¾OCH2Oiy [e H H OH 155 CH2OCH2O e CH2OCH2O and H OH 156 CH2OCH2OEt CH2OCH2OEt H OH 157 CH20 (CH2) 2OMe CH20 (CH2) 2OMe H OH Pir = Pyridyl Piperidine Morpholine Tetrahydropyrrole Piperazine Pirm = Pyrimidine Tiazl = Tiazoline Tet = Tetrazol Imid = Imidazole (Benz) Thiazole = Benzothiazole (Benz) Imid = Benzimidazole * Replace group C02CH3 with C¾OH TABLE B See U.S. Patent Nos. 6,306,849 and WO97 / 49406, incorporated herein by reference in its entirety. The compounds are derivatives of the represented by the following structure K-252a has an indolocarbazole skeleton which is described in U.S. Patent No. 4,555,402 and Japanese Unexamined Published Patent Application No. 41489/85. K-252a is a natural indolocarbazole compound of the bacterial species Nocardiosis. The activity of these compounds can be demonstrated using the cultivated spinal choline acetyltransferase (ChAT) assay. Formula III represents an ethylthiomethyl analogue of K-252a, CEP-1347, which showed greater efficacy (250% control) and potency (EC50 = 50 nM) than K-252a in spinal cord ChAT assays (Kaneko et al., J. "Med.Chem, June 6; 40 (12): 1863-9 (1997).) In certain aspects, the methods of the invention use CEP-1347 as an inhibitor of MLKl.

Formula III (CEP-1347) (* refers to a chiral center) Some described compounds contain a chiral center. The presence of chiral centers in a molecule gives rise to stereoisomers. For example, a pair of optical isomers, indicated as "enantiomers", exists for all the chiral centers of a molecule; and a pair of diastereomers exists for each chiral center of a compound having two or more chiral centers. When the structural formulas do not explicitly represent the stereochemistry, it should be appreciated that these formulas include the free enantiomers of the corresponding optical isomer, racemic mixtures, mixtures enriched in an enantiomer relative to their corresponding optical isomer, a free diastereomer of other diastereomers, a pair of free diastereomers of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched in relation to the other diastereomer (s) ) and mixtures of diastereomeric pairs where a diastereomeric pair is enriched with respect to the other diastereomeric pairs (s). In addition, compounds of Structural Formula IV (which are described in WO 03/064428AI) are useful in the methods described herein as inhibitors of the MLK kinase family. Structural Formula IV: where ? represents O or S; W represents O, NH, NR1; R 4 and R 5 are independently selected from the group represented by hydrogen, halogen, cyano, nitro, alk (in / in) yl C x 6 alkyl (in / in) yloxy ¾-5, al (in / in) iloxy Ci- 6-alkyl (en / in) yl C ± s, alkyl (en / in) ilsulfañilo Ci_6, hydroxy, hydroxy-alk (en / in) yl Ci_6, halo-alk (en / in) ilo < ¾ ._,;, halo-alk (in / in) iloxy Cx-6, cycloalk (en) yl C3_8, cycloalk (en) il C3-8 alk (en / in) ilo ¾-6, acyl, alk (in / in) iloxycarbonyl Ci_s, alkyl (en / in) ilsulfonyl Ca_s, -NR7RS and R7RaN-alqu (en / in) ilo R3 represents hydrogen, halogen, alkyl (en / in) yl Ci-, cycloalk (en / in) yl C3_8, aryl, a heterocycle, hydroxy, hydroxyalk (en / in) yl Ci_6, alk (en / in) iloxy Ca-6, alk (en / in) iloxy Ci_6-alk (en / in) ilo Ci_6, cycloalk (in / in) oxy C3_8, alk (in / in) ilsulfañilo Ci_s, acyl, R7R¾T-alqu (en / in ) ilo Ci_6 or -NR7R8; or R3 represents a group of formula -R9-Ar2 where R9 represents 0, NH, R1 ', S, -C0NR1'-, -C0- or C1-6 alkyl, C2-6 alkenyl, which may be optionally substituted with OH, halogen, C-6 alkoxy or C3_8 cycloalkyl; Rs represents alk (en / in) yl cycloalk (en / in) yl C3-8, cycloalk (en) yl C3_8-alk (en / in) yl 01-6 or Ar1, - Ar1 and Ar2 are independently selected from the group represented by aryl, a heterocycle or a carbocycle, all of which may optionally be substituted one or more times with halogen, cyano, nitro, alk (in / in) ilo -.-6, alk (in / in) iloxy Cx.6, alk (en / in) iloxy Cx-g-alkyl (en / in) yl (??? 6 / alk (en / in) iloxy Ci-S-alqu (en / in) iloxi Ci_6-alqu (en / in) ilaryloxy Ci_6, aryl-alk (en / in) iloxy 0a_e, halo-alk (en / in) iloxy Cx-6, alk (en / in) il-sulfañilo C ^ sr hydroxy, hydroxy-alk (en / in) ilo Ca_e, halo-alk (in / in) yl C x s, cyano-alk (in / in) yl Ci_6 / NR 7 R 8, NR 7 R 8 -alk (in / in) yl? 6? Cycloalk (en) yl C3.8, cycloalk ( en) il C3.8-alk (en / in) yl Ci-6, al (in / in) ylsulfonyl Ca_6 / aryl, acyl, alk (en / in) yloxy-carbonyl <l, e (en / in) il C1.s-CONR1-alk (en / in) yl Ci_e, alk (en / in) il Ci-g-CONR1 '-, -CONR7R8 or R7R8NCO-alk (en / in) i the R7 and R8 are independently selected from the group represented by hydrogen and alk (en / in) yl Cx_6 which may be further substituted by hydroxy, halogen, alkoxy QL-6, cyano, nitro, cycloalk (en) yl C3_8, cycloalk (en ) il C3.8-alk (en / in) ilo ¾_6, aryl or a heterocycle; or R7 and R8 together with the nitrogen to which they are attached form a 3-7 membered ring optionally containing one or more additional heteroatoms and may be optionally substituted with halogen, alk (en / in) yl ε-e, hydroxy, hydroxy -alqu (in / in) ilo 02_6 or acyl; the aryls can be further substituted with halogen, cyano, nitro, alk (in / in) yl Ci_6 / al (in / in) yloxy Ci_6, al (in / in) ilsulfañilo 0? .5? hydroxy, hydroxy-alky (in / in) yl Ci_6, halo-alk (in / in) yl Ci_e, halo-alk (in / in) yloxy CX-e, cycloalk (en) yl C3-8, cycloalk (en) C3, 8 -alk (en / in) yl Ci_s / acyl, alk (en / in) yloxycarbonyl Ci_6, alk (en / in) ylsulphonyl CXs or -NR7'R8 'where - R7'R8' is as it has been defined for -NR7R8 above, with the proviso that any aryl substituent of -R7 R8 is not further substituted; and R1 and R1 are independently selected from the group represented by C3_6 alk (en / in) yl, C3.8 cycloalk (en) yl, aryl, hydroxy-alk (en / in) yl Ci-s, cycloalk (en) yl C3_8-alk (in / in) yl Ci_6 and acyl; or a pharmaceutically acceptable salt thereof The term "alkyl" refers to a monovalent group derived from a saturated straight or branched chain hydrocarbon by the removal of a unitary hydrogen atom. The alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso-, tere-butyl and the like. The term "hydroxyalkyl" represents an alkyl group, as defined above, substituted with one to three hydroxyl groups with the proviso that not more than one hydroxy group may be attached to a carbon atom unitary of the alkyl group. The term "alkylamino" refers to a group having the structure - HR 'where R' is alkyl, as defined above, and where the examples of alkylamino include methylamino, ethylamino, iso-propylamino and the like. The term "alkanoyl" represents an alkyl group, as defined above, attached to the remainder of the parent molecule through a carbonyl group. The alkanoyl groups are exemplified by formyl, acetyl, propionyl, butanoyl, and the like. The term "alkanoylamino" refers to an alkanoyl group, as defined above, attached to the remainder of the parent molecule through a nitrogen atom. Examples of the alkanoylamino include formamido, acetamido and the like. The term "N-alkanoyl-N-alkylamino" refers to an alkanoyl group, as defined above, linked to the remainder of the parent molecule through an aminoalkyl group. Examples of N-alkanoyl-N-alkylamino include N-methylformamido, N-methyl-acetamido and the like. The terms "alkoxy" or "alkoxy" refer to an alkyl group, as defined above, attached to the remainder of the parent molecule through an oxygen atom. Representative alkoxy groups include methoxy, ethoxy, propoxy, butoxyl and the like. The term "alkoxyalkoxy" refers to an alkyl group, as defined above, linked through an oxygen to an alkyl group, as defined above, in turn bound through an oxygen to the rest of the parent molecule . Examples of alkoxyalkoxy include methoxymethoxy, methoxyethyl, ethoxyethoxy and the like. The term "alkoxyalkyl" refers to an alkoxy group, as defined above, linked through an alkylene group to the remainder of the parent molecule. The term "alkoxycarbonyl" represents an ester group; that is, an alkoxy group, attached to the rest of the parent molecule through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like. The term "alkenyl" refers to a monovalent group derived from a hydrocarbon containing at least one carbon-carbon double bond by removal of a unitary hydrogen atom. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like. The term "alkylene" refers to a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1, 3- propylene, 2, 2-dimethylpropylene and the like. The term "alkenylene" refers to a divalent group derived from a straight or branched chain hydrocarbon which. contains at least one carbon-carbon double bond. Examples of alkenylene include -CH-CH-, -CH2 CH = CH-, -C (CH3) = CH-, -CH2CH = CHCH2- and the like. The term "cycloalkylene" refers to a divalent group derived from a saturated carbocyclic hydrocarbon by the removal of two hydrogen atoms, for example cyclopentylene, cyclohexylene and the like. The term "cycloalkyl" refers to a monovalent group derived from a carbocyclic, saturated, monocyclic or bicyclic ring compound by removal of a unitary hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptanyl, and bicyclo [2.2.2] octanyl. The term "alkynylene" refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing a carbon-carbon triple bond. Examples of alkynylene include -CH2CH-, -CH2CH-CH2-, -CH2CH ~ CH (CH3) - and the like. The term "carbocyclic aryl" refers to a monovalent carbocyclic ring group derived by the removal of a unitary hydrogen atom from a fused or non-condensed, monocyclic or bicyclic ring system that complies with the n + 2 p electron rule or the Huckel aromaticity rule Examples of carbocyclic aryl groups include phenyl, 1- and 2-naphthyl, biphenylyl, fluorenyl and the like The term "(carbocyclic aryl) alkyl" refers to a carbocyclic aryl ring group as defined previously, attached to the remainder of the parent molecule through an alkylene group Representative (aryl carbocyclic) alkyl groups include phenylmethyl, phenylethyl, phenylpropyl, 1-naphthylmethyl and the like The term "halo or halogen" refers to fluorine, chlorine , bromine or iodine The term "haloalkyl" refers to an alkyl group, as defined above, having one, two or three halogen atoms attached thereto and exemplified ica with groups such as chloromethyl, bromoethyl, trifluoromethyl and the like. The term "hydroxyalkyl" represents an alkyl group, as defined above, substituted with one to three hydroxyl groups with the proviso that no more than one hydroxy group can be attached to a carbon atom unitary of the alkyl group. The term "phenoxy" refers to a phenyl group attached to the rest of the parent molecule through an oxygen atom. The term "phenylthio" refers to a phenyl group attached to the remainder of the parent molecule through a sulfur atom. The term "pyridyloxy" refers to a pyridyl group attached to the remainder of the parent molecule through an oxygen atom. The terms "heteroaryl" or "heterocyclic aryl" as used herein refer to 5 or 6-membered, substituted or unsubstituted ring-containing aromatic groups containing one oxygen atom, one, two, three or four nitrogen atoms , a nitrogen atom and a sulfur atom, or a nitrogen atom and an oxygen atom. The term "heteroaryl" also includes bi- or tricyclic groups in which the aromatic heterocyclic ring is condensed to one or two benzene rings. Representative heteroaryl groups are pyridyl, thienyl, indolyl, pyrazinyl, isoquinolyl, pyrrolyl, pyrimidyl, benzothienyl, furyl, benzo [b] furyl, imidazolyl, thiazolyl, carbazolyl and the like. The term "heteroarylalkyl" refers to a heteroaryl group, as defined above, attached to the remainder of the parent molecule through an alkylene group. The term "heteroaryloxy" refers to a heteroaryl group, as defined above, attached to the remainder of the parent molecule through an oxygen atom. The term "heteroarylalkoxy" refers to a heteroarylalkyl group, as defined above, linked to the remainder of the parent molecule through an oxygen atom. The expression "alk (en / in) yl Ci_s" means an alkyl group Ci_e, C2-alkenyl or C2_6 alkynyl- The term "cycloalk (en) yl C3_8" means a C3_8 cycloalkyl or cycloalkenyl group. The term Ci_6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2 -methyl-2-propyl and 2-methyl-1-propyl. Likewise, C2 ^ alkenyl and C2-alkynyl, respectively, refer to groups having from two to six carbon atoms, including a double bond and a triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl. The term C3.8 cycloalkyl refers to a monocyclic or bicyclic carbocyclic having from three to eight C atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc. The term C3-3 cycloalkenyl refers to a monocyclic or bicyclic carbocyclic having from three to eight C atoms including a double bond. In the term cycloalkyl (en) yl C3_8-alk (in / in) yl Ci_S; cycloalk (en) yl C3_s and alk (en / in) yl Ca_6 are as defined above. The terms alk (in / in) iloxy Cx_e, alk (in / in) iloxy Ci_s-alk (in / in) ilo Ci_s, al (in / in) ilsulfañilo Ci_6, hydroxy-alqu (en / in) ilo < ¾_6, halo-alk (in / in) ilo L-6, halo-alk (in / in) iloxy QL_6 / alk (in / in) ilsulfonyl Ci_e, cyano-alk (in / in) ilo Ci_6, hydroxy-alk ( in / in) ilo (¼._6, NRXRY-alqu (in / in) ilo Ci_e, NR ^ CO- (in / in) ilo Ci_6, etc. refer to groups in which the (in / in) ilo part Ci_6 is as defined above The terms halo-, hydroxy-, cyano-, etc. must be seen as the (in / in) ilo Ci_6 part which may be substituted one or more times with said substituents. refers to halogen as defined above.

As used herein, the term (in / in) iloxycarbonyl ¾_6 refers to groups of the formula -CO- (in / in) yl Cx-e, where (in / in) yl ¾_6 are as defined above. As used herein, the term "acyl" refers to a formyl group, alkyl (en / in) ylcarbonyl ¾_6, arylcarbonyl, aryl-alk (en / in) ylcarbonyl ¾_6, cycloalk (en) ylcarbonyl C3-8 or cycloalk ( en) il C3-8-alkyl (en / in) il-carbonyl Ci-S. The term "heterocycle" refers to rings such as 5-membered monocyclic rings such as 3H-1,2,3-oxathiazole, 1,2,3-oxathiazole, 1,3-dioxazole, 3H-1,2,3- dithiazole, 1, 3, 2-dithiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isoxazole, oxazole, isothiazole, thiazole, 1H-imidazole, IH- pyrazole, IH-pyrrole, furan or thiophene and 6-membered monocyclic rings such as 1,2,3-oxathiazine, 1,2-oxathiazine, 1, 2, 5-oxathiazine, 1,4,2-oxathiazine, 1, 4,3-oxathiazine, 1,2,3-dioxazine, 1, 2,4-dioxazine, 4H-1,3,2-dioxazine, 1,4, 2-dioxazine, 2H-1, 5, 2-dioxazine, 1,2,3-dithiazine, 1, 2, 4-dithiazine, 4H-1, 3, 2-dithiazine, 1,4,2-dithiazine, 2H-1, 5, 2-dithiazine, 2H-1, 2, 3-oxadiazine, 2H-1,2,4-oxadiazine, 2H-1, 2, 5-oxadiazine, 2H-1, 2,6-oxadiazine, 2H-1,3, -oxadiazine, 2H-1, 2, 3 -thiadiazine, 2H-1, 2,4-thiadiazine, 2H-1,2,5-thiadiazine, 2H-1, 2,6-thiadiazine, 2H-1,3,4-thiadiazine, 1, 2, 3-triazine , 1, 2, 4-triazine, 2H-1 , 2-oxazine, 2H-1, 3-oxazine, 2H-1, 4-oxazine, 2H-1, 2-thiazine, 2H-1,3-thiazine, 2H-1, 4-thiazine, pyrazine, pyridazine, pyrimidine , 4H-1, 3-oxathiane, 1,4-oxathiine, 4H-1, 3-dioxin, 1,4-dioxin, 4H-1,3-dithiona, 1,4-dithmine, pyridine, 2H-pyran or 2H-thiine, bicyclic compounds where the above rings condense to a benzene ring, such as indole, benzofuran, isobenzofuran, benzothiophene, benzimidazole, quinoline, isoquinoline, dihydroguinoline, or fully saturated rings such as morpholine, piperidine, azepine, piperazine, homopiperazine and ring systems fused to a benzene ring, such as benzodioxane, benzodithiodioxane, benzo [1.3] dioxole, dihydroindole, dihydrobenzofuran or dihydrobenzothiophene. The term "aryl" refers to aromatic, carbocyclic systems such as phenyl, naphthyl, anthracene, and phenanthrene. The terms aryloxy and aryl-alk (en / in) iloxy ¾_6 refer to aryl as defined and alk (en / in) iloxy Cx-g as defined above. The term "carbocyclic" refers to partially or fully saturated systems such as cyclohexene, indane or flurene. The term "heteroatom" refers to carbon atoms other than hydrogen, such as nitrogen, oxygen and sulfur. Examples of organic acid addition salts according to the invention are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenosalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspic, stearic, palmic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic, as well as the 8-haloteophyllins, for example 8-bromoteophylline.

Examples of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids. In addition, the compounds used in the methods of this invention can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of this invention. Some of the compounds of the present invention contain chiral centers and such compounds exist in the form of isomers (e.g., enantiomers). The invention includes all these isomers and any mixture thereof including racemic mixtures. The racemic forms can be resolved in the optical antipodes by known methods, for example, by chromatography on an optically active matrix. The compounds of the present invention can also be resolved by the formation of diastereomeric derivatives. Methods conventional in the art can be used to determine compounds that modulate the activity of the protein kinase of the MLK family, in particular MKL1. For example, the activity of the protein kinase of the MLK family can be determined by measuring the activity of a kinase substrate of the MLK family. These substrates are well known to those skilled in the art. The substrate is preferably a member of the family of mitogen-activated kinases or downstream substrates (eg, JNK1, JK2, JK3, ERK1, ER2,? 38a,? 38β,? 38 ?,? 38d, MEK1, MEK2, ??? 3, ??? 4 (SEK1), ??? 5, ?? 6, ??? 7, jun AFT2 and ELK1, or other members of the route described in FIG. 1). In addition, general substrates of Ser / Thr protein kinases such as myelin basic protein (MBP) can also be used. Those skilled in the art also know reagents and methods for measuring the activity of substrates. The presence of MLK can also be determined by measuring the amount of MLK protein or mRNA encoding the MLK protein, such as the methods described below. EVALUATION OF RISK HAPLOTYPES A "haplotype", as described herein, refers to a combination of genetic markers ("alleles"), such as those indicated in Tables 1 and 2. In a certain aspect, the haplotype may comprise one or more alleles, two or more alleles, three or more alleles, four or more alleles, or five or more alleles. Genetic markers are particular "alleles" in "polymorphic sites" associated with MAPK9. A nucleotide position in which more than one sequence is possible in a population (a natural population or a synthetic population, eg, a library of synthetic molecules) is referred to herein as a "polymorphic site". When a polymorphic site has a single nucleotide length, the site is called a single nucleotide polymorphism ("SNP"). For example, if in a particular chromosomal location, a member of a population has an adenine and another member of the population has a thymine in the same position, then this position is a polymorphic site and, more specifically, the polymorphic site is a SNP . Polymorphic sites may allow differences in sequences based on substitutions, insertions and deletions. Each version of the sequence with respect to the polymorphic site is referred to herein as the "allele" of the polymorphic site. Thus, in the previous example, the SNP allows both an adenine allele and a thymine allele. Typically, a reference sequence refers to a particular sequence. Alleles that differ from the reference are called "variant" alleles. For example, the MAP3K9 reference sequence is described herein by SEQ ID NO: 1. The term "MA.P3K9 variant", as used herein, refers to a sequence that differs from SEQ ID NO: 1. N ": 1, but otherwise is substantially similar. The genetic markers that constitute the haplotypes described in this document are variants of ??? 3? 9. Other variants may include changes that affect a polypeptide, for example, the polypeptide ??.? 3? 9. These sequence differences, when compared to a reference nucleotide sequence, can include the insertion or deletion of a single nucleotide, or more than one nucleotide, resulting in a phase change; the change of at least one nucleotide, resulting in a change in the encoded amino acid; the change of at least one nucleotide, resulting in the generation of a premature stop codon; the deletion of several nucleotides, resulting in a deletion of one or more amino acids encoded by the nucleotides; the insertion of one or several nucleotides, such as by unequal recombination or gene conversion, resulting in an interruption of the coding sequence of a reading phase; duplication of all or part of a sequence; transposition; or a rearrangement of a nucleotide sequence, as described in detail above. These sequence changes alter the polypeptide encoded by a MAP3K9 nucleic acid. For example, if the change in the nucleic acid sequence causes a phase change, the phase change may cause a change in the encoded amino acids, and / or may result in the generation of a premature stop codon, producing the generation of a truncated polypeptide. Alternatively, a polymorphism associated with a susceptibility to MI, ACS, apoplexy or PAOD may be a synonym change in one or more nucleotides (i.e., a change that does not cause a change in the amino acid sequence). This polymorphism can alter, for example, splicing sites, affect the stability or transport of the AR m or otherwise affect the transcription or translation of the polypeptide. The polypeptide encoded by the reference nucleotide sequence is the "reference" polypeptide with a particular reference amino acid sequence, and polypeptides encoded by variant alleles are referred to as "variant" polypeptides with variant amino acid sequences. According to the NCBI (National Information Center Biotechnology), AceView, MAP3K9 is expressed at high levels. The sequence of this gene is confirmed by 48 sequences of 40 cDNA clones and produces, by alternative splicing, 5 different transcripts aDec03 (variant a), bDec03 (variant b), cDec03 (variant c), dDec03, (variant d ) and eDec03 (variant e), coding together 5 different isoforms of the protein. As indicated in Table C. Table C Variant Site data NCBI Ace view of aDec03 mRNA This whole mRNA has a length of 7028 7028bp bp. Here the sequence obtained at AM_5541pb is recorded from the genome, although the best route through the available clones differs from it in 1 position. It has 13 exons. It has a very long 3 'UTR. The pre-messenger covers 82.46 kb in the genome of NCBI build 34, August 2003. The protein (1071 aa, 118.9 kDa, pl 6.1) contains a SH3 domain motif, a protein kinase motif. It also contains a spirally wound section [Psort2]. Taxblast (Threshold 10 ^ -3) places it as an ancestor of Viruses and Eukaryotes. bDec03 This complete CDS mRNA has a length AM_5096bp of 5096 bp. Its sequence corresponds exactly with the genome. It has 11 exons. It has a very long 3 'UTR. The premensajero covers 55.33 kb in the genome of NCBI build 34, August 2003. The protein (869 aa, 96.5 kDa, pl 6.9) contains a protein kinase motif. It also contains a spirally wound section [Psort2]. Taxblast (threshold 10A-3) places it as an ancestor of Viruses and Eukaryotes. cDec03 This mRNA has a length of 1829 bp.

It has 3 exons. It may be incomplete at the 5 'end. The pre-messenger covers 9.56 kb in the genome of NCBI build 34, August 2003. The protein contains a SH3 domain motif, a guinase protein motif. Taxblast (threshold 10 ^ -3) places it as an ancestor of Viruses and Eukaryotes. dDec03 This full CDS ARLSTm has a length 572bp of 572 pb. It has only one exon. He AM_569pb premensajero covers 0.57 kb in the genome of NCBI build 34, August 2003. The protein (85 aa, 9.2 kDa, pl 7.7) does not contain any Pfam motif. Predictably it is located in the cytoplasm [Psort2]. eDec03 This partial AR, incomplete at 3 ', has 411 bp a length of 411 bp. It has only one exon. AM_411pb It is partial, it is truncated at the 3 'end. The premensajero covers 0.41 kb in the genome of NCBI build 34, August 2003. The partial protein (80 aa, 9.5 kDa, pl 5.3) does not contain any Pfam motif. It contains an ER membrane domain [Psort2]. Taxblast (threshold 10a-3) places it as an ancestor of Bilateria.

Haplotypes are a combination of genetic markers, for example, particular alleles at polymorphic sites. The haplotypes described herein, for example, having markers such as those shown in Table 1 are found more frequently in individuals with asthma than in individuals without asthma. Therefore, these haplotypes have predictive values to detect an asthma susceptibility in an individual. The haplotypes described in this document in some cases are a combination of various genetic markers, for example, SNPs and microsatellites. Therefore, haplotype detection can be performed by methods known in the art to detect polymorphic on-site sequences, such as the methods described above. In certain methods described in this document, an individual at risk for asthma is an individual in whom a haplotype of risk is identified. In one aspect, the risk haplotype is one that confers a significant risk of asthma. In one aspect, the meaning associated with a haplotype is measured by a prevalence ratio (odds ratio). In another aspect, meaning is measured by a percentage. In one aspect, a significant risk is measured as a prevalence ratio of at least about 1.2, including but not limited to: 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 , 1,8 and 1,9. In another aspect, a prevalence ratio of at least 1.2 is significant. In another aspect, a prevalence ratio of at least about 1.5 is significant. In another aspect, a significant increase in risk is at least about 1.7 and is significant. In another aspect, a significant increase in risk is at least about 20%, including but not limited to about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70 %, 75%, 80%, 85%, 90%, 95% and 98%. In another aspect, a significant increase in risk is at least about 50%. However, it is understood that the identification of whether a risk is medically significant may also depend on a variety of factors, including the specific disease, the haplotype and often environmental factors. A haplotype of risk in, or comprising, portions of the gene of ??? 3 9, is one in which the haplotype is present more frequently in an individual at risk of asthma (affected) compared to the frequency of its presence in a healthy individual (control), and where the presence of the haplotype indicates susceptibility to asthma. An example of a simple correlation test would be an exact Fisher test on a two-by-two table. Given a chromosome cohort, the two-by-two table is constructed by the number of chromosomes that include the two haplotypes, one of the haplotypes but not the other and none of the haplotypes. In certain aspects of the invention, the risk haplotype is a risk haplotype in or near MAP3K9 that correlates significantly with a haplotype such as a haplotype shown in Table 1. In other aspects, a haplotype of risk comprises a haplotype of risk within or | close to ??? 3? 9 that correlates significantly with the. susceptibility to asthma. In one aspect, the risk haplotype is characterized by the following microsatellite markers: DG14S399, DG14S404 and DG14S406, where the presence of a haplotype 13, 0, 4 is diagnostic of asthma or a susceptibility to asthma. In another aspect, the risk haplotype is characterized by the following microsatellite markers: DG14S399 and DG14S404, where the presence of a haplotype 13, 4 is diagnostic of asthma or a susceptibility to asthma. Other haplotype aspects are shown in Table 1. Conventional techniques for genotyping can be used with respect to the presence of SNPs and / or microsatellite markers, such as fluorescence-based techniques (C in, et al., Genome Res. 9, 492 (1999)), PCR, LCR, PCR nested and other techniques for the amplification of nucleic acids. In a preferred aspect, the method comprises evaluating in an individual the presence or frequency of SNPs and / or microsatellites, comprising portions of the MAP3K9 gene, where an excess or a higher frequency of the SNP and / or microsatellites compared to an individual of Healthy control indicates that the individual is susceptible to MI, ACS, stroke or PAOD. See, for example, Table 3 (shown below) in relation to SNPs and markers that can form haplotypes that can be used as research tools. These markers and SNPs can be identified in risk haplotypes. For example, a risk haplotype can include microsatellite and / or SNP markers such as those indicated in Table 1. The presence of the haplotype indicates susceptibility to asthma and, therefore, indicates an individual that is within a target population for the methods of treatment described in this document. Haplotype analysis involves the definition of a candidate susceptibility locus using LOD scores. The regions defined later are mapped more precisely with microsatellite markers with an average marker spacing of less than 100 Kb. All usable microsatellite markers found in public databases can be used and mapped within that region.

In addition, microsatellite markers identified within the assembly of the CODE genetic sequence of the human genome can be used. The frequencies of the haplotypes in the patient and in the control groups can be estimated using an expectation-maximization algorithm (Dempster A. et al., 1977. J "R. Stat. Soc. B, 39: 1-389) An application of this algorithm that can handle erroneous genotypes and uncertainty with the phase can be used.According to the null hypothesis, it is assumed that patients and controls have identical frequencies.Using a likelihood strategy, an alternative hypothesis where a haplotype of Candidate risk, which may include the markers described in this document, may have a higher frequency in patients than in controls, while it is assumed that the relationships of the frequencies of other haplotypes are the same in the two groups.The likelihoods are maximized separately according to both hypotheses and a statistical parameter of the corresponding 1-df likelihood ratio is used to evaluate the statistical significance. risk in the 1-lod reduction, for example, the association of all possible combinations of genotyped markers is studied, provided that these markers cover a practical region. The patient and the control groups combined can be randomly divided into two groups, the same size as the original group of patients and controls. Then the haplotype analysis is repeated and the most significant p-value registered is determined. This randomization scheme can be repeated, for example, more than 100 times to construct an empirical distribution of values of p. In a preferred aspect, a p value of < 0.05 indicates a risk haplotype. Following is a detailed discussion of haplotype analysis. Haplotype analysis The general strategy of the present applicants for haplotype analysis involves the use of plausibility-based deductions applied to nested models (NEsted MOdels). The method is executed in the NEMO program of the present applicants, which allows many polymorphic markers, SNPs and microsatellites. The method and software are designed specifically for case control studies where the objective is to identify haplotype groups that confer different risks. It is also a tool to study LD structures. When haplotypes constructed from many markers are investigated, apart from studying each haplotype individually, significant abstracts often require that the haplotypes be placed in groups. A particular partition of the haplotype space is a model that assumes that haplotypes within a group have the same risk, while haplotypes from different groups may have different risks. Two models / partitions are nested when one, the alternative model, is a thinner partition compared to the other, the null model, that is, the alternative model allows some haplotypes that are supposed to have the same risk in the null model have different risks. The models are nested in the classical sense that the null model is a special case of the alternative model. Therefore, traditional generalized likelihood ratio assays can be used to test the null model against the alternative model. Note that, with a multiplicative model, if the haplotypes h ± and hj are assumed to have the same risk, this corresponds to assuming that x¿ / p¿ = fj / pj where f and p indicate haplotype frequencies in the affected population and the population of control respectively.

A common way to manipulate phase uncertainty and missing genotypes is a two-stage method in which the number of haplotypes is first estimated and then the amount estimated as the exact amount is treated, a method that can sometimes be problematic ( for example, see the information measurement section presented below) and may require randomization to appropriately evaluate the statistical significance. In NEMO, the maximum likelihood estimates, the likelihood ratios and the p values are calculated directly, with the help of the EM algorithm, treating the observed data as a problem of missing data. NEMO allows full flexibility for partitions. For example, the first haplotype problem described in the Methods section of the Statistical Analysis considers the trial if i¾ has the same risk as the other haplotypes i¾, i¾. In this case, the alternative grouping is [2¾], [h2r .. ·, hk] and the null grouping is [hlr hk¡ · The second haplotype problem in the same section implies three haplotypes h¡_ = G0, h2 = GX and h3 = AX, and the focus is on the comparison ¾. and h2. The alternative grouping is [i¾], [h2], [h3] and the null grouping is [¾., I¾], [¾]. If there are compound alleles, these alleles could be collapsed in one in the data processing phase, and the assay could be performed as described. This is a perfectly valid strategy and, in fact, whether they collapse or not does not make any difference if there is no missing information in relation to the phase. But with the actual data, if each of the alleles that constitute a compound correlates differently with the SNP alleles, this will provide some partial information about the phase. The collapse in the data processing phase will not necessarily increase the amount of missing information. In this scenario, a structure of nested models / partition can be used. Suppose that h2 is divided into h2b, ||||, 2e, and h3 is divided into ¾a, h2b, ¾e- Then the alternative grouping is [¾_], [h2a, h2b, ...., h2e], h2a, h2b, h3e] and the null grouping is [hlr h2a, h2b, ····, h2e], [3a, h3b, h3e]. The same method can be used to manipulate compounds when collapse in the data processing phase is not even an option since Lc represents multiple haplotypes constructed from multiple SNPs. As an alternative, a 3-way trial with the alternative grouping of [¾.], [H2a, h2b, ...., h2e], [h3a, h3b, h3e] versus the null grouping of [h ±, h2a, h2b, ...., h2e, 3a, h3bl h3e] | Note that the statistical parameter of the generalized likelihood ratio test would have two degrees of freedom instead of one Measurement of information Although it would be possible to rely on the tests of likelihood ratio based on the likelihoods calculated directly for the observed data, that have captured the lost information due to the uncertainty in phase and the missing genotypes, to give valid p values, it would be interesting to know how much information has been lost due to the fact that the information is not complete. Interestingly, the loss of information can be measured by considering a two-step procedure to evaluate the statistical meaning that seems natural but occurs systematically in an anticonservative fashion. Suppose that the maximum likelihood estimates for the haplotype frequencies in the population calculated under the alternative hypothesis that there are differences between the affected population and the control population are calculated, and these frequency estimates are used as estimates of the observed frequencies of number of haplotypes in the affected sample and in the control sample. Then suppose that a likelihood ratio test is performed that treats these estimated haplotype quantities as if they were the actual quantities. An exact Fisher test could also be performed, but it would be necessary to round these estimated quantities, since they are not whole numbers in general. This test in general will be anticonservative because the treatment of the quantities estimated as if they were exact quantities ignores the uncertainty with the quantities, overestimates the effective size of the sample and underestimates the sampling variation. This means that the statistical parameter of the chi-squared likelihood ratio test calculated in this way, and indicated by? *, Will generally be greater than?, The statistical likelihood ratio test parameter calculated directly from the data observed as it is described in the methods section. But? * Is useful because it turns out that the relation? /? * Is a good measure of information, or 1- (? /? *) Is a measure of the fraction of information lost due to missing information. This measure of information for haplotype analysis is described in Nicolae and Kong, Technical Report 537, Department of Statistics, University of Statistics, University of Chicago, Revised for Biometries (2003) as a natural extension of the information measures defined for the linkage analysis, and it is executed in NEMO. Statistic analysis. For the association of a single marker to the disease, Fisher's exact test can be used to calculate bilateral p-values for each individual allele. All p values are presented unadjusted for multiple comparisons unless specifically indicated. The presented frequencies (for microsatellites, SNPs and haplotypes) are allele frequencies instead of carrier frequencies. To minimize any deviation due to the relationship of patients who were recruited as families for the linkage analysis, relatives can be eliminated. of first and second degree of the list of patients. In addition, the assay can be repeated to correct the association for any remaining relationship between patients by extending an adjustment of variance procedure described in Risch, N. &; Teng, J. [Genome Res., 8: 1278-1288 (1998). The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases I. DNA pooling. (ijid)) for siblings so that it can be applied to general family relationships, and have both adjusted and unadjusted P values for comparison. The differences in general are very small as expected. To evaluate the significance of the association of a single marker corrected for multiple assays, a randomization assay was performed using the same genotypic data. Patients and controls cohorts can be randomized and linkage analysis can be repeated multiple times (for example up to 500,000 times) and the value of p is the fraction of replications that produces a p value for some marker alleles that is less than or equal to the value of p that was observed using the original cohorts of patients and controls. Both for the analysis of a single marker and for the analysis of haplotypes, the relative risk (RR) and the risk attributable to the population (PAR) can be calculated assuming a multiplication model (relative risk model of haplotype) (Terwilliger, JD &Ott, J., Hum Hered, 42, 337-46 (1992) and Falk, CT &Rubinstein, P, Ann Hum Genet 51 (Pt 3), 227-33 (1987)), i.e. risks of two alleles / haplotypes that a person carries multiply. For example, if RR is the risk of A with respect to, then the risk of a homozygous AA will be RR times that of a heterozygote Aa and RR2 times that of a homozygote aa. The multiplicative model has a good property that simplifies analysis and calculations - the haplotypes are independent, that is, in the Hardy-Weinberg equilibrium, within the affected population as well as within the control population. As a consequence, the number of haplotypes of affected individuals and controls has muominomial distributions, but with different haplotype frequencies under alternative hypotheses. Specifically, for two haplotypes h ± and hj, risk. { hi) / risk (hj) = (ii / i) / (fj / pj), where f and p indicate respectively frequencies in the affected population and in the control population. Although there is some power loss if the true model is not multiplicative, the loss tends to be slight except in extreme cases. More importantly, the values of p are always valid, since they are calculated with respect to the null hypothesis. In general, the haplotype frequencies are estimated by maximum likelihood and the differences between cases and controls trials are carried out using a "general-likelihood ratio assay" (Rice, JA Mathematical Statistics and Data Analysis, 602 (International Thomson Publishing, ( 1995).) The deCODE haplotype analysis program called NEMO, which represents the nested models, can be used to calculate all haplotype results.To manipulate the uncertainties with the phase and the missing genotypes, it is emphasized that a common two-step strategy for association assays, where the number of haplotypes is first estimated, possibly with the use of the EM algorithm, Dempster, (AP, Laird, NM &Rubin, DB, Journal of the Royal Statistical Society B, 39 , 1-38 (1971)) and then trials are conducted treating the estimated quantities as if they were true quantities, a method that can sometimes be problematic and may require randomization to appropriately evaluate the statistical significance. In fact, with NEMO, in the estimates of maximum likelihood, the likelihood ratios and p-values are calculated with the help of the EM algorithm directly for the observed data, and therefore the loss of information due to the uncertainty with the Phase and absent genotypes are automatically captured by likelihood ratios. Even so, it is interesting to know how much information is retained, or is lost, due to incomplete information. This document describes such a measure that is natural under the likelihood framework. For a fixed series of markers, the simplest tests performed compare a selected haplotype against all others. Let's call the selected haplotype hx and the other h2, ..., i¾. Assume that px, pk indicate the population frequencies of the haplotypes in the controls, and fi, _¾ indicate the population frequencies of the haplotypes in the affected individuals. According to the null hypothesis, f ± = p ± for all the i. The alternative model used for the trial assumes that h2, hk have the same risk while allowing hx to have a different risk. This implies that although px may be different from flf f ± /. { f2 + ... + fk) = /(p2+...+Pk) = ß ± for 1 = 2, k. Representing f ~ a / p for r, and indicating that / 32 + - + / ¾: = 1, the statistical parameter of the test based on the generalized likelihood ratios is? = 2 [i (f, Pi, / ¾, ·. ·, J¾_i) - £. { l, Pi, / ¾,. ·., h-i)] where £ indicates likelihood loge and ~ y denote the maximum likelihood estimates under the null hypothesis and the alternative hypothesis respectively. ? it has asymptomatically a chi-square distribution with 1-df, under the null hypothesis. Null hypotheses and slightly more complicated alternatives can also be used. For example, suppose that h is G0, h2 is GX, and 3 is AX. When G0 is compared with GX, that is, this is the test that gives an estimated RR of 1.46 and a p-value of 0.0002, the null hypothesis assumes that GO and GX have the same risk, but AX may have a different risk. The alternative hypothesis allows, for example, that three haplotype groups have different risks. This implies that, under the null hypothesis there is a limitation that ?? ? = f "2 p2, or w = [f" i pi] / [f2 / 2] = 1. The statistical test parameter based on the generalized likelihood ratios is? = 2 [£ (f1p2, w) - i (p /! ¾ 1)] which again has an asymptotic chi-square distribution with 1-df under the null hypothesis. If there are composite haplotypes (for example ¾ and ¾), they are handled in a natural way under the framework of nested models. The LD between pairs of SNPs can be calculated using the conventional definition of D 'and R2 (Lewontin, R., Genetics 49, 49-67 (1964) and Hill, W. G. &; Robertson, A. Theor. Appl. Genet 22, 226-231 (1968)). Using NEMO, the frequencies of the two combinations of marker alleles are estimated by maximum likelihood and the deviation of the linkage equilibrium is evaluated by the likelihood ratio test. The definitions of D 'and R2 are extended to include microsatellites by averaging the values of all possible allele combinations of the two markers weighted by the probabilities of the marginal allele. When the combination of all the markers is represented to clarify the LD structure in a particular region, D 'is represented in the upper left corner and the value of p in the lower right corner. In the LD graphs, the markers can be represented equidistant instead of according to their physical location, if desired.

Statistical methods for linkage analysis In the analysis, multiple methods of alleles shared only by those affected can be used to evaluate the evidence of linkage. The results, both the LOD score and the nonparametric linkage score (NPL), can be obtained using the Allegro program (Gudb artsson et al., Nat. Genet, 25: 12-3, 2000). Basal linkage analysis uses the Spairs score function (hittemore, AS, Halpern, J. (1994), Biometrics 50: 118-27, Kruglyak L, et al. (1996), Am J Hum Genet 58: 1347-63 ), the exponential shared allele model (Kong, A. and Cox, NJ (1997), Am J "Hum Genet 61: 1179-88) and a family weighting scheme that is halfway on the logarithmic scale between the weighting of each affected pair equally and the weighting of each family equally.The measure of information used is part of the Allegro program and the information value equals zero if the marker genotypes are completely non-informative and equals one if the genotypes determine the exact number of alleles shared by a considerable number of affected relatives (Gretarsdottir et al., Am. J. Hom. Genet, 70: 593-603, (2002).) P values of two are calculated. different forms and the least significant result is presented The first value of P pu ede calculated based on a large sample theory, - the distribution of ?? G = D (2 [loge (10) LOD]) approximates a standard normal variable under the null hypothesis of non-association (Kong, A. and Cox) , NJ (1997), Am J Hum Genet 61: 1179-88). The second value of P can be calculated by comparing the observed LOD score with its sampling distribution of complete data under the null hypothesis (eg, Gudbjartsson et al., Nat. Genet 25: 12-3, 2000). When the data consist of more than a few families, these two P values tend to be very similar. Methods to obtain the mRNA expression data: Real-time PCR (RT) -PCR is used to examine the levels of ML RNA -1 in blood cells and lung tissue of patients with asthma and controls. Total RNA is extracted using Trizol and purified with Qia RNaeasy centrifugation columns (Qiagen Inc. Valencia, CA). Two μg of total RNA are treated with DNasal and the RNA is subjected to reverse transcription using the TaqMan Reverse Transcription Reagent Kit (N808-0234) and random hexamers. Five ABI SYBR green assays are constructed for the estimation of MLK-1 transcripts (variant A-E, Table A). PCR reactions are performed on a plate 384 wells in a total volume of 10 μ? in the PRISM 7900HT sequence detection system from Applied Biosystems (95 ° C for 10 minutes followed by 40 cycles of 95 ° C for 15 seconds, 60 ° C for 1 minute with a subsequent dissociation step, 95 ° C for 15 seconds , 60 ° C for 15 seconds, 95 ° C for 15 seconds identifying melting temperatures of the PCR products, thus ensuring its specificity). The reaction consisted of 1 μ? of cDNA, 1 x SYBR Green PCR master mix (part number 4309155) and 900 nM primers. All reactions were performed in quadruplicate for the five isoforms of MLK-1 and the internal gene (Beta actin). RNA levels (number of copies) are determined using sequence-specific probes that hybridize with the MLK kinase PCR products (e.g. MLK1) employing the 5'31 exonuclease activity of the Taq DNA polymerase in RNA samples that are isolate from cells that have been exposed to specific cytokine activators that activate the JNK pathway (such as IL1b and TNFa) against the vehicle alone (without activation). The TaqMan probe consists of a sequence with site specificity labeled with a fluorescent indicator dye and a fluorescent quencher dye. During PCR, the TaqMan probe hybridizes with its complementary single-stranded DNA sequence within the PCR target. When amplification occurs, the TaqMan probe degrades due to 5'-exonuclease activity - >; 3 'of the Taq DNA polymerase thus separating the indicator inactivator during extension. Due to the release of the inactivation effect on the indicator, the fluorescence intensity of the indicator dye increases. During the entire amplification process, this light emission increases exponentially, measuring the final level by spectrophotometry after finishing the PCR. In addition to the TaqMan probes specific to the MLK kinase sequence (e.g., MLK1), SYBR Green is also used as the fluorescent dye. This dye only fluoresces when it binds to double-stranded DNA, that is, when unique primers are attached to the MLK kinase (e.g., MLK1) and satisfactorily allows the extension of the Taq DNA polymerase from DNA fragments representing the gene of the MLK kinase (e.g., MLK1). The use of primers located in unique exons will ensure that the tag DNA polymerase fragments represent the mature structure of RNA, in addition the use of TaqMan probes specific to the MLK kinase sequence (eg, MLK1) allows discrimination between different cutting variants and RNA splicing. To correct the number of samples repeated for variation between plates, three calibrators are used. All values are subsequently normalized to standard internal corrected gene values. EVALUATION OF MAP3K9 GENE RELEASE In one aspect, the invention relates to methods for measuring RNA levels of MLK kinases (e.g. MLK1) using a quantitative real-time PCR assay in which specific oligonucleotides are used for members of the MLK kinase family (e.g., MLK1) to amplify reverse transcribed RNA (cDNA) on RNA samples that are isolated from blood leukocytes or other tissue samples. The method includes obtaining a sample of cells from the patient and determining RNA levels using sequence-specific probes that hybridize with MLK kinase PCR products (e.g., MLK1) using 5'-exonuclease activity. > 3 'of Taq DNA polymerase on RNA samples that are isolated from cells that have been exposed to specific cytokine activators that activate the pathway ÜTSTK (such as IL1b or TNFa) against the vehicle alone (ie, without activation). In one aspect, the TaqMan probe consists of a site-specific sequence labeled with a fluorescent indicator dye and a fluorescent quencher dye where, during the PCR reaction, the TaqMan probe hybridizes with its complementary single-stranded DNA sequence within the PCR target , measuring the final level by spectrophotometry after finishing the PCR. In another aspect, the expression of the MLK kinase (e.g., MLK1) is determined using SYBR Green as a fluorescent dye. This dye only fluoresces when it binds to double-stranded DNA, that is, when it binds to uniquely designed primers for the MLK kinase (e.g., MLK1) and allows for the successful extension of the Taq DNA polymerase from the DNA fragment it represents. the MLK kinase gene (for example MLK1). As such, the use of TaqMan probes specific for MLK kinase sequence (eg MLK1) allows discrimination between different variants of RNA splicing. In another aspect, the invention relates to methods that determine the role of ??? 3? 9 or its related pathway genes, by obtaining a sample of cells from patients with asthma or other respiratory or inflammatory disorders, the determination of ??? 3? 9 RNA levels or their route-related genes in cells exposed to specific pathway activators (such as ILlb or TNFa) or vehicle alone (without activation), and comparing them with levels of RNA reference of the gene in cells isolated from subjects without asthma or other inflammatory / respiratory disorders. In another aspect, the invention relates to methods for predicting the efficacy of an inhibitory drug, including obtaining a sample of cells from patients with asthma or other respiratory / inflammatory disorder, the determination of RNA levels of MAP3k9 or their route-related genes in cells isolated from patients who are taking the drug compared to those who are not taking the drug. In another aspect, the invention relates to methods for predicting the efficacy of an inhibitory drug, including obtaining a sample of cells from patients with asthma or other respiratory / inflammatory disorder, the determination of RNA levels of MAP3k9 or its route-related genes after exposure of the cells to the inhibitory drug in v tro. CONTROL OF TREATMENT PROGRESS The present invention also relates to methods for controlling the response of an individual, such as an individual in one of the target populations described above, to treatment with a kinase inhibitor of the MLK family. As the level of inflammatory markers "may be elevated in individuals who are in the target populations described above, an assessment of the level of inflammatory markers of the individual both before and during treatment with the kinase inhibitor of the MLK family may indicate whether the treatment has successfully reduced the production of MLK in the wall of the respiratory tract (such as in ASM cells) or in inflammatory cells derived from bone marrow (such as peripheral blood mononuclear cells (PBM).) For example, in one aspect of invention, an individual that is a member of a target population as described above (eg, an individual at risk of asthma, such as an individual at risk due to a MAP3K9 haplotype) can be evaluated with respect to response to treatment with a kinase inhibitor of the MLK family, examining individual MLK kinase levels in different cells and fluids bodily MLK kinases can be measured in blood, serum, plasma or urine (for example MLK1) or the ex vivo production of MLK kinases (e.g., MLK1) before and during or after treatment with the kinase inhibitor of MLK1. the MLK family. The level of MLK or kinase of the MLK family before treatment is compared to the kinase level of the MLK family during or after treatment. The efficacy of the treatment is indicated by a reduction in MLK production: a kinase level of the MLK family during or after treatment that is significantly lower than the kinase level of the MLK family before treatment indicates efficacy. A level that is lower during or after treatment may show, for example, by a reduction of the MLK levels in serum or urine, or a reduction of the ex vivo production of kinases of the MLK family. A level that is "significantly lower," as used herein, is a level that is lower than the amount typically found in control individuals or is lower in a comparison of disease risk in a population associated with the others measurement bands (for example, the median or median, the highest quartile or the highest quintile) compared to smaller measurement bands (for example, the median or median, the other quartiles; or the other quintiles). For example, in one aspect of the invention, the level of a kinase of the MLK family is evaluated in an individual prior to treatment with kinase inhibitor of the MLK family; and during or after treatment with the kinase inhibitor of the MLK family, and the levels are compared. A kinase level of the MLK family during or after treatment that is significantly lower than the kinase level of the MLK family before treatment indicates efficacy of treatment with the kinase inhibitor of the MLK family. In another aspect, the production of a kinase from the MLK family is analyzed in. a first test sample of the individual and is also determined in a second test sample of the individual, during or after treatment with the kinase inhibitor of the MLK family, and the level of production in the first test sample is compared to the level of production of the kinase of the MLK family in the second test sample. A level of the kinase of the MLK family in the second test sample that is significantly lower than the level of the kinase of the MLK family in the first test sample indicates efficacy of treatment with the kinase inhibitor of the MLK family. In another aspect of the invention, an individual who is a member of a target population of individuals at risk for asthma (eg, an individual in a target population described above) can be evaluated with respect to response to treatment with a kinase inhibitor. of the MLK family, by examining the levels of inflammatory markers in the individual.For example, the levels of an inflammatory marker in an appropriate test sample (eg, serum, plasma or urine) can be measured before, during or after treatment with The kinase inhibitor of the MLK family The level of the inflammatory marker before treatment is compared to the level of the inflammatory marker during or after treatment The efficacy of the treatment is indicated by a reduction in the level of the inflammatory marker, ie a level of inflammatory marker during or after treatment that is significantly different (eg, significantly less) than The level of inflammatory marker before treatment indicates efficacy. Representative inflammatory markers include plasma levels of IL-2, IL-2, IL-1jS and TNF-α? and exhaled nitric oxide (NO). PHARMACEUTICAL COMPOSITIONS The present invention also relates to pharmaceutical compositions comprising agents described herein, for example, an agent that is a kinase inhibitor of the MLK family as described herein. For example, a kinase inhibitor of the MLK family can be formulated with a physiologically acceptable carrier or excipient to prepare a pharmaceutical composition. The vehicle and composition can be sterile. The formulation must be adapted to the mode of administration. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), saline, buffered saline, alcohols, glycerol, ethanol, arabic range, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, dextrose, magnesium stratum, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrrolidone, etc., as well as combinations thereof. The pharmaceutical preparations, if desired, may be mixed with auxiliary agents, for example, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavoring and / or aromatic substances and the like which do not react in a harmful way with the active agents. If desired, the composition may also contain less amounts of wetting or emulsifying agents or buffering agents of H. The composition may be a liquid suspension solution, emulsion, tablet, pill, capsule, sustained release formulation or powder. The composition can be formulated as a suppository, with binders and traditional carriers such as triglycerides. The oral formulation may include conventional vehicles such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrrolidone, sodium saccharin, cellulose, magnesium carbonate, etc. The nebulized formulation for inhalation may include sodium chloride, saccharin sodium or sorbitan trioleates, while inhalation through the carbonate formulation compressed in an inhaler may include 1,1,1,2-tetrafluoroethane, monofluorotrichloromethane, tetrafluorodichloroethane p difluorodichloromethane. Methods of introducing these compositions include, but are not limited to, the intradermal, intramuscular, intraperitoneal, intraocular, intravenous, subcutaneous, topical, oral, inhaled and intranasal routes. Other suitable methods of introduction may also include gene therapy (as described below), rechargeable or biodegradable devices, particle acceleration devices ("gene guns") and slow release polymeric devices. The pharmaceutical compositions of this invention can also be administered as part of a combination therapy with other agents. The composition can be formulated according to routine procedures as a pharmaceutical composition adapted for administration to humans. For example, compositions for intravenous administration are typically solutions in sterile isotonic aqueous buffer. When necessary, the composition may also include a solubilizing agent and a local anesthetic to avoid pain at the injection site. Generally, the ingredients are supplied separately or mixed together in a unit dosage form, for example, as a dry lyophilized powder or a waterless concentrate in a sealed container such as an ampoule or sachet indicating the amount of active agent. When the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing water of sterile pharmaceutical grade, saline or dextrose / water. When the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed before administration. Administration by inhalation includes a mixture of the active drug and the ingredients mentioned above. For topical application, non-sprayable forms, from viscous to semi-solid or solid, comprising a vehicle compatible with topical application and having a dynamic viscosity preferably greater than water can be employed. Suitable formulations include, but are not limited to, solutions, suspensions, emulsions, creams, ointments, powders, enemas, lotions, sols, liniments, ointments, aerosols, etc. which, if desired, are sterilized or mixed with auxiliary agents, for example, preservatives, stabilizers, wetting agents, buffers or salts to influence the osmotic pressure etc. The agent can be incorporated into a cosmetic formulation. For topical application, sprayable aerosol preparations are also suitable where the active ingredient, preferably in combination with an inert solid or liquid carrier material, is packaged in a pressure flask or in admixture with a normally pressurized volatile gaseous propellant, for example, air under presure. The agents described herein can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as the hydrochloric, phosphoric, acetic, oxalic, tartaric, etc. derivatives. and those formed with free carboxyl groups such as the sodium, potassium, ammonium, calcium derivatives, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. The agents are administered in a therapeutically effective amount. The amount of agents that will be therapeutically effective in treating a particular disorder or condition will depend on the nature of the disorder or condition and can be determined by conventional clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify the optimal dosage ranges. The precise dose to be used in the formulation will also depend on the route of administration and the severity of the symptoms, and should be decided according to the criteria of a doctor and the circumstances of each patient. Effective doses can be extrapolated from dose-response curves obtained from animal or in vitro model test systems.

The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally, with said container or containers a note may be associated in the form prescribed by the Government Agency that regulates the manufacture, use or sale of pharmaceutical or biological products, said note reflecting the approval by the manufacturing, use or sale agency for administration. human The package or kit may be labeled with information regarding the mode of administration, sequence of administration of the drug (eg, separately, sequentially or simultaneously) or the like. The package or kit may also include means to remind the patient to take the therapy. The package or kit may be a single unit dosage of the combination therapy or may be a plurality of unit dosages. In particular, the agents can be separated, mixed together in any combination, present in a single vial or tablet. Agents assembled in a blister or in another distribution medium are preferred. For the purpose of this invention, it is understood that the unit dosage means a dosage that depends on the individual pharmacodynamics of each agent and is administered in dosages approved by the FDA at conventional time periods. NUCLEIC ACIDS OF THE INVENTION MAP3K9 Nucleic Acids, Portions and Variants The complete sequence of the MAP3 9 gene is shown in SEQ ID NO: 1 and in FIGS. 7.1 to 7.19. Other single nucleotide polymorphisms are presented in Table 5 and may or may not be shown in SEQ ID NO: 1. It should be understood that the nucleic acids and their gene products included by the invention include the nucleotide sequence indicated in SEQ ID NO. No. 1 and may further comprise at least one polymorphism as shown in Table 5. Three new SMPs have been identified. Accordingly, the invention relates to isolated nucleic acid molecules comprising the human MAP3K9 nucleic acid. The term "MAP3K9 nucleic acid" as used herein, refers to an isolated nucleic acid molecule that encodes a MAP3K9 polypeptide (e.g., a? 3? 9 gene, as shown in FIG. SEQ ID NO: 1). The ??? 3? 9 nucleic acid molecules of the present invention can be RNA, for example, mRNA, or DNA, such as cDNA and genomic DNA. DNA molecules can be double-stranded or single-stranded; the RNA or single-stranded DNA can be the coding, or sense, or the non-coding or antisense strand. The nucleic acid molecule can include all or a portion of the gene coding sequence and can further comprise other non-coding sequences such as introns and non-coding 3 'and 5' sequences (including, for example, regulatory sequences). For example, the MAP3K9 nucleic acid may be the genomic sequence shown in FIGS. 7.1 to 7.19, or a portion or fragment of the isolated nucleic acid molecule (e.g., cDNA or gene) encoding MAP3 polypeptide 9. In addition, the nucleic acid molecules of the invention can be fused to a marker sequence, for example, a sequence encoding a polypeptide to aid in the isolation or purification of the polypeptide. These sequences include, but are not limited to, those encoding a glutathione-S-transferase (GST) fusion protein and those encoding a polypeptide marker of influenza hemagglutinin A (HA). An "isolated" nucleic acid molecule, as used herein, is one that is separated from nucleic acids that normally flank the gene or nucleotide sequence (as in geonomic sequences) and / or has been completely or partially purified from other transcribed sequences (for example, as in an AR library). For example, an isolated nucleic acid of the invention can be substantially isolated from the complex cellular medium in which it exists naturally, or culture medium when produced by recombinant techniques, or chemical precursors or other chemical agents when chemically synthesized. In some cases, the isolated material will form part of a composition (for example, a crude extract containing other substances) buffer system or mixture of reagents. In other circumstances, the material can be purified to an essential homogeneity, for example as determined by PAGE or column chromatography such as HPLC. Preferably, an isolated nucleic acid molecule comprises at least about 50, 80 or 90% (on a molar basis) of all macromolecular species present. With respect to genomic DNA, the term "isolated" may also refer to nucleic acid molecules that are separated from the chromosome with which the genomic DNA is naturally associated. For example, the isolated nucleic acid molecule can contain less than about 5 kb, but is not limited to 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotides flanking the molecule. nucleic acid in the genomic DNA of the cell from which the nucleic acid molecule originates. The nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered isolated. In this manner, the recombinant DNA contained in a vector is included in the definition of "isolated" as used herein. In addition, the isolated nucleic acid molecules include recombinant DNA molecules in heterologous host cells, as well as partial DNA molecules or substantially purified in solution. The "isolated" nucleic acid molecules also include RNA transcripts in vivo and in vitro of the DNA molecules of the present invention. An isolated nucleic acid molecule can include a nucleic acid molecule or a nucleic acid sequence that is synthesized chemically or by recombinant means. Therefore, the recombinant DNA contained in a vector is included in the definition of "isolated" as used herein. In addition, the isolated nucleic acid molecules include recombinant DNA molecules in heterologous organisms, as well as partial DNA molecules or substantially purified in solution. The "isolated" nucleic acid sequences also include RNA transcripts in vivo and in vitro of the DNA molecules of the present invention. Such isolated nucleic acid molecules are useful in the manufacture of the encoded polypeptide, as probes for isolating. homologous sequences (e.g., from other mammalian species) for gene mapping (e.g., by in situ hybridization with chromosomes) or to detect gene expression in a tissue (e.g., human tissue), such as by analysis of Northern or Southern transfer. The present invention also relates to nucleic acid molecules that are not necessarily found in nature but that encode a MAP3K9 polypeptide, or another splice variant of a ??? 3? 9 polypeptide or polymorphic variant thereof. Thus, for example, the invention relates to DNA molecules comprising a sequence that is different from the natural nucleotide sequence but which, due to the degeneracy of the genetic code, encodes a MAP3 polypeptide 9 of the present invention. The invention also includes nucleic acid molecules that encode portions (fragments) or that encode variant polypeptides such as analogs or derivatives of a ??? 3? 9 polypeptide. These variants may occur naturally, such as in the case of allelic variation or single-nucleotide polymorphisms, or they may not be natural, such as those induced by various mutagenic and mutagenic processes. The desired variations include, but are not limited to, addition, deletion and substitution of one or more nucleotides that can produce conservative or non-conservative amino acid changes, including additions and deletions. Preferably, the nucleotide changes (and / or resulting amino acids) are silent or conserved; that is, they do not alter the characteristics or activity of a ??? 3? 9 polypeptide. In one aspect, the nucleic acid sequences are fragments comprising one or more polymorphic microsatellite markers. In another aspect, the nucleotide sequences are fragments comprising one or more polymorphisms of a single nucleotide in a MAP3K9 gene. Other alterations of the nucleic acid molecules of the invention may include, for example, labeling, methylation, internucleotide modifications such as uncharged bonds (eg, methyl phosphonates, phosphotriesters, phosphoramidates, carbamates), charged bonds (eg phosphorothioates, phosphorodithioates). ), pendant moieties (for example polypeptides), intercalators (for example, acridine, psoralen), chelants, alkylating agents and modified bonds (for example anomeric alpha nucleic acids). Also included are synthetic molecules that mimic nucleic acid molecules in the ability to bind to a sequence designed by hydrogen bonds and other chemical interactions. These molecules include, for example, those in which the peptide bonds replace the phosphate bonds in the backbone of the molecule. The invention also relates to nucleic acid molecules that hybridize under high stringency hybridization conditions, such as for selective hybridization, to a nucleotide sequence described herein (e.g., nucleic acid molecules that specifically hybridize to a sequence of nucleotides encoding polypeptides described herein and, optionally, have a polypeptide activity). In one aspect, the invention includes variants described herein that hybridize under high stringency hybridization conditions (e.g., for selective hybridization) to a nucleotide sequence that encodes an amino acid sequence or a polymorphic variant thereof. In another aspect, the variant that hybridizes in the condition of high stringency hybridizations have an activity of a MA.P3K9 polypeptide. Such nucleic acid molecules can be detected and / or isolated by specific hybridization (for example, under conditions of high stringency). "Specific hybridization" as used herein, refers to the ability of a first nucleic acid to hybridize with a second nucleic acid in such a manner that the first nucleic acid does not hybridize to any nucleic acid other than the second nucleic acid (e.g. , when the first nucleic acid has a greater similarity with the second nucleic acid than with any other nucleic acid in a sample in which the hybridization is to be performed). "Stringency conditions" for hybridization is a term of the art which refers to the conditions of incubation and washing, for example, temperature conditions and buffer concentration, which allow the hybridization of a particular nucleic acid with a second nucleic acid; the first nucleic acid can be perfectly (ie 100%) complementary to the second, or the first and second nucleic acids can share some degree of complementarity that is less than the perfect (eg 70%, 75%, 85%, 90%, 95%,). For example, certain conditions of high stringency that distinguish nucleic acids perfectly complementary to those with less complementarity can be used. "Conditions of high stringency", "conditions of moderate stringency" and "conditions of low stringency" for nucleic acid hybridizations are explained on pages 2.10.1-2.10.16 and pages 6.3.1-6.3.6 in Current Protocols in Molecular Biology (Ausubel, F., et al., "Current Protocols in Molecular Biology", John Wiley &Sons, (2001)), whose teachings are incorporated herein by reference). The exact conditions that determine the stringency of hybridization depend not only on the ionic strength (for example, 0.2 X SSC, 0.1 X SSC), temperature (for example, room temperature, 42 ° C, 68 ° C) and the concentration of destabilizing agents such as formamide or denaturing agents such as SDS, but also factors such as the length of the nucleic acid sequence, the composition of bases, the percentage of decoupling between the hybridization sequences and the frequency of occurrence of subseries of that sequence within other non-identical sequences. In this way, equivalent conditions can be determined by varying one or more of these parameters while maintaining a similar degree of identity or similarity between the two nucleic acid molecules. Typically, conditions are used so that the sequences with an identity of at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 95% or more identical to each other remain hybridized to each other. By varying the hybridization conditions from a level of stringency in which hybridization does not occur to a level at which hybridization is first observed, conditions can be determined that will allow a given sequence to hybridize (eg selectively) with the most similar sequences present. in the sample.

Illustrative conditions are described in Krause, M. H. and S. A. Aaronson, Methods in Enzymology 200: 546-556 (1991), and in, Ausubel, et al., "Current Protocole in Molecular Biology," John iley & Sons, (2001), which describes the determination of washing conditions for conditions of moderate or low stringency. Washing is the stage in which conditions are usually set to determine a minimum level of complementarity of the hybrids. Generally, starting from the lowest temperature at which only a homologous hybridization occurs, each ° C by which the final wash temperature is reduced (keeping the SSC concentration constant) allows an increase of 1% in the maximum degree of uncoupling between the sequences that hybridize. Generally, doubling the SSC concentration gives an increase in Tm of -17 ° C. Using these guidelines, the wash temperature can be determined empirically for high, moderate or low stringency, depending on the level of decoupling sought. For example, a low stringency wash may comprise washing in a solution containing 0.2 X SSC / 0.1% SDS for 10 minutes at room temperature; a moderate stringency wash may comprise washing in a preheated solution (42 ° C) containing 0.2 X SSC / 0.1% SDS for 15 minutes at 42 ° C; and a high stringency wash may comprise washing in preheated solution (68 ° C) containing 0.1 X SSC / 0.1% SDS for 15 minutes at 68 ° C. In addition, the washings may be repeated or sequentially to obtain a desired result as is known in the art. Equivalent conditions can be determined by varying one or more of the parameters provided as an example, as is known in the art, while maintaining a similar degree of identity or similarity between the target nucleic acid molecule and the primer or probe used. The percentage of homology or identity of two nucleotide or amino acid sequences can be determined by aligning the sequences for optimal comparison (for example, gaps can be introduced into the sequence of a first sequence for optimal alignment). The nucleotides or amino acids are then compared at the corresponding positions and the percent identity between the two sequences is a function of the number of identical positions shared by the sequences (ie,% identity = N ° of identical positions / N ° of total positions x 100). When a position in a sequence is occupied by the same nucleotide or amino acid residue as the corresponding position in the other sequence, then the molecules are homologous in that position. As used herein, "nucleic acid or amino acid homology" is equivalent to "nucleic acid or amino acid identity". In certain aspects, the length of an aligned sequence for comparative purposes is at least 30%, preferably at least 40%, in some aspects at least 60% and in other aspects at least 70%, 80%, 90% or 95% of the length of the reference sequence. The actual comparison of the two sequences can be performed by well-known methods, for example, using a mathematical algorithm. A preferred non-limiting example of such a mathematical algorithm is described in Karlin et al., Proc. Nati Acad. Sci. USA 90: 5873-5877 (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) as described in Altschul et al., Nucleic Acids Res. 25: 389-3402 (1997). When the BLAST and Gapped BLAST programs are used, the default parameters of the respective programs (for example, NBLAST) can be used. In one aspect, the parameters for the comparison of the sequences can be set at a score = 100, word length = 12, or they can vary (for example = 5 or W = 20). Another preferred non-limiting example of a mathematical algorithm used for the comparison of sequences is the algorithm of Myers and Miller, CABIOS 4 (1): 11-17 (1988). This algorithm is incorporated into the ALIGN program (version 2.0) that is part of the GCG sequence alignment software package (Accelrys, Cambridge, UK). When the ALIGN program is used to compare amino acid sequences, a weighted residuals table PAM120, a gap length penalty of 12, and a gap penalty of 4 can be used. Other algorithms for sequence analysis are known in the art. include ADVANCE and ADAM as described in Torellis and obotti, Comput. Appl. Biosci. 10: 3-5 (1994); and FASTA described in Pearson and Lipman, Proc. Nati Acad. Sci. USA 85: 2444-8 (1988). In another aspect, the percent identity between two amino acid sequences can be made using the GAP program in the GCG software package using a BLOSUM63 matrix or a PA 250 matrix and a hole weight of 12, 10, 8, 6, or 4 and a length weight of 2, 3, or 4. In another aspect, the percent identity between two nucleic acid sequences can be determined using the GAP program in the GCG software package using a hole weight of 50 and a weight of length of 3.

The present invention also provides isolated nucleic acid molecules that contain a fragment or portion that hybridizes under high stringency conditions to a nucleotide sequence of SEQ ID NO: 1 or the complement of said sequence, and also provides nucleic acid molecules isolates containing a fragment or portion that hybridizes under conditions of high stringency with a nucleotide sequence encoding an amino acid sequence or a polymorphic variant thereof. The nucleic acid fragments of the invention have a length of at least about 15, preferably at least about 18, 20, 23 or 25 nucleotides and can have a length of 30, 40, 50, 100, 200 or more nucleotides. Particularly useful are longer fragments, for example, 30 or more nucleotides in length, encoding antigenic polypeptides described herein, such as for the generation of antibodies as described below. Probes and Primers In a related aspect, the nucleic acid fragments of the invention are used as probes or primers in assays such as those described herein. "Probes" or "primers" are oligonucleotides that hybridize in a base-specific manner with a complementary strand of nucleic acid molecules. These probes and primers include polypeptide nucleic acids as described in Nielsen et al., Science 254: 1497-1500 (1991). A probe or primer comprises a nucleotide sequence region that hybridizes to at least about 15, for example about 20-25 and in certain aspects about 40, 50 or 75 consecutive nucleotides of a nucleic acid molecule comprising an adjacent nucleotide sequence. of SEQ ID NO: 1 or a polymorphic variant thereof. In other aspects, a probe or primer comprises 100 or fewer nucleotides, in certain aspects from 6 to 50 nucleotides, for example from 12 to 30 nucleotides. In other aspects, the probe or primer has an identity of at least 70% with the contiguous nucleotide sequence or contiguous nucleotide sequence complement, for example, at least 80% identity, in certain aspects an identity of less 90% and in other aspects an identity of at least 95%, or even capable of selectively ibriding with the contiguous nucleotide sequence or with the complement of the contiguous nucleotide sequence. Often, the probe or primer further comprises a label, e.g., radioisotope, fluorescent compound, enzyme, or enzyme co-factor. The nucleic acid molecules of the invention such as those described above can be identified and isolated using conventional molecular biology techniques and the sequence information provided herein. For example, nucleic acid molecules can be amplified and isolated by the polymerase chain reaction using synthetic oligonucleotide primers designed based on the sequence of SEQ ID 1: 1 or the complement of said sequence, or designed based on nucleotides based on sequences that encode one or more of the amino acid sequences provided herein. See generally PCR Technology: Principles and Applications fox DNA Amplification (ed. H. A. Erlich, Freeman Press, Y, NY, 1992); Protocole PCR: A Guide to Methods and Applications (Eds. Innis et al., Academic Press, San Diego, CA, 1990); Mattila et al., Nucí. Acids Res. 19: 4967 (1991); Eckert et al., PCR Methods and Applications 1: 17 (1991); PCR (eds. McPherson et al., IRL Press, Oxford); and United States Patent 4.S83.202. Nucleic acid molecules can be amplified using cDNA, mRNA or genomic DNA as a template, can be cloned into an appropriate vector and can be characterized by analysis of the DNA sequence. Other suitable amplification methods include the ligase chain reaction (LCR) (see Wu and allace, Genomics 4: 560 (1989), Landegren et al., Science 241: 1077 (1988), transcription amplification (Kwoh et al., Proc. Nati, Acad. Sci. USA 86: 1173 (1989)), and replication of the self-sustained sequence (Guatelli et al., Proc. Nat. Acad. Sci. USA 87: 1874 (1990)) and sequence amplification based on nucleic acid (NASBA). The last two amplification methods involve isothermal reactions based on isothermal transcription, which produce both single-stranded RNA (ssRNA) and double-stranded DNA (dsDNA) and amplification products in a ratio of approximately 30 or 100 to 1, respectively. The amplified DNA can be labeled, for example, radiolabeled, and used as a probe to select a cDNA library from human RNAm cells in zap express, ZIPLOX or other suitable vector. Corresponding clones can be isolated, DNA can be obtained after an in vivo excision, and the cloned insert can be sequenced in one or both of the orientations by art-recognized methods to identify the correct reading phase encoding a polypeptide of the appropriate molecular weight. For example, direct analysis of the nucleotide sequence of nucleic acid molecules of the present invention can be performed using well-known methods that are commercially available. See for example, Sambrook et al., Molecular Cloning, A Laboratory Manual (2nd Ed., CSHP, New York 1989); Zyskind et al., Recombinant DNA Laboratory Manual, (Acad. Press, 1988)). In addition, fluorescence methods are also available for analyzing nucleic acids (Chen et al., Genome Res. 9, 492 (1999)) and polypeptides. Using these methods or similar methods, the polypeptide and the DNA encoding the polypeptide can be isolated, sequenced and further characterized. Antisense nucleic acid molecules of the invention can be designed using the nucleotide sequence of SEQ ID NO: 1 and / or the complement or a portion and constructed using chemical synthesis and enzymatic binding reactions using methods known in the art. For example, an antisense nucleic acid molecule (eg, an antisense oligonucleotide) can be chemically synthesized using natural nucleotides or modified nucleotides of various forms designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the acids antisense and sense nucleics, for example, phosphorothioate derivatives and nucleotides substituted with acridine. Alternatively, the antisense nucleic acid molecule can be produced biologically using an expression vector within which a nucleic acid molecule has been subcloned in an antisense orientation (i.e., the RNA transcribed from the inserted nucleic acid molecule will be an antisense orientation with respect to the target nucleic acid of interest). Nucleic acid sequences can also be used to compare with endogenous DNA sequences in patients to identify one or more of the disorders described above, and as probes, such as to hybridize and discover related DNA sequences or eliminate known sequences from a sample. Nucleic acid sequences can also be used to obtain primers for genetic characterization, to induce anti-polypeptide antibodies using DNA immunization techniques and as an antigen to induce anti-DNA antibodies to induce immune responses. The portions or fragments of the nucleotide sequences identified in this document (and the corresponding complete gene sequences) can be used in numerous ways, such as polynucleotide reagents. For example, these sequences can be used to: (i) locate their respective genes on a chromosome; and in this way, to locate gene regions ciated with genetic diseases; (ii) identify an individual from a small biological sample (tissue typing); and (iii) st in the forensic identification of a biological sample. In addition, the nucleotide sequences of the invention can be used to identify and express recombinant polypeptides for analysis, characterization or therapeutic use, or as markers for tissues in which the corresponding polypeptide is expressed, constitutively, during tissue differentiation or in different states. of disease. In addition, the nucleic acid sequences can be used as reagents in the screening and / or diagnostic ys described herein and can also be included as kit components (e.g., reagent kits) for use in screening and / or screening ys. diagnosis described in this document. Kits (e.g., Reagent Kits) useful in the diagnostic method comprise useful components in any of the methods described herein including, for example, hybridization probes or primers as described herein (e.g., probes or labeled primers) reagents for the detection of labeled molecules, restriction enzymes (e.g., for RFLP analysis), oligonucleotides with allele specificity, antibodies that bind to altered or unaltered MAP3K9 polypeptide (native), media for amplification of nucleic acids comprising a? 3? 9 nucleic acid, or means for analyzing the nucleic acid sequence of a MAP3K9 nucleic acid or for analyzing the amino acid sequence of a ??? 3? 9 polypeptide as described in this document, etc. In one aspect, the kit for diagnosing asthma or asthma susceptibility may comprise primers for the amplification of nucleic acids from a region of the nucleic acid of λ 3 9 9 comprising a risk haplotype that is present most frequently in a individual who has asthma or who is susceptible to asthma. The primers can be designed using portions of the nucleic acids flanking SPN that are indicative of asthma. In a certain aspect, the primers are designed to amplify regions of the MA.P3K9 gene associated with a haplotype at risk for asthma, as shown in Table 1.

Vectors and Host Cells Another aspect of the invention relates to nucleic acid constructs containing a nucleic acid molecule described herein and its complements (or a portion thereof). The constructs comprise a vector (e.g., an expression vector) into which a sequence of the invention has been inserted in a sense or antisense orientation. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double-stranded DNA loop into which additional DNA segments can be attached. Another type of vector is a viral vector, where additional DNA segments can be joined in the viral genome. Certain vectors can be replicated autonomously in a host cell into which they are introduced (eg, bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell and therefore replicate together with the host genome. Expression vectors can direct the expression of genes to which they are operatively linked. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. However, the invention is intended to include other forms of expression vectors such as viral vectors (eg, retroviruses with replication defects, adenoviruses and adeno-associated viruses) that have equivalent functions. In certain aspects, the recombinant expression vectors of the invention comprise a nucleic acid molecule of the invention in a form suitable for the expression of the nucleic acid molecule in a host cell. This means that the recombinant expression vectors include one or more regulatory sequences, selected based on the host cells to be used for expression, which are operably linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably linked" is intended to mean that the nucleotide sequence of interest is linked to a regulatory sequence in a manner which allows expression of the nucleotide sequence (eg, in a system of transcription / translation in vitro or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). These regulatory sequences are described, for example, in Goeddel, "Gene Expression Technology", Methods in Enzymology 185, Academic Press, San Diego, CA (1990). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in many types of host cell and those which direct expression of the nucleotide sequence only in certain host cells (eg, regulatory sequences tissue specific). Those skilled in the art will appreciate that the design of the expression vector may depend on factors such as the choice of the host cell to be transformed and the level of expression of the desired polypeptide. The expression vectors of the invention can be introduced into host cells to thereby produce polypeptides, including fusion polypeptides, encoded by nucleic acid molecules as described. The recombinant expression vectors of the invention can be designed for expression of a polypeptide of the invention in prokaryotic or eukaryotic cells, for example, bacterial cells such as E. coli, insect cells (using baculovirus expression vectors), cells yeast or mammalian cells. In Goeddel, supra suitable host cells are further described; alternatively, the recombinant expression vector can be transcribed and translated in vi tro, for example using regulatory sequences of the T7 promoter and T7 polyem.

Another aspect of the invention relates to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell" "recombinant host cell" are used interchangeably herein. It is understood that these expressions refer not only to the particular cell but also to the offspring or potential offspring of said cell. As in later generations certain modifications may occur due to mutations or environmental influences, it is possible that this offspring is not identical to the parental cell, but even so it is included within the scope of the expression used in this document.

A host cell can be any prokaryotic or eukaryotic cell. For example, a nucleic acid molecule of the invention can be expressed in bacterial cells (e.g., E. coli), insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). . Those skilled in the art will know other suitable host cells. The vector DNA can be introduced into prokaryotic or eukaryotic cells by means of conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are understood to refer to a variety of techniques recognized in the art for introducing a foreign nucleic acid molecule (e.g., DNA) into a host cell, including co-precipitation with calcium phosphate or calcium chloride, transfection mediated by DEAE-dextran, lipofection or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al.,. { supra} , and other laboratory manuals. For stable transfection of mammalian cells, it is known that, depending on the expression vector and the transfection technique used, only a small fraction of cells can integrate the foreign DNA into their genome. To identify and select these integrants, a gene encoding a selective marker (for example for resistance to antibiotics) is generally introduced into the host cells together with the gene of interest. Preferred selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid molecules encoding a selective marker can be introduced into a host cell in the same vector as the nucleic acid molecule of the invention or can be introduced into a separate vector. Cells transfected stably with the introduced nucleic acid molecule can be identified by drug selection (for example, cells that have incorporated the selective marker gene will survive while the other cells will die). A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (ie, express) a polypeptide of the invention. Accordingly, the invention further provides methods for producing a polypeptide using the host cells of the invention. In one aspect, the method comprises culturing the host cell of the invention (into which a recombinant expression vector encoding a polypeptide of the invention has been introduced) in a suitable medium such that the polypeptide is produced. In another aspect, the method further comprises isolating the polypeptide from the medium or the host cell. The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one aspect, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which a nucleic acid molecule of the invention has been introduced (e.g., an exogenous MAP3K9 gene or a nucleic acid). exogenous coding for a polypeptide of ??? 3? 9). These host cells can then be used to create transgenic non-human animals into which exogenous nucleotide sequences have been introduced into the genome or homologous recombinant animals in which endogenous nucleotide sequences have been altered. These animals are useful for studying the function and / or activity of the nucleotide sequence and the polypeptide encoded by the sequence and for identifying and / or evaluating modulators of their activity. As used in this document, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens and amphibians. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and which remains in the mature animal's genome thereby directing the expression of a gene product encoded in one or more cell types or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule. introduced into an animal cell, for example, an embryonic cell of the animal, before the development of the animal. Methods for generating transgenic animals through embryonic manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866 and 4,870. 009, in U.S. Patent No. 4,873,191 and in Hogan, Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1986). Methods for constructing homologous recombination vectors and homologous recombinant animals are also described in Bradley, Current Opinion in BioTechnology 2: 823-829 (1991) and in PCT Publications No. WO 90/11354, WO 91/01140, WO 92/0968 , and WO 93/04169. Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut et al., Nature 385: 810-813 (1997) and in PCT Publications No. WO 97/07668 and WO 97 / 07669 RIBONUCLEIC ACID (RNA) OF THE INVENTION: In one aspect, the invention relates to methods for measuring RNA levels of MLK kinases (e.g. MLK1) using quantitative real-time PCR assays in which specific oligonucleotides are used to members of the MLK kinase family (e.g. MLK1) to amplify reverse transcribed RNA (cDNA) or RNA samples that are isolated from blood leukocytes or other tissue samples. The method includes obtaining a sample of patient cells and determining RNA levels using sequence-specific probes that hybridize with MLK kinase PCR products (e.g. MLKl) using 5'-exonuclease activity - >3 'of Taq DNA polymerase on RNA samples that are isolated from cells that have been exposed to specific cytokine activators that activate the JNK pathway (such as ILlb or TNF) against the vehicle alone (ie, without activation). In one aspect, the TaqMan probe consists of a site-specific sequence labeled with a fluorescent reporter dye and a fluorescent quencher dye where, during the PCR reaction, the TaqMac probe hybridizes with its complementary single-stranded DNA sequence within the PRC target. The final level was measured by spectrophotometry after the termination of the PCR. In another aspect, the expression of the MLK kinase (e.g., MLK1) is determined using SYBR Green as a fluorescent dye. This dye emits fluorescence only when it binds to double-stranded DNA, that is, when primers designed solely for the MLK kinase are attached (eg, MLK1) and allow discrimination between different variants of RNA splicing. In another aspect, the invention relates to methods that determine the role of MAP3K9 or its related genes, obtaining a sample of cells from patients with asthma or other respiratory or inflammatory disorders, determining ARA levels of ??? 3? 9 or its route-related genes in cells exposed to specific pathway activators (such as ILlb or TNFoc) or vehicle alone (inactivation) and comparing them with reference RNA levels of the gene in cells isolated from subjects without asthma or other disorders inflammatory / respiratory In another aspect, the invention relates to methods for predicting the efficacy of an inhibitory drug, including obtaining a sample of cells from patients with asthma or another respiratory / inflammatory disorder, by determining RNA levels of ??? 3? 9 or its route-related genes in cells isolated from patients who are taking the drug compared to those who are not taking the drug. In another aspect, the invention relates to methods for predicting the efficacy of an inhibitory drug, including obtaining a sample of cells from patients with asthma or other respiratory / inflammatory disorders, by determining RNA levels of MAP3K9 or its genes related pathways after exposure of the cells to the inhibitory drug in vi tro. POLYPEPTIDES OF THE INVENTION The present invention also relates to isolated polypeptides encoded by ??? 3? 9 nucleic acids ("MAP3K9 polypeptides," or "??? 3? 9 proteins," such as the protein shown in FIG. SEQ ID NO: 2, FIG 8, FIG 9 and accession number NCBI XM_027237; (mRNA), the entire sequence of which is incorporated herein by reference and fragments and variants thereof, as well as nucleotide-encoded polypeptides described herein (eg, other splice variants.) The term "polypeptide" refers to a polymer of amino acids and not to a specific length, thus, within the definition of a polypeptide include peptides, oligopeptides and proteins As used herein, a polypeptide is said to "isolate" or "purify" when it lacks substantially cellular material when it is isolated from recombinant and non-recombinant cells, or lacks precursors monkeys or other chemicals when chemically synthesized. However, a polypeptide can bind to another polypeptide with which it is not normally associated in a cell (e.g., in a "fusion protein") and can be "isolated" or "purified". The polypeptides of the invention can be purified to homogeneity. However, it is understood that preparations in which the polypeptide is not purified to homogeneity are useful. The critical feature is that the preparation allows the desired function of the polypeptide, even in the presence of considerable amounts of other components. In this way, the invention includes various degrees of purity. In one aspect, the language "substantially free of cellular material" includes preparations of the polypeptide having less than about 30% (by dry weight) of other proteins (ie, contaminating proteins), less than about 20% of other proteins, less than about 10% of other proteins or less than about 5% of other proteins. When a polypeptide is produced recombinantly, it may also be substantially lacking in culture medium, ie, the culture medium represents less than about 20%, less than about 10%, or less than about 5% of the volume of the culture. polypeptide preparation. The term "substantially free of chemical precursors or other chemical agents" includes preparations of the polypeptide in which it is separated from chemical precursors or other chemical agents that are involved in its synthesis. In one aspect, the expression "substantially free of chemical precursors or other chemical agents" includes preparations of the polypeptide having less than about 30% (by dry weight) of chemical precursors or other chemical agents, less than about 20% of chemical precursors or other chemical agents, less than about 10% chemical precursors or other chemical agents, or less than about 5% chemical precursors or other chemical agents. In one aspect, a polypeptide of the invention comprises an amino acid sequence encoded by a nucleic acid molecule comprising a nucleotide sequence of SEQ ID NO: 1, or the complement of said nucleic acid, or portions thereof, or a polymorphic portion or variant thereof. However, the polypeptides of the invention also include fragments and sequence variants. The variants include a substantially homologous polypeptide encoded by the same genetic locus in an organism, ie, an allelic variant, as well as other splice variants. The variants also include polypeptides derived from other genetic loci in an organism, but having substantial homology to a polypeptide encoded by a nucleic acid molecule comprising a nucleotide of SEQ ID NO: 1 or a complement of said sequence, or portions of it or polymorphic variants thereof. The variants also include polypeptides substantially homologous or identical to those polypeptides but derived from another organism, i.e. an ortholog. Variants also include polypeptides that are substantially homologous or identical to those polypeptides that are produced by chemical synthesis. Variants also include polypeptides that are substantially homologous or identical to those polypeptides that are produced by recombinant methods. As used herein, two polypeptides (or a region of the polypeptides) are substantially homologous or identical when the amino acid sequences have a homology or identity of at least about 45-55%, in certain aspects of at least about one 70-75%, and in other aspects at least approximately 80-85% and in other aspects greater than approximately 90%. A substantially homologous amino acid sequence, according to the present invention, will be encoded by a nucleic acid molecule that hybridizes with a nucleic acid of the invention or portion thereof or polymorphic variant thereof or under the same stringent conditions as has described in more detail above. The invention also includes polypeptides that have a lower degree of identity but are sufficiently similar to perform one or more of the same functions performed by a polypeptide encoded by a nucleic acid molecule of the invention. The similarity is determined by substitution of conserved amino acids where a given amino acid in a polypeptide is substituted by another amino acid of similar characteristics. It is likely that conservative substitutions are phenotypically silent. Replacements are typically seen as conservative replacements, between each other, between the amino acids Ala, Val, Leu e lie; the exchange of the hydroxyl radicals Ser and T r, the exchange of the acid residues Asp and Glu, the substitution between the amide residues Asn and Gln, the exchange of the basic residues Lys and Arg and replacements between the aromatic residues Phe and Tyr . Guidelines are found regarding amino acid changes that are likely to be phenotypically silent in Bowie et al., Science 247: 1306-1310 (1990). A variant polypeptide may differ in the amino acid sequence by one or more substitutions, deletions, insertions, inversions, fusions and truncations or a combination thereof. In addition, the variant polypeptides may be fully functional or may lack function in one or more activities. Fully functional variants typically contain only a conservative variation or variations in non-critical residues or non-critical regions. Functional variants may also contain substitution of similar amino acids that do not produce any change or a significant change in function. Alternatively, these substitutions may affect the function positively or negatively to some extent. Non-functional variants typically contain one or more substitutions, deletions, insertions, inversions or truncation of non-conservative amino acids or truncation or substitution, insertion, inversion, or deletion in a critical moiety or critical region. Amino acids that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine scanning mutagenesis (Cunningham et al., Science 244: 1082-1185 (1989)). This last procedure introduces mutations of a single alanine in each residue of the molecule. The in vitro biological activity or the in vitro proliferative activity of the resulting mutant molecules is then tested. Sites that are critical for polypeptide activity can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity mating (Smith et al., J. Mol. Biol. 224: 899-904 (1992); et al., Science 255: 306-312 (1992)).

The invention also includes fragments of polypeptides of the polypeptides of the invention. The fragments can be derived from a polypeptide encoded by a nucleic acid molecule comprising SEQ ID NO: 1 or a complement of said nucleic acid or other variants. However, the invention also includes fragments of the variants of the polypeptides described herein. As used herein, a fragment comprises at least 6 contiguous amino acids. Useful fragments include those that retain one or more of the biological activities of the polypeptide as well as fragments that can be used as an immunogen to generate antibodies with polypeptide specificity. Biologically active fragments (peptides having a length, for example, of 6, 9, 12, 15, 16, 20, 30, 35, 36, 37, 38, 39, 40, 50, 100 or more amino acids) can comprise a domain, segment or motif that has been identified by analysis of the polypeptide sequence using well known methods, eg, signal peptides, extracellular domains, one or more transmembrane segments or loops, ligand binding regions, zinc finger domains, DNA binding domains, acylation sites, glycosylation sites, or phosphorylation sites. The fragments may be discrete (not fused to other amino acids or polypeptides) or they may be within a larger polypeptide. In addition, several fragments may be comprised within a single larger polypeptide. In one aspect, a fragment designed for expression in a host may have pre-and pro-polypeptide regions fused to the amino terminus of the polypeptide fragment and an additional region fused to the carboxyl end of the fragment. In this manner, the invention provides chimeric or fusion polypeptides. These comprise a polypeptide of the invention operably linked to a heterologous protein or polypeptide having an amino acid sequence not substantially homologous to the polypeptide. "Operably linked" indicates that the polypeptide and the heterologous protein are fused in phase. The heterologous protein may be fused to the N-terminus or the C-terminus of the polypeptide. In one aspect, the fusion polypeptide does not affect the function of the polypeptide per se. For example, the fusion polypeptide can be a GST fusion polypeptide in which the polypeptide sequences are fused to the C-terminus of the GST sequences. Other types of fusion polypeptides include, but are not limited to, enzymatic fusion polypeptides, for example, fusions with β-galactosidase, fusions with yeast double-hybrid GAL, fusions with poly-His and fusions with Ig. These fusion polypeptides, particularly fusions with poly-His, can facilitate purification of the recombinant polypeptide. In certain host cells (e.g., mammalian host cells), the expression and / or secretion of a polypeptide can be increased using a heterologous signal sequence. Therefore, in another aspect, the fusion polypeptide contains a heterologous signal sequence at its N-terminus. EP-A-0 464 533 discloses fusion proteins comprising various portions of immunoglobulin constant regions. The Fe fragment is useful in therapy and diagnosis and thus, better pharmacokinetic properties (EP-A 0232 262). In drug discovery, for example, human proteins have been fused with Fe portions in order to perform high throughput screening assays to identify antagonists. Bennett et al., Journal of "Molecular Recognition, 8: 52-58 (1995) and Johanson et al., The Journal of Biological Chemistry, 270, 16: 9459-9471 (1995)." Thus, this invention also includes soluble fusion polypeptides containing a polypeptide of the invention and various portions of the constant regions of heavy or light chains of immunoglobulins of various subclasses (IgG, IgM, IgA, IgE). A chimeric or fusion polypeptide can be produced by conventional recombinant DNA techniques. For example, DNA fragments encoding the different polypeptide sequences in phase are linked together according to conventional techniques. In another aspect, the fusion gene can be synthesized by conventional techniques including automatic DNA synthesizers. Alternatively, a PCR amplification of nucleic acid fragments can be performed using anchor primers that produce complementary overhangs between two consecutive nucleic acid fragments that can subsequently hybridize and reamplify to generate a chimeric nucleic acid sequence (see Ausubel et al., Current Protocole in Molecular Biology, 1992). In addition, many expression vectors that already encode a fusion moiety (eg, a GST protein) are available on the market. A nucleic acid molecule encoding a polypeptide of the invention can be cloned into said expression vector such that the fusion moiety is in-frame to the polypeptide. The isolated polypeptide can be purified from cells that express it naturally; it can be purified from cells that have been altered to express it (recombinants), or synthesized using known protein synthesis methods. In one aspect, the polypeptide is produced by recombinant DNA techniques. For example, a nucleic acid molecule encoding the polypeptide is cloned into an expression vector, the expression vector is introduced into a host cell and the polypeptide is expressed in the host cell. The polypeptide can then be isolated from the cells by an appropriate purification scheme using standard protein purification techniques. The polypeptides of the present invention can be used to create antibodies or induce an immune response. The polypeptides can also be used as a reagent, for example, a labeled reagent, in assays to quantitatively determine the levels of the polypeptide or a molecule to which it binds (e.g., a ligand) in biological fluids. The polypeptides can also be used as markers for cells or tissues in the. that the corresponding polypeptide is preferably expressed, constitutively, during tissue differentiation or in a disease state. The polypeptides can be used to isolate a corresponding binding agent, e.g., ligand or receptor, such as, for example, in an interaction capture assay and to select antagonists or peptide agonists or small molecules of the binding interaction.

ANTIBODIES OF THE INVENTION Polyclonal antibodies and / or monoclonal antibodies which bind specifically to one form of the gene product but not to the other form of the gene product are also provided. Antibodies that bind to a portion of the variant or reference gene product that contains the polymorphic site or sites are also provided. The term "antibody", as used herein, refers to immunoglobulin molecules and to immunologically active portions of immunoglobulin molecules, ie, molecules that contain antigen-binding sites that specifically bind to an antigen. A molecule that specifically binds to a polypeptide of the invention is a molecule that binds to that polypeptide or a fragment thereof, but does not bind substantially to other molecules of a sample, eg, a biological sample, which contains natural the polypeptide. Examples of immunologically active portions of immunoglobulin molecules include F (ab) and F (ab ') 2 fragments that can be generated by treating the antibody with an enzyme such as pepsin. The invention provides polyclonal and monoclonal antibodies that bind to a polypeptide of the invention. The term "monoclonal antibody" or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one species of an antigen-binding site capable of presenting an immunological reaction with an particular epitope of a polypeptide of the invention. Thus, a monoclonal antibody composition typically exhibits a single binding affinity for a particular polypeptide of the invention with which it exhibits an immunological reaction. Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a desired immunogen, for example, a polypeptide of the invention or a fragment thereof. The titration of antibody in the immunized subject can be controlled over time by conventional techniques, such as with an enzyme-linked immunosorbent assay (ELISA) using an immobilized polypeptide. If desired, antibody molecules directed against the polypeptide can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as protein A chromatography to obtain the IgG fraction. At an appropriate time after immunization, for example, when the antibody titers are maximal, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by conventional techniques, such as the hybridoma technique originally described by Kohler and Milstein. , Nature 256: 495-497 (1975), the human B-cell hybridoma technique (Kozbor et al., Immunol. Today 4: 72 (1983)), the EBV-hybridoma technique (Colé et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, 1985, Inc., pp. 77-96) or trioma techniques. The technology for producing hybridomas is well known (see in general Current Protocole in Immunology (1994) Coligan et al., (Eds.) John Wiley &Sons, Inc., New York, NY). Briefly, an immortal cell line (typically a myeloma) is fused with lymphocytes (typically splenocytes) from a mammal immunized with an immunogen as described above, and the culture supernatants from the resulting hybridoma cells are selected or investigated for identifying a hybridoma that produces a monoclonal antibody that binds to a polypeptide of the invention. Any of the many well-known protocols used to fuse lymphocytes and immortalized cell lines can be applied to generate a monoclonal antibody against a polypeptide of the invention (see, for example, Current Protocole in Xmmunology, supra; Galfre et al., Nature 266: 55052 (1977), RH Kenneth, in Monoclonal Antibodies: A New Dimension in Biological Analyzes, Plenum Publishing Corp., New York, New York (1980); and Lerner, Yale J. Biol. Med. 54: 387-402 (1981)). In addition, the usual specialist will appreciate that there are many variations of these methods that may also be useful. As an alternative to the preparation of hybridomas secreting monoclonal antibodies, a monoclonal antibody against a polypeptide of the invention can be identified and isolated by the selection of a recombinant immunoglobulin combinatorial library (eg, a phage display library of antibodies). with the polypeptide, to thereby isolate members of the immunoglobulin library that bind to the polypeptide. Kits for generating and selecting phage display libraries are available on the market (eg, The Pharmacy Recombinant Phage Antibody System, Catalog No. 27-9400-01) and the SurfZAP ™ Phage Display Kit, No. catalog 240612). In addition, examples of methods and reagents particularly susceptible for use in the generation and selection of antibody display libraries can be found, for example, in U.S. Patent No. 5,223,409; in the PCT publication M ° WO 92/18619; in PCT publication No. WO 91/17271; in PCT publication No. WO 92/20791; in PCT publication No. WO 92/15679; in PCT publication No. WO 93/01288; in PCT publication No. WO 92/01047; in PCT publication No. WO 92/09690; in PCT publication No. WO 90/02809; Fuchs et al., Bio / Technology 9: 1370-1372 (1991); Hay et al., Hum. Antibod. Hybridomas 3: 81-85 (1992); Huse et al., Science 246: 1275-1281 (1989); and Griffiths et al., EMBO J. 12: 725-734 (1993). Further, within the scope of the invention are recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be obtained using conventional recombinant DNA techniques. These chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art. In general, the antibodies of the invention (eg, a monoclonal antibody) can be used to isolate a polypeptide of the invention by conventional techniques, such as affinity chromatography or immunoprecipitation. An antibody with polypeptide specificity can facilitate the purification of the native polypeptide from the cells and from the recombinantly produced polypeptide expressed in host cells. In addition, an antibody specific for a polypeptide of the invention can be used to detect the polypeptide (e.g., in a cell lysate, cell supernatant or tissue sample) to evaluate the abundance and expression pattern of the polypeptide. Antibodies can be used as diagnostics to control protein levels in tissues as part of a clinical test procedure, for example, to determine for example the efficacy of a given treatment regimen. The antibody can be coupled to a detectable substance to facilitate its detection. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinyl amine, fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin and aequorin, and examples of radioactive materials include 125I, 1311, 35S or 3H. DIAGNOSTIC ANALYSIS The nucleic acids, probes, primers, polypeptides and antibodies described herein can be used in methods for diagnosing asthma.; a susceptibility to asthma; or a condition associated with a MAP3K9 gene, as well as in kits (eg, useful for the diagnosis of asthma, a susceptibility to asthma, or a condition associated with a MAP3K9 gene.) In one aspect, the kit comprises primers that can used to amplify the markers of interest In one aspect of the invention, diagnosis is made of a disease or condition associated with a ??? 3? 9 gene (eg, diagnosis of asthma or of an asthma susceptibility) by detecting a polymorphism in a MAP3K9 nucleic acid as described herein.The polymorphism may be a change in the nucleic acid of ??? 3? 9, such as insertion or deletion of a single nucleotide, or more than one nucleotide, resulting in a phase change, the change of at least one nucleotide, resulting in a change in the encoded amino acid, the change of at least one nucleotide, resulting in the generation of a premature stop codon; of vari nucleotides, resulting in a deletion of one or more amino acids encoded by the nucleotides; the insertion of one or several nucleotides, such as by unequal recombination or gene conversion, resulting in an interruption of the coding sequence of the gene; duplication of all or a part of the gene; transposition of all or a part of the gene; or redisposition of all or part of the gene. More than one such change may be present in a single gene. These sequence changes produce a difference in the polypeptide encoded by a MAP3K9 nucleic acid. For example, if the difference is a phase change, the phase change may cause a change in the encoded amino acids and / or may result in the generation of a premature stop codon, causing the generation of a truncated polypeptide. Alternatively, a polymorphism associated with a disease or condition or a susceptibility to a disease or condition associated with a ??? 3? 9 nucleic acid may be a synonymous alteration in one or more nucleotides (i.e., an alteration that does not produces a change in the polypeptide encoded by a ??? 3? 9 nucleic acid). This polymorphism can alter the splice sites, affect the stability or transport of the A Nm or otherwise affect the transcription or translation of the gene. A MAP3K9 nucleic acid having any of the changes or alterations described above is referred to herein as "altered nucleic acid". In a first method of diagnosing asthma or an asthma susceptibility, or another disease or condition associated with a MAP3K9 gene, hybridization methods, such as Southern analysis, Northern analysis, or in situ hybridizations, can be used (see Current Protocols in Molecular Biology, Ausubel, F. et al., Eds, John Wiley &Sons, including all supplements until 1999). For example, a biological sample (a "test sample") is obtained from a test subject (the "test subject") of genomic DNA, RNA or cDNA from an individual, such as an individual suspected of being that it has, is susceptible or is predisposed to, or carries a detector for the disease or condition, or the susceptibility to the disease or condition associated with a MAP3K9 gene (eg, asthma). The individual can be an adult, child, or fetus. The test sample may be from any source containing genomic DNA, such as a blood sample, amniotic fluid sample, cerebrospinal fluid sample, or a tissue sample of skin, muscle, buccal mucosa or conjunctiva, placenta, gastrointestinal tract or other organs. A DNA test sample of fetal cells or tissues can be obtained by appropriate methods, such as by amniocentesis or chorionic hair sampling. Then, the DNA, RNA or cDNA sample is examined to determine if a polymorphism is present in the MAP3K9 nucleic acid and / or to determine which splice variant (s) encoded by MAP3K9 is present. The presence of the polymorphism or of the splice variant (s) can be indicated by hybridization of the gene in the genomic ADM, RNA or cDNA with a nucleic acid probe. A "nucleic acid probe", as used herein, may be a DNA probe or an RNA probe; the nucleic acid probe may contain, for example, at least one polymorphism in a MAP3K9 nucleic acid (eg, as indicated in Table 2) and / or may contain a nucleic acid encoding a particular splice variant of a MAP3K9 nucleic acid. The probe can be any of the nucleic acid molecules described above (eg, the gene or nucleic acid, a fragment, a vector comprising the gene or nucleic acid, a probe or primer, etc.). To diagnose asthma, or a susceptibility to asthma, or other condition associated with a MAP3K9 gene, a hybridization sample is formed by contacting the test sample containing an AP3K9 nucleic acid with at least one nucleic acid probe. A preferred probe for detecting mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to the mRNA or genomic DNA sequences described herein. The nucleic acid probe can be, for example, a full-length nucleic acid molecule or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient as to hybridize specifically under stringent conditions with the appropriate genomic mRNA or DNA. For example, the nucleic acid probe can be all or a part of one of SEQ ID NOS: 4-37 or its complement or a portion thereof. Other probes suitable for use in the diagnostic assays of the invention have been described above (e.g., see the probes and primers described under the title "Nucleic Acids of the invention"). The hybridization sample is maintained under conditions that are sufficient to allow specific hybridization of the nucleic acid probe with a γ 3 κ nucleic acid. "Specific hybridization", as used herein, indicates the exact hybridization (eg, without uncoupling). Specific hybridization can be carried out under conditions of high stringency or under conditions of moderate stringency, for example, as described above. In a particularly preferred aspect, the hybridization conditions for the specific hybridization are of high stringency. The specific hybridization is then detected, if present, using conventional methods. If a specific hybridization occurs between the nucleic acid probe and the.? 3? 9 nucleic acid in the test sample, then the ??? 3? 9 has the polymorphism or is the splice variant that is present in the nucleic acid probe. Also, more than one nucleic acid probe can be used simultaneously in this method. Specific hybridization of any one of the nucleic acid probes indicates a polymorphism in the? 3? 9 nucleic acid, or the presence of a particular splice variant that encodes the MAP3K9 nucleic acid and therefore serves as a diagnosis of a susceptibility to a disease or condition associated with a? 3? 9 nucleic acid (eg, asthma). In Northern analysis (see Current Protocols xn Molecular Biology, Ausubel, F. et al., eds., John Wiley &Sons, supra) the hybridization methods described above are used to identify the presence of a particular polymorphism or splice variant, associated with a susceptibility to a disease or condition associated with a gene of? ?? 3? 9 (for example, asthma). For Northern analysis, an RNA test sample is obtained from the individual by appropriate means. Specific hybridization of a nucleic acid probe, as described above, with RNA of the individual indicates a polymorphism in a nucleic acid of ??? 3? 9 or the presence of a particular splicing variant encoded by a nucleic acid of MAP3 9 and therefore serves as a diagnosis of asthma or a susceptibility to asthma or a condition associated with a MAP3K9 nucleic acid (e.g., asthma). As representative examples of the use of nucleic acid probes, see, e.g., U.S. Patent Nos. 5,288,611 and 4,851,330. Alternatively, a peptide nucleic acid (PNA) probe can be used in place of a nucleic acid probe in the hybridization methods described above. A PNA is a molecule that mimics DNA that has an inorganic skeleton resembling a peptide, such as N- (2-aminoethyl) glycine units, with an organic base (A, G, C, T or U) attached to the nitrogen glycine through a methylene carbonyl linker (see, for example, Nielsen, p.E. et al., Bioconjugate Chemistry 5, American Chemical Society, p.1 (1994) .The PNA probe can be designed to specifically hybridize with a gene having a polymorphism associated with a susceptibility to a disease or condition associated with a MAP3K9 nucleic acid (eg, asthma) Hybridization of the PNA probe with a MAP3K9 gene diagnoses asthma or an asthma susceptibility or a state associated with a MAP3K9 nucleic acid In another method of the invention, an analysis of the restriction digestion alteration can be used to detect an altered gene, or genes that contain one or more polymorphisms, if the alteration (mutation) or polymorphisms or in the gene results in the creation or removal of a restriction site. A test sample containing genomic DNA is obtained from the individual. Polymerase chain reaction (PCR) can be used to amplify a MAP3K9 nucleic acid (and, if necessary, flanking sequences) in the genomic DNA test sample from the test individual. An RFLP analysis is performed as described (see Current Protocols in Molecular Biology, supra). The digestion model of the relevant DNA fragment indicates the presence or absence of the alteration or polymorphism in the MAP3K9 nucleic acid, and therefore indicates the presence or absence of asthma or the susceptibility to a disease or condition associated with a nucleic acid. of ??? 3? 9.

Sequence analysis can also be used to detect specific polymorphisms in a MAP3K9 nucleic acid. A test sample of DNA or RNA is obtained from the test individual. PCR or other appropriate methods can be used to amplify the gene or nucleic acid, and / or its flanking sequences, if desired. The sequence of a ??? 3? 9 nucleic acid or a fragment of the nucleic acid, or cDNA, or a fragment of the cDNA, or mRNA or fragment of the mRNA, is determined using conventional methods. The sequence of the nucleic acid, nucleic acid fragment, cDNA, fragment of ANDc, mRNA, or fragment of mRNA is compared to the known nucleic acid sequence of the gene or cDNA or mRNA as appropriate. The presence of a polymorphism in MAPE3K9 indicates that the individual has asthma or a susceptibility to asthma. Oligonucleotides with allele specificity can also be used to detect the presence of a polymorphism in a MAP3K9 nucleic acid, by using dot-blot hybridization of oligonucleotides amplified with oligonucleotide probes with allele specificity (ASO) (see, for example Saiki , R. et al., Nature 324: 163-166 (1986)). An "allelic specificity oligonucleotide" (also referred to herein as an "allele specific oligonucleotide probe") is an oligonucleotide of about 10-50 base pairs, preferably about 15-30 base pairs, that hybridizes specifically with an acid MAP3K9 nucleic acid, and that it contains a polymorphism associated with a susceptibility to a disease or condition associated with a MAP3K9 nucleic acid. An oligonucleotide probe with allele specificity that is specific for particular polymorphisms in a? 3? 9 nucleic acid can be prepared using conventional methods (see Current Protocols in Molecular Biology, supra). To identify polymorphisms in the gene that are associated with a disease or condition associated with a? 3? 9 nucleic acid or a susceptibility to a disease or condition associated with a ??? 3? 9 nucleic acid, one obtains a DNA test sample from the individual. PCR can be used to amplify all or a fragment of the MAP3K9 nucleic acid and its flanking sequences. The DNA containing the amplified MAP3K9 nucleic acid (or fragment of the gene or nucleic acid) is subjected to dot-blot, using conventional methods (see Current Protocols in Molecular Biology, supra), and the transfer stain is contacted. with the oligonucleotidic probe. The presence of specific hybridization of the probe with the amplified? 3? 9 nucleic acid is then detected. Hybridization of an oligonucleotide probe with allele specificity to the individual's DNA indicates a polymorphism in the MAP3K9 nucleic acid, and therefore indicates a disease or condition associated with a nucleic acid of ??? 3? 9 or susceptibility to a disease or condition associated with a ≥ 3 9 nucleic acid (eg, asthma). The invention further provides oligonucleotides with allelic specificity that hybridize to the reference allele or variant of a gene or nucleic acid comprising a single nucleotide polymorphism or with the complement thereof. These oligonucleotides can be probes or primers.

A primer with allele specificity hybridizes to a site in the target DNA that overlaps with a polymorphism and only primes the amplification in an allelic manner with which the primer exhibits perfect complementarity. See Gibbs, Nucleic Acid Res. 17, 2427-2448 (1989). This primer is used together with a second primer, which hybridizes at a distal site. The amplification proceeds from the two primers, resulting in a detectable product, which indicates the particular allelic form that is present. A control is usually carried out with a second pair of primers, one of which shows a uncoupling of a single base at the polymorphic site and the other has a perfect complementarity with a distal site. The uncoupling of a single base prevents amplification and no detectable product is formed. The method works best when the decoupling is included in the 31st position of the oligonucleotide aligned with the polymorphism, because this position is more destabilizing for elongation of the primer (see, for example, WO 93/22456). With the addition of these analogs as blocked nucleic acids (LNA), the size of the primers and probes can be reduced to only 8 bases. LNAs are a new class of bicyclic DNA analogues in which the 2 'and 4' positions in the furanose ring are linked through an O-methylene (oxy-LNA), S-methylene (thio-LNA) moiety , or amino methylene (amino-LNA). It is common for all these variants of LNA an affinity for complementary nucleic acids, which by far is the highest presented for a DNA analogue. For example, it has been shown that all particular oxy-LNA nonamers have melting temperatures of 64EC and 74EC when they are complexed with complementary DNA or RNA, respectively, instead of 28EC for both DNA and RNA in the case of the DNA nonamer correspondent. Substantial increases in Tm are also obtained when thionomers of LNA are used in combination with DNA or RNA monomers. In the case of the primers and probes, depending on where the LNA monomers are included (for example, the 3 'end, the 5' end or in the intermediate zone), the Tm could increase considerably. In another aspect, arrays of oligonucleotide probes that are complementary to segments of the target nucleic acid sequence of an individual can be used to identify polymorphisms in a MAP3 nucleic acid 9. For example, in one aspect, an oligonucleotide series can be used. The oligonucleotide arrays typically comprise a plurality of different oligonucleotide probes that are coupled to a surface of a substrate at different known locations. These oligonucleotide arrays, also described as "Genechips ™," have been generally described in the art, for example, in U.S. Patent No. 5,143,854 and PCT Patent Publication Nos. WO 90/15070 and 92. / 10092. These series can generally be produced using mechanical synthesis methods or light-directed synthesis methods that incorporate a combination of photolithographic methods and solid-phase oligonucleotide synthesis methods. See Fodor et al., Science 251: 767-777 (1991), Pirrung et al., U.S. Patent No. 5,143,854 (see also PCT Application No. WO 90/15070) and Fodor et al., Publication. PCT ND WO 92/10092 and U.S. Patent No. 5,424,186, the entire teachings of which are incorporated herein by reference. Techniques for the synthesis of these series are described using mechanical synthesis methods, for example, in U.S. Patent No. 5,384,261; whose entire teachings are incorporated in this document as a reference. In another example, linear series can be used. Once the oligonucleotide series is prepared, a nucleic acid of interest hybridizes with the array and the polymorphism is explored. Hybridization and scanning are generally performed by methods described herein and also, for example, in published PCT Application No. WO 92/10092 and WO 95/11995, and in U.S. Patent No. 5,424,186, which In brief, a target nucleic acid sequence that includes one or more previously identified polymorphic markers is amplified by well known amplification techniques, eg, PCR Typically, this involves the use of primer sequences which are complementary to the two strands of the target sequence both upstream and downstream of the polymorphism.Asymmetric PCR techniques can also be used.Afterwards, hybridize the amplified target, generally incorporating a marker, with the series under the appropriate conditions. Hybridization and washing of the series, the series is explored to determine the position in the series with which hybrid The target sequence The hybridization data obtained from the scan are typically in the form of fluorescence intensities as a function of the location in the series.

Although they are described mainly in terms of a single detection block, for example, to detect a single polymorphism, the series can include multiple detection blocks and thus be able to analyze multiple specific polymorphisms. In alternative aspects, it will generally be understood that the detection blocks can be grouped within a single series or in multiple separate series so that variable optimal conditions can be used during the hybridization of the target to the series. For example, it may often be desirable to provide detection of polymorphisms that fall within G-C-rich stretches of a genomic sequence, separately from those that fall into segments rich in A-T. This allows the separate optimization of the hybridization conditions for each situation. Other uses of oligonucleotide arrays for the detection of polymorphisms can be found, for example, in U.S. Patent Nos. 5,858,659 and 5,837,832, the entire teachings of which are incorporated herein by reference. Other methods of nucleic acid analysis can be used to detect polymorphisms in an asthma gene or variants encoded by an asthma gene. Representative methods include direct manual sequencing (Church and Gilbert, Proc. Nati, Acad. Sci. USA 81: 1991-1995 (1988), Sanger, F., Et al., Proc. Nati. Acad. Sci. USA 74: 5463 -5467 (1977); Beavis et al., U.S. Patent No. 5,288,644); automatic fluorescent sequencing; single-strand conformation polymorphism assays (SSCP); gel electrophoresis with limited denaturation (CDGE); denaturing gradient gel electrophoresis (S effield, VC et al., Proc. Nati, Acad. Sci. USA 86: 232-236 (1989)), mobility change analysis (Orita, M. et al., Proc. Nati, Acad. Sci. USA 86: 2766-2770 (1989)), analysis with restriction enzymes (Flavell et al., Cell 15: 25 (1978); Geever, et al., Proc. Nati. Acad. Sci. USA 78: 5081 (1981)); heteroduplex analysis; chemical decoupling cleavage (CMC) (Cotton et al., Proc. Nati, Acad. Sci. USA 85: 4397-4401 (1985)); RNase protection assays (Myers, R. M. et al., Science 230: 1242 (1985)); use of polypeptides recognizing decoupling of nucleotides such as the mutS protein from E. coli; PCR with allele specificity, for example. In one aspect of the invention, a diagnosis of a disease or condition associated with a ??? 3? 9 nucleic acid (eg, asthma) or a susceptibility to a disease or condition associated with a MAP3K9 nucleic acid can also be made. (for example, asthma) by expression analysis by quantitative PCR (kinetic thermal cycles). This technique, which uses TaqMan® assays, can evaluate the presence of an alteration in the expression or composition of the polypeptide encoded by a ??? 3? 9 nucleic acid or splice variants encoded by a nucleic acid ??? 3? 9. TaqMan® probes can also be used to allow the identification of polymorphisms and if a patient is homozygous or heterozygous. In addition, the expression of the variants can be quantified as physically or functionally different. In another aspect of the invention, the diagnosis of asthma or a susceptibility to asthma or a condition associated with a MAP3K9 gene can be made by examining the expression and / or composition of a? 3? 9 polypeptide, by a variety of methods , including enzyme-linked immunosorbent assays (ELISA), Western blots, immunoprecipitations and immunofluorescence. A test sample from an individual is evaluated with respect to the presence of an alteration in the expression and / or an alteration in the composition of the polypeptide encoded by a ??? 3? 9 nucleic acid, or with respect to the presence of a particular variant encoded by a ??? 3? 9 nucleic acid. An alteration in the expression of a polypeptide encoded by a MAP3K9 nucleic acid can be, for example, an alteration in the quantitative expression of the polypeptide (i.e., the amount of polypeptide produced); an alteration in the composition of a polypeptide encoded by a MAP3K9 nucleic acid is an alteration in the qualitative expression of the polypeptide (for example, the expression of an altered MAP3K9 polypeptide or a different splice variant). In a preferred aspect, the diagnosis of the disease or condition associated with the MAP3 9 nucleic acid or the susceptibility to a disease or condition associated with a ??? 3? 9 nucleic acid is made by detecting a particular splice variant. encoded by ??? 3? 9 nucleic acid or a particular model of splice variants. These two alterations may also be present (quantitative and qualitative). The term "alteration" in the expression of the polypeptide or composition, as used herein, refers to an alteration in the expression or composition in a test sample, as compared to the expression or composition of a polypeptide by a nucleic acid. of ??? 3? 9 in a control sample. A control sample is a sample that corresponds to the test sample (eg, it is from the same cell type) and comes from an individual that is not affected by susceptibility to a disease or condition associated with a nucleic acid. ?? 3? 9. An alteration in the expression or composition of the polypeptide in the test sample, compared to the control sample, indicates a susceptibility to a disease or condition associated with a MA.P3K9 nucleic acid. Similarly, the presence of one or more different splice variants in the test sample, or the presence of significantly different amounts of different splice variants in the test sample, compared to the control sample, indicates a disease or condition associated with a? 3? 9 nucleic acid with susceptibility to a disease or condition associated with a MAP3K9 nucleic acid. Various means can be used to examine the expression or composition of the polypeptide encoded by a λ 3 9 nucleic acid, including: spectroscopy, calorimetry, electrophoresis, isoelectric focusing, and immunoassays (e.g. David et al., U.S. Patent 4,376,110) such as immunoblotting (see also Current Protocole in Molecular Biology, particularly chapter 10). For example, in one aspect, an antibody capable of binding to the polypeptide (e.g., as described above), preferably an antibody with a detectable label, can be used. The antibodies can be polyclonal or more preferably monoclonal. An intact antibody or a fragment thereof (for example Fab or F (ab ') 2) can be used. The term "labeled", with respect to the probe or antibody, is intended to include direct labeling of the probe or antibody by coupling ( that is, physical association) of a detectable substance with the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include the detection of a primary antibody using a fluorescently labeled secondary antibody and the terminal labeling of a biotin DNA probe such that it can be detected with fluorescently labeled streptavidin. Western blot analysis using an antibody as described above that specifically binds to a polypeptide encoded by an altered MA.P3K9 nucleic acid or an antibody that specifically binds a polypeptide encoded by an undisturbed nucleic acid, or an antibody that specifically binds to a particular splice variant encoded by a nucleic acid can be used to identify the presence in the test sample of a particular splice variant or of a polypeptide encoded by a MAP3K9 nucleic acid. polymorphic or altered, or the absence in a test sample of a particular splice variant or of a polypeptide encoded by a non-polymorphic or non-altered nucleic acid. The presence of a polypeptide encoded by a polymorphic or altered nucleic acid, or the absence of a polypeptide encoded by a non-altered non-polymorphic nucleic acid, is diagnostic of a disease or condition associated with a MAP3K9 nucleic acid or a susceptibility to a disease or a condition associated with a nucleic acid of A.P3K9 (for example asthma), as is the presence (or absence) of particular splicing variants encoded by the ??? 3? 9 nucleic acid. In one aspect of this method, the level or amount of polypeptide encoded by a MAP3K9 nucleic acid in a test sample is compared to the level or amount of the polypeptide encoded by MAP3K9 in a control sample. A level or amount of the polypeptide in the test sample that is greater or less than the level or amount of the polypeptide in the control sample, such that the difference is statistically significant, indicates an alteration in the expression of the polypeptide encoded by the?.? 3? 9 nucleic acid and is diagnostic of a disease or condition associated with a ??? 3 nucleic acid? 9 or the susceptibility to a disease or condition associated with that MAP3K9 nucleic acid (eg, asthma). Alternatively, the composition of the polypeptide encoded by a? 3? 9 nucleic acid in a test sample is compared to the composition of the polypeptide encoded by ??? 3? 9 nucleic acid in a control sample (by example, the presence of different splice variants). A difference in the composition of the polypeptide in the test sample, compared to the composition of the polypeptide in the control sample, is diagnostic of a disease or condition associated with a nucleic acid of ??? 3? 9 or a susceptibility to a disease or condition associated with that MAP3K9 nucleic acid (e.g. asthma). In another aspect, both the level or amount and the composition of the polypeptide can be evaluated in the test sample and in the control sample. A difference in the amount or level of the polypeptide in the test sample, compared to the control sample; a difference in composition in the test sample, compared to the control sample; or both a difference in the amount or level and a difference in composition, indicates a disease or condition associated with a MAP3K9 nucleic acid or susceptibility to a disease or condition associated with that nucleic acid of ??? 3? 9. The invention furthermore relates to a method for the diagnosis or identification of an asthma susceptibility in an individual, by means of the identification of a risk haplotype (for example, a haplotype comprising a nucleic acid of ??? 3? 9 ). Haplotypes associated with MAP3K9, for example, those described in the examples section, describe a series of genetic markers ("alleles"). In a certain aspect, the haplotype may comprise one or more alleles, two or more alleles, three or more alleles, four or more alleles, or five or more alleles. Genetic markers are particular "alleles" in "polymorphic sites" associated with ??? 3? 9. A nucleotide position in which more than one sequence is possible in a population (a natural population or a synthetic population, eg, a library of synthetic molecules) is referred to herein as a "polymorphic site". When a polymorphic site has a single nucleotide length, the site is called a single nucleotide polymorphism ("SNP"). For example, if it is in a particular chromosomal location, one member of the population has an adenine and another member of the population has a thymine in the same position, then this position is a polymorphic site and, more specifically, the polymorphic site is a SNP. Polymorphic sites can allow differences in sequences based on substitutions, insertions or deletions. Each version of the sequence with respect to the polymorphic site is referred to herein as the "allele" of the polymorphic site. Thus, in the previous example, the SNP allows both an adenine allele and a thymine allele. Typically, a reference sequence refers to a particular sequence. Alleles that differ from the reference sequence are called "variant" alleles. For example, the reference sequence of MAP3 9 is described herein by SEQ ID NO: 1. The term "MA.P3K9 variant", as used herein, refers to a sequence that differs from SEQ ID. N °: 1 but otherwise is substantially similar.The genetic markers that constitute the haplotypes described herein are variants of ??? 3? 9. The variants of ??? 3? 9 that are used to determine the described haplotypes in this document of the present invention they are associated with asthma or asthma susceptibility Other variants may include changes that affect a polypeptide, for example, the polypeptide of ??? 3? 9. These sequence differences, when compared with a reference nucleotide sequence, they can include the insertion or deletion of a single nucleotide, or more than one nucleotide, resulting in a phase change, the change of at least one nucleotide, resulting in a change in the amino acid codi the change of at least one nucleotide, resulting in the generation of a premature stop codon; the deletion of several nucleotides, resulting in a deletion of one or more amino acids encoded by the nucleotides; the insertion of one or several nucleotides, such as by unequal recombination or gene conversion, resulting in an interruption of the coding sequence of a reading phase; duplication of all or part of a sequence; transposition; or a rearrangement of a nucleotide sequence, as described in detail above. These sequence changes alter the polypeptide encoded by the ??? 3? 9 nucleic acid. For example, if the change in the nucleic acid sequence causes a phase change, the phase change may produce a change in the encoded amino acids and / or may result in the generation of a premature stop codon., causing the generation of a truncated polypeptide. Alternatively, a polymorphism associated with asthma or an asthma susceptibility may be a synonym change in one or more nucleotides (i.e., a change that does not result in a change in the amino acid sequence). This polymorphism, for example, can alter splicing site, affect the stability or transport of the mRNA or otherwise affect the transcription or translation of the polypeptide. The polypeptide encoded by the reference nucleotide sequence is the "reference" polypeptide with a particular reference amino acid sequence, and the polypeptides encoded by variant alleles are referred to as "variant" polypeptides with variant amino acid sequences. Haplotypes are a combination of genetic markers, for example, particular alleles at polymorphic sites. The haplotypes described herein, for example, having markers such as those shown herein, are found more frequently in individuals with asthma than in individuals without asthma. Therefore, these haplotypes have predictive value for detecting asthma or an asthma susceptibility in an individual. The haplotypes described in this document are a combination of various genetic markers, for example, SPN and microsatellites. Therefore, haplotype detection can be performed by methods known in the art to detect sequences at polymorphic sites, such as the methods described above. RNA EXPRESSION LEVELS: In one aspect, the invention relates to methods for measuring RNA levels of MLK kinases (e.g. MLK1) using real-time quantitative PCR. The method includes obtaining a sample of cells from the patient, and determining the levels of RNA expression using probes with sequence specificity that hybridize with MLK kinase PCR products (e.g., MLK1) in RNA samples that are isolate from cells that have been exposed to specific cytokine activators that activate the JNK pathway (such as IL1b or TNFa) against the vehicle alone (ie without activation). In another aspect, the invention relates to methods that determine the role of MAP3k9 or its route-related genes by obtaining a sample of cells from patients with asthma or other respiratory or inflammatory disorders, determining RNA levels of ??? 3 ? 9 or their route related genes in cells exposed to specific pathway activators (such as ILlb or TNFa) or vehicle alone (without activation), and comparing them with the reference RNA levels of the gene in cells isolated from subjects without asthma or other inflammatory / respiratory disorders. In another aspect, the invention relates to methods for predicting the efficacy of an inhibitory drug, including obtaining a sample of cells from patients with asthma or other respiratory / inflammatory disorder, and determining RNA levels of MAP3K9 or its route related genes in cells isolated from patients who are taking the drug compared to those who are not taking the drug. In another aspect, the invention relates to methods for predicting the efficacy of an inhibitory drug, including obtaining a sample of cells from patients with asthma or other respiratory / inflammatory disorders, and determining the levels of? RNA. ?? 3? 9 or its related genes route after exposure of the cells to the inhibitory drug in vitro. SELECTION TESTS AND AGENTS IDENTIFIED BY THEMSELVES.

The invention provides methods (also referred to herein as "screening assays") for identifying the presence of a nucleotide that hybridizes with a nucleic acid of the invention, as well as for identifying the presence of polypeptide encoded by a nucleic acid of the invention. In aspect, the presence (or absence) of a nucleic acid molecule of interest (eg, a nucleic acid having significant homology to a nucleic acid of the invention) in a sample can be evaluated by contacting the sample with an acid nucleic acid comprising a nucleic acid of the invention under stringent conditions as described above, and then evaluating in the sample the presence (or absence) of hybridization. In one aspect, conditions of high stringency are appropriate conditions for selective hybridization. In another aspect, a sample containing the nucleic acid molecule of interest is contacted with a nucleic acid containing a contiguous nucleotide sequence (e.g., a primer or a probe as described above) that is at least partially complementary to a part of the nucleic acid molecule of interest (eg, a MA.P3K9 nucleic acid) and in the sample that has been contacted the presence or absence of hybridization is evaluated. In another aspect, the nucleic acid containing a contiguous nucleotide sequence is completely complementary to a part of the nucleic acid molecule of interest. In any of these aspects, all or a portion of the nucleic acid of interest can be subjected to amplification before performing the hybridization. In another aspect, the presence (or absence) of a polypeptide of interest, such as a polypeptide of the invention or a fragment or variant thereof, in a sample can be evaluated by contacting the sample with an antibody that hybridizes specifically with the polypeptide of interest (e.g., an antibody such as those described above) and then evaluating in the sample the presence (or absence) of binding of the antibody to the polypeptide of interest. In another aspect, the invention provides methods for identifying agents (e.g., fusion proteins, polypeptides, peptidomimetics, prodrugs, receptors, binding agents, antibodies, small molecules or other drugs, or ribozymes) that alter (e.g., increase or decrease ) the activity of the polypeptides described herein, or that interact in other ways with the polypeptides herein. For example, these agents can be agents that bind polypeptides described herein (eg, MAP3K9 binding agents); having a stimulatory or inhibitory effect, for example, on the activity of the polypeptides of the invention; or that change (e.g., increase or inhibit) the ability of the polypeptides of the invention to interact with "binding" agents (eg, receptors or other binding agents), or that alter post-translational processing of ??? 3? 9 polypeptide (e.g., agents that alter proteolytic processing to direct the polypeptide from where it is normally synthesized to another location in the cell, such as the cell surface; agents that alter proteolytic processing in such a way that more polypeptides are released from the cell, etc. In one aspect, the invention provides assays for screening candidate agents or assay agents that bind or modulate the activity of polypeptides described herein (or biologically active portions thereof), as well as agents identifiable by the assays.The assay agents can be obtained using any of the numerous strategies in comb library methods. known in the art, including: biological libraries; solid phase or phase-responsive parallel-phase libraries; synthetic library methods that require unwinding; the library method of "one pearl one compound"; and methods of synthetic libraries that use selection by affinity chromatography. The strategies of biological libraries are limited to polypeptide libraries, while the other four strategies are applicable to polypeptides, non-peptidic oligomers or libraries of small molecules of compounds (Lam, S., Anticancer Drug Des. 12: 145 (1997)) . In one aspect, to identify agents that alter the activity of a MAP3K9 polypeptide, a cell, cell lysate or solution containing or expressing a MAP3 9 polypeptide, or another splicing variant encoded by a ??? 3 gene 9 or a fragment derived therefrom (as described above), can be contacted with an agent to be tested; alternatively, the polypeptide can be contacted directly with the agent to be tested. The level (amount) of activity of ??? 3? 9 is evaluated (for example, the level (amount) of activity of ??? 3? 9 is measured, directly or indirectly) and compared with the level of activity in a control (i.e., the level of activity of the polypeptide of ??? 3? 9 or the active fragment or derivative thereof in the absence of the agent to be tested). If the level of activity in the presence of the agent differs by an amount that is statistically significant from the level of activity in the absence of the agent, then the agent is an agent that alters the activity of a polypeptide of ??? 3? 9. An increase in the activity level of ??? 3? 9 with respect to a control sample indicates that the agent is an agent that improves (is an agonist) the activity of ??? 3? 9. Similarly, a reduction in the activity level of ?? 3? 9 with respect to a control indicates that the agent is an agent that inhibits (is an antagonist of) the activity of ??? 3? 9. In another aspect, the activity level of an M &P3K9 polypeptide or a derivative or fragment thereof in the presence of the agent to be tested is compared to a control level that has been previously established. A level of activity in the presence of the agent that differs from the control level by an amount that is statistically significant indicates that the agent alters MAP3K9 activity. The present invention also relates to an assay for identifying agents that alter the expression of a ??? 3? 9 nucleic acid (eg, antisense nucleic acids, fusion proteins, polypeptides, peptidomimetics, prodrugs, receptors, binding agents , antibodies, small molecules or other drugs or ribozymes) that alter (e.g., increase or decrease) the expression (e.g., transcription or translation) of the gene or that interact in other ways with the nucleic acids described herein, as well as agents identifiable by the tests. For example, a solution containing a nucleic acid encoding a ??? 3? 9 polypeptide (eg, a ??? 3? 9 gene or nucleic acid) can be contacted with an agent to be tested. The solution may comprise, for example, cells containing the nucleic acid or cell lysate containing the nucleic acid; alternatively, the solution may be another solution comprising elements necessary for the transcription / translation of the nucleic acid. If desired, cells not suspended in solution can also be used. The level and / or expression pattern of ??? 3? 9 (for example, the level and / or model of ARWm or protein expressed, such as the level and / or pattern of different adjustment variants) is evaluated and compare with the level and / or expression pattern in a control (ie, the level and / or pattern of the expression of ??? 3? 9 in the absence of the agent to be tested). If the level and / or pattern in the presence of the agent differs by an amount or in a manner that is statistically significant from the level and / or pattern in the absence of the agent, then the agent is an agent that alters the expression of an asthma gene. . The increase in expression of ??? 3? 9 indicates that the agent is an agonist of the activity of MA.P3K9. In a similar way, the inhibition of MAP3K9 expression indicates that the agent is an antagonist of ??? 3? 9 activity. In another aspect, the level and / or pattern of polypeptide or polypeptides of AP3K9 (eg, different fit variants) in the presence of the agent to be tested, is compared to a level and / or control standard that have been previously established. A level and / or pattern in the presence of the agent that differs from the level and / or control pattern in a quantity or manner that is statistically significant indicates that the agent alters the expression of MA.P3K9. In another aspect of the invention, agents that alter the expression of a MAP3K9 nucleic acid or that interact in other ways with the nucleic acids described herein can be identified using a cell, cell lysate or solution containing a nucleic acid encoding the promoter region of the ??? 3? 9 gene or nucleic acid operably linked to a reporter gene. After contact with an agent to be tested, the level of expression of the reporter gene is evaluated (e.g., the level of mRNA or expressed protein) and compared to the level of expression in a control (i.e., the level of expression of the reporter gene in the absence of the agent to be tested). If the level in the presence of the agent differs by an amount or in a manner that is statistically significant from the level in the absence of the agent, then the agent is an agent that alters the expression of MAP3K9, as indicated by its ability to alter the expression of a gene that is operably linked to the promoter of the ??? 3? 9 gene. The increased expression of the indicator indicates that the agent is an agonist of the activity of ??? 3? 9. Similarly, the inhibition of the expression of the indicator indicates that the agent is an antagonist of the activity of Δ 3 9. In another aspect, the level of expression of the indicator in the presence of the agent to be tested is compared to a level of control that has been previously established. A level in the presence of the agent that differs from the control level by an amount or in a manner that is statistically significant indicates that the agent alters the expression. Agents that alter the amounts of different splice variants encoded by a MAP3K9 nucleic acid (eg, an agent that improves the activity of a first splice variant and that inhibits the activity of a second adjustment variant) as well as agents that are activity agonists of a first splice variant and activity antagonists of a second splice variant, can be easily identified using these methods described above. In other aspects of the invention, assays can be used to evaluate the impact of a test agent on the activity of a polypeptide in relation to a ??? 3? 9 binding agent. For example, a cell that expresses a compound that interacts with a polypeptide of γ-3? 9 (referred to herein as "? 3? 9 binding agent", which may be a polypeptide or other molecule that interacts with a ??? 3? 9 polypeptide, such as a receptor) is contacted with a MAP3K9 in the presence of a test agent and the ability of the test agent to alter the interaction between the ??? 3? 9 and the MAP3K9 binding agent. Alternatively, a cell lysate or a solution containing the?. 3? 9 binding agent can be used. An agent that binds the 3 3 9 or the binding agent of AP3K 9 can alter the interaction by interfering with or improving the 3 3 9 ability to bind or associate or otherwise interact. with the union agent of ??? 3? 9. The determination of the ability of the test agent to bind with a MAP3 9 nucleic acid or a ??? 3? 9 binding agent can be performed, for example, by coupling the test agent with a radioisotope or enzymatic label of such an agent. Thus, the binding of the test agent to the polypeptide can be determined by detecting the agent labeled with 125 I., 35S, 14C or 3H, directly or indirectly, and the radioisotope can be detected by direct counting of radioemission or by scintillation counting. Alternatively, the assay agents can be labeled enzymatically, for example, with horseradish peroxidase, alkaline phosphatase or luciferase, and the enzyme label can be detected by determining the conversion of an appropriate substrate into a product. It is also within the scope of this invention to determine the ability of a test agent to interact with the polypeptide without labeling any of the interacting agents. For example, a microphysiometry can be used to detect the interaction of a test agent with a Δ3 9 polypeptide, a Δ3 9 -binding agent without labeling the test agent, the Δ3 polypeptide. 3? 9 or the MA.P3K9 binding agent. McConnell, H. M. et al., Science 257: 1906-1912 (1992). As used herein, a "microphysiometer" (e.g., Citosensor ™) is an analytical instrument that measures the rate at which a cell acidifies its environment using a light-sensitive potentiometric detector (LAPS). Changes in this rate of acidification can be used as an indicator of the interaction between the ligand and the polypeptide. In this way, these receptors can be used to select compounds that are agonists or antagonists for use in the treatment of a susceptibility to a disease or condition associated with a gene or nucleic acid of ??? 3 9, or to study a susceptibility to a disease or condition associated with a ??? 3? 9 (for example asthma). Drugs could be designed to regulate the activation of MAP3K9 which in turn can be used to regulate signaling pathways and downstream gene transcription events. In another aspect of the invention, assays can be used to identify polypeptides that interact with one or more MAP3K9 polypeptides, as described herein. For example, a yeast double hybrid system such as that described by Fields and Song (Fields, S. and Song, O., Nature 340: 245-246 (1989)) can be used to identify polypeptides that interact with one or more polypeptides. of ??? 3? 9. In this yeast double hybrid system, vectors are constructed based on the flexibility of a transcription factor having two functional domains (a DNA binding domain and a transcription activation domain). If the two domains are separated but fused to two different proteins that interact with each other, activation of transcription and transcription of specific markers (eg, nutritional markers such as His and Ade, or color markers such as lacZ) can be achieved to identify the presence of interaction and activation of transcription. For example, in the methods of the invention, a first vector is used that includes a nucleic acid encoding a DNA binding domain and also a MAP3K9 polypeptide, a splice variant or a fragment derived therefrom, and a second vector that includes a nucleic acid encoding a transcription activation domain and also a nucleic acid encoding a polypeptide that can potentially interact with the MAP3K9 polypeptide, splice variant or fragment or derivative thereof (e.g. a MAP3K9 polypeptide binding or receptor agent). Incubation of yeasts containing the first vector and the second vector under appropriate conditions (eg, matching conditions such as those used in the Matchmaker ™ system of Clontech (Palo Alto, California, USA)) allows the identification of expressing colonies the markers of interest. These colonies can be examined to identify polypeptides that interact with the polypeptide of ??? 3 9 or the fragment or derivative thereof. These polypeptides can be useful as agents that alter the expression activity of a ??? 3? 9 polypeptide as described above. In more than one aspect of the above test methods of the present invention, it may be desirable to immobilize the gene or the nucleic acid of ??? 3? 9, the polypeptide of MA.P3K9, the binding agent of MAP3K9 or other components of the assay on a solid support, to facilitate the separation of the completed forms of the uncomplexed ones of one or both polypeptides, as well as to accommodate the automation of the assay. The binding of a test agent to the polypeptide, or the interaction of the polypeptide with a binding agent in the presence and absence of a test agent, can be carried out in a container suitable for containing the reagents. Examples of these containers include microtiter plates, test tubes and microcentrifuge tubes. In one aspect, a fusion protein (e.g., a glutathione-S-transferase fusion protein) can be provided which adds a domain that allows a MAP3K9 nucleic acid, MAP3K9 polypeptide, or a binding agent of ??? 3? 9 is attached to a matrix or other solid support. In another aspect, modulators of the expression of nucleic acid molecules of the invention are identified in a method in which a cell, cell lysate or solution containing a MAP3K9 nucleic acid is contacted with a test agent and determined the expression of the appropriate mRNA or polypeptide (e.g., splice variants) in the cell, cell lysate or solution. The level of expression of the appropriate mRNA or polypeptide or polypeptides in the presence of the test agent is compared to the level of expression of the mRNA or polypeptide or polypeptides in the absence of the test agent. The assay agent can then be identified as an expression modulator based on this comparison. For example, when the expression of the mRNA or polypeptide is higher (from a statistically significant point) in the presence of the test agent than in its absence, the test agent is identified as a stimulator or enhancer of mRNA or polypeptide expression. Alternatively, when the mRNA or polypeptide expression is lower (from a statistically significant point of view) in the presence of the assay agent than in its absence, the test agent is identified as an inhibitor of the mRNA or polypeptide expression. The level of mRNA or polypeptide expression in the cells can be determined by methods described herein to detect mRNA or polypeptides. This invention also relates to new agents identified by the screening assays described above. Accordingly, the additional use of an agent identified as described herein in an appropriate animal model is included within the scope of this invention. For example, an agent identified as described herein (for example, an assay agent that is a modulating agent, an antisense nucleic acid molecule, a specific antibody or a polypeptide binding agent) in an animal model for determine the efficacy, toxicity or side effects of treatment with said agent. Alternatively, an agent identified as described herein may be used in an animal model to determine the mechanism of action of said agent. In addition, this invention relates to uses of new agents identified by the screening assays described above for treatments as described herein. In addition, an agent identified as described herein can be used to alter the activity of a polypeptide encoded by a MAP3K9 nucleic acid, or to alter the expression of a ??? 3? 9 nucleic acid, by contacting the polypeptide or the nucleic acid, (or by contacting a cell comprising the polypeptide or the nucleic acid) with the agent identified as described herein. PHARMACEUTICAL COMPOSITIONS OF NUCLEIC ACID The present invention also relates to pharmaceutical compositions that purchase nucleic acids described herein., particularly nucleotides encoding the polypeptides described herein (e.g., a MAP3K9 polypeptide); which comprises polypeptides described herein and / or which comprises other cutting variants? splices encoded by a ??? 3? 9 nucleic acid; and / or an agent that alters (enhances or inhibits) the expression of the Δ 3 κ nucleic acid or the activity of the MAP3K9 polypeptide as described herein. For example, a polypeptide, protein (e.g., a MAP3K9 nucleic acid receptor), an agent that alters the expression of a MAP3K9 nucleic acid, or a binding agent or? 3 binding molecule? , fragment, fusion protein or prodrug thereof, or a nucleotide or nucleic acid construct (vector) comprising a nucleotide of the present invention, or an agent that alters MAP3K9 polypeptide activity, can be formulated with a carrier or physiologically acceptable excipient for preparing a pharmaceutical composition. The vehicle and the composition can be sterile. The formulation must be adapted to the mode of administration.

Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (e.g., NaCl), saline, buffered saline, alcohols, glycerol, ethanol, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates, etc. such as lactose, amylose or starch, dextrose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc., as well as combinations thereof. The pharmaceutical preparation, if desired, may be mixed with auxiliary agents, for example, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavors and / or aromatic substances and the like which do not react in a harmful way with the active agents. ' If desired, the composition may also contain minor amounts of wetting or emulsifying agents, or agents for buffering the pH. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation or powder. The composition can be formulated as a suppository, with binders and traditional carriers such as triglycerides. The oral formulation may include conventional vehicles such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinylpyrrolidone, sodium saccharin, cellulose, magnesium carbonate etc. Methods of introducing these compositions include, but are not limited to, intradermal, intramuscular, intraperitoneal, intraocular, intravenous, subcutaneous, topical, oral and intranasal. Other suitable methods of introduction may also include gene therapy (as described below), rechargeable or biodegradable devices, particle acceleration devices ("gene guns") and slow release polymeric devices. The pharmaceutical compositions of this invention can also be administered as part of a combinatorial therapy with other agents. The composition can be formulated according to routine procedures as a pharmaceutical composition adapted for administration to humans. For example, compositions for intravenous administration are typically solutions in sterile isotonic aqueous buffer. When necessary, the composition may also include a solubilizing agent and a local anesthetic to eliminate pain at the site of injection. Generally, the ingredients are supplied separately or mixed in a unit dosage form, for example, as a dry lyophilized powder or a waterless concentrate in a hermetically sealed container such as a blister or sachet indicating the amount of active agent. When the composition is to be administered by infusion, it can be distributed with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose / water. When the composition is administered by injection, a sterile water ampoule for injection or saline can be provided so that the ingredients can be mixed prior to administration. For topical application, non-sprayable forms, viscous to semi-solid or solid forms comprising a vehicle compatible with topical application and having a dynamic viscosity preferably greater than that of water may be employed. Suitable formulations include, but are not limited to, solutions, suspensions, emulsions, creams, ointments, powders, enemas, lotions, suns, linings, ointments, aerosols, etc. which, if desired, are sterilized or mixed with auxiliary agents, for example preservatives, stabilizers, wetting agents, buffers or salts to influence the osmotic pressure etc. The agent can be incorporated into a cosmetic formulation. For topical application, sprayable aerosol preparations are also suitable where the active ingredient, preferably in combination with a solid or liquid inert carrier material, is packaged in a pressure flask or in a mixture with a volatile, normally gaseous, pressurized propellant, for example pressurized air. The agents described herein can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as the hydrochloric, phosphoric, acetic, oxalic, tartaric acid derivatives, etc., and those formed with free carboxyl groups such as the sodium, potassium, ammonium, calcium derivatives, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. The agents are administered in a therapeutically effective amount. The amount of agents that will be therapeutically effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition and can be determined by conventional clinical techniques. In addition, in vitro or in vivo assays can optionally be used to help identify optimal dosage ranges. The precise dose to use in the formulation also. It will depend on the route of administration and the severity of the symptoms, and should be decided according to the criteria of a doctor and the circumstances of each patient. Effective doses can be extrapolated from dose-response curves derived from test systems in animal or in vitro models. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with said container may be an indication in the manner prescribed by the governmental agency that regulates the manufacture, use or sale of pharmaceutical or biological products, which reflects the approval by the manufacturing, use or sale agency for human administration. The package or kit may be labeled with information regarding the mode of administration, sequence of administration of the drug (eg, separate, sequential or concurrent) or the like. The package or kit may also include means to remind the patient to take the therapy. The package or kit may be a single unit dosage of the combination therapy or may be a plurality of unit dosages. In particular, the agents can be separated, mixed in any combination, present in a single vial or tablet. Agents mounted in a blister or other distribution means are preferred. To stop the purposes of this invention, it is understood that unit dosage means a dose that depends on the individual pharmacodynamics of each agent and administered in dosages approved by the FDA in conventional time courses. The present invention is illustrated below by means of the following examples, which are not intended to be limiting in any way. All references cited in this document are incorporated by reference in their entirety. EXAMPLES EXAMPLE 1 Population of Patients The original list of patients contained the names of more than 7,000 patients seen in private clinics or outpatient allergist clinics practicing in the allergy / lung divisions of the National University Hospital of Iceland during the years of 1977 to 2001 (ECRHSG; 1997). For this study, patients with asthma diagnosed by a physician who were being treated with asthma drugs and who were related to at least one other patient in the study who included 6 meiotic events (6 meiotic events separate second cousins) were selected as revealed by a computerized genealogical database. The ages ranged from 12 to 70 years (average 39.3 years) and 62% were female. Information was collected regarding age at diagnosis, medications, hospital administrations and family history of atopy and asthma. The diagnosis of asthma and atopy was reconfirmed clinically in the study by means of a new physical examination, skin test reactivity measurements to 12 aeroallergens (including birch, grass, Rumex crispus, cat, dog, horse, Cladosporium, Mucor, Alternarla, Dermatophagoides pteronyssinus, D. farinae and Lepidoglyphus destructor), total IgE levels, and pulmonary function tests (PFT). ? less than the forced expiratory baseline volume by 1 s (FEV1) < 70% of the predicted value (based on sex, height, and race), a methacholine exposure test (MCh) was conducted. Phenotype, PFT and methacholine assays were performed according to the ATS guidelines (Cockcroft, et al., 1977; Palmquist, et al., 1988). The patients were considered atopic if their reaction in the prick skin test was positive (ie = 3 mm or = 50% of the positive control response of histamine). The diagnosis of asthma in Iceland is based on the diagnostic criteria indicated by the NHLB and the American Thoracic Society (National Institutes of Health 1997, American Thoracic Society 1995) and includes any of the following measures: • Patient who has recurrent symptoms of coughing and sneezing for more than 2 years and demonstrating clinical response to bronchodilator therapy (measured by an> 15% increase in after treatment with the bronchodilator). • Patient having reduced FEV1 (FEV1 <80%) initially before therapy with a bronchodilator and showing improvement > 15% in FEV1 after therapy with the bronchodilator. • Patient who has recurrent symptoms of coughing and sneezing and in the methacholine exposure trial, conducted in accordance with the guidelines of the ATS (American Thoracic Society 1995), has a reduction > 20% in FEV1 at methacholine concentrations < _ 8 mg / 1. The severity of asthma was determined by the combination of signs and symptoms, PFT, MCh values, and need for therapy, based on these criteria, approximately 90% of patients were considered with mild to moderate asthma and 10% with severe asthma. A FEV1 > 80% expected was considered normal. Before obtaining the blood samples, all patients included in the study were re-examined by the same two allergists who confirmed the asthma phenotype and level of severity and monitored the measurements of total IgE levels, spirometry and skin test. before obtaining blood samples. In this study, a reduction in FEV1 of 20% plus at a MCh concentration of 8 mg / 1 or less is considered a positive exposure test. The participation rate of patients for the study exceeded 90%. All patients signed an informed consent, donated blood samples and completed a detailed medical questionnaire in all trials necessary for proper phenotyping. The study was approved by the data protection commission of Iceland and the National Bioethics Committee. The personal identities of the patients and their family members were subsequently hidden by the data protection commission of Iceland (Gulcher et al., 2000). All blood and DNA samples were also coded in the same way. And all the participants were asked, by means of a questionnaire, if they had been diagnosed with asthma and / or atopy and if they were receiving drugs to treat themselves if that was the case.

The names of the drugs were registered and it was confirmed that they were medications against asthma and / or against allergy. Blood was also collected from close family members and Index cases to increase the information available for the linkage analysis. The lung function of all the participants had been measured at the time of blood extraction for the study.

Genealogía deCODE has built a computerized genealogical database with more than 650,000 names that includes the 285,000 inhabitants of Iceland and most of their ancestors (Gulcher and Stefansson 1998). The database has a connectivity of more than 95% in the 20th century and 86% in the 19th century. Its maternal connections have an accuracy of 99.3% as measured by mitochondrial polymorphisms of individuals related by the mother (Helgason et al., 2000). The genealogical database was used to group patients into lineages. The genealogical database is reversibly hidden by the data protection commission of Iceland before being used in the laboratory of the present applicants (Gulcher and Stefansson 1998). Recursive algorithms with hidden personal identifiers are used to find all the ancestors in the database that are related to any member of the patient list within a given number of generations ago. Then the grouping function identifies the ancestors that are common to any two or more members of the patient list. Genotyping Five hundred and ninety-six patients were genotyped with asthma belonging to 175 families, in which each patient was related to at least one other patient in the study and included 6 meiotic events. DNA samples from the 596 patients and 538 relatives were successfully genotyped using 976 specific fluorescence-labeled primers with an initial mean separation of 3-4 cM at the genome level. A series of microsatellite selections was created based in part on the ABI linkage marker selection series (v2) and the ABI linkage marker interleave series (v2) in combination with more than 500 custom made markers. All markers were extensively tested for multiple PCR reactions. The PCR amplifications were prepared and assembled using Cyberlab robots. The volume of reaction used was 5"μ? And for each PCR reaction 20 ng of genomic DNA were amplified in the presence of 2 pmol of each primer, 0.25 U of AmpliTag Gold, 0.2 mmol / 1 of dNTP and 2.5 mmol / l of MgCl2 The PCR conditions used were 95 ° C for 10 minutes, then 37 cycles of 15 s at 94 ° C, 30 s at 55 ° C and 1 minute at 72 ° C. supplemented with the internal size standard and the groups were separated and detected in an Applied Biosystems model 3700 sequencer using the Genescan v3.0 spike software.The alleles were automatically called with the DAC program (Fjalldal et al., 2001) , and the program, DecodeGT, was used to fractionate according to the quality and edit the so-called genotypes (Palsson et al., 1999) In regions demonstrating linkage using the series of structural markers, the marker density was further increased ( that is, to perform a fine mapping of the locus) by microsatellite markers a to obtain coverage of 0.2 cM in the average in those regions. Statistical Analysis An association scan was performed at the genome level using a structural map of 976 microsatellite markers. The data were analyzed using the Allegro program (Gudbj artsson et al., 2000) and the statistical significance was determined by applying allele methods shared only in those affected (without specifying any particular inheritance model). The Allegro program, a linkage program developed in deCODE genetics, calculates LOD values based on multi-point calculations (Gudbjartsson et al., 2000; Kruglyak et al., 1996; Kong and Cox 1997) and is available for free use by non-commercial users by sending an e-mail to allegro@decode.is. The linkage analysis strategy uses the Spairs scoring function (Kruglyak et al., 1996, Whittemore and Halpern 1994), the exponential shared allele model (Kong and Cox 1997), and a weighting scheme of the family that is half way, in the logarithmic scale, between the weighting of each affected pair equally and the weighting of each family equally. All genotyped individuals who are not affected are treated as "unknowns". The values of P are calculated based on the large sample theory; Zlr = V (2 loge (10) LOD) is roughly distributed as a standard normal distribution under the null-null hypothesis (Kong and Cox 1997) and the observed LOD score is compared to its sampling distribution of complete data under the null hypothesis (Gudbjartsson et al., 2000). The measure of information that part of the result of the Allegro program is used (Nicolae 1999) and is closely related to a classical measure (Dempster et al., 1977). The information is equivalent to zero if the marker genotypes are completely non-informative and is equivalent to one if the genotypes determine the exact amount of allele shared by the descendants among the affected relatives. The order of the marker and the positions for the preparation of the structural mapping were obtained using a high density genetic map created in deCODE. We analyzed data from 146 nuclear families in Iceland (brothers with genotypes for two to seven siblings and the two parents) providing 1257 meiosis to estimate genetic distances. For comparison, the distances in the Marshfield genetic map were estimated based on 188 meiosis. The distances between markers in the peak region after enrichment with four markers were estimated using an adaptation of the EM algorithm (Dempster 1977) within Allegro. Association Analysis A list of more than 7,000 patients from the National University Hospital of Iceland was compared to the genealogical database. In the present study, patients with asthma diagnosed by a physician who were related by 6 or fewer meiotic events with other patients with asthma were included (6 meiotic events separate second cousins). These were 596 patients from 175 families with asthma. In the present study, more than 30 families had at least 6 affected members. Two of these families used in the analysis are presented in FIG 2. The demographic data of the patients, the geometric average values of IgE, the pulmonary function tests (including the percentage of predicted FEV1 and FEVl / FEVC ratio), the results of the methacholine challenge test and the skin test results of the most common aeroallergens in Iceland are shown in FIG. 4. 73% of the patients were atopic as defined by a positive reaction in the skin test.

More than 400 of the study patients underwent airway reactivity testing using MCh exposure. As shown in FIG. 4, although 67% of the patients tested had a greater than 20% reduction in FEV1 at a concentration of MCh less than 2 mg / 1, more than 90% of the patients gave a positive result at a MCh concentration of 8 mg / 1 or less. This would be consistent with a moderate to severe hyperresponsiveness of the respiratory tract in 2/3 of the asthma study population of the present study. The spirometric values presented in FIG. 4 are those obtained during the study, at the time when most patients had stable asthma and were undergoing a complete therapy; however, all these patients have previous spirometric values with FEV1 < 80% expected at one or more previous time points on your medical cards (data not shown). The reversibility of the bronchodilator was tested in selective cases including patients who had negative results from exposure to MCh and in whom the physician determined that the trial was necessary to confirm the asthma phenotype. Thirty-three percent of patients had a history of having smoked more than one pack-year. Of these, 47 percent had smoked less than 10 pack-years. The possibility that some of the study participants who were smokers had mild coexisting COPD can not be excluded; however, only 0.5% of study patients who were 55 or older had smoked more than 20 pack-years (FIG 4). In contrast, all subjects in the study have asthma as defined by the criteria of the ATS (American Thoracic Society, 1995); which is the phenotype used for this study, minimizing in this way the potential to confuse the effects of COPD. Five hundred ninety-six patients and 538 of their unaffected relatives (ie, non-asthmatics) were genotyped using 976 microsatellite markers in a linkage scan at the genome level. The disease status of the relatives was obtained by a questionnaire. The data were analyzed and the statistical significance was determined by applying allele methods shared only in those affected (which does not specify any particular inheritance model) (Gulcher et al., 2001). As the association exploration was performed only on those affected, it is not possible to confuse the effect of the relatives even if an affected relative was not identified in the group. The genomic region that showed the strongest evidence of linkage with the asthma phenotype was chromosome 14q24 with an LOD score of 2.66 (simple test test p = 2.16 x 10"4). the identity by alleles shared among ancestors in the region was less than 85% (ie, 0.77%), which is less than preferred, another 34 microsatellite markers were added under this peak to ensure that the results are a true reflection of the information contained in the material, this increased the information content in the peak to more than 95% and produced a lod score of 4.00 (individual test test p = 8.70 x 10 ~ 6). Significant on a genome-wide basis, even allowing the assay of multiple markers, and corresponds to a P-value adjusted at the genome level of less than 0.05 (Krugylak and Lander 1996.) This locus was termed locus one of asthma ( ASI) .The peak of the locus is centered in the Arcs D14S588 and D14S603, which are separated by 84 kb. The locus, defined by a reduction of approximately 1.0 in the LOD score, is between the centromeric and telomeric markers D14S1069 and D14S289, respectively. The segment with a reduction of 1-LOD is approximately 3.9 centimorgans and is estimated to correspond to approximately 3.0 million bases. The genome scan shows for the first time a significant linkage of asthma to markers located on chromosome 14q24. It should be noted that an association to this locus has been previously demonstrated by researchers from the United Kingdom (Mansur 1999) and the United States (The Collaborative Study of the Genetics of Asthma 1997). Chromosome 14q24 contains many genes that may contribute to asthma susceptibility, including genes encoding EGF response factor-1, glycol class-I phosphatidylinositol, secreted modular calcium-binding protein 1, disintegrin and metalloproteinase domain 20 and 21, and the mediator of transcription regulation of RNA polymerase II, to name a few. EXAMPLE 2 Evaluation of MAP3 9 expression in human respiratory tract tissue: Lung tissue was studied in 2 patients with asthma and 2 controls (all four were smokers who developed lung cancer and needed resection). Airway tissue was isolated from a non-cancerous (healthy) part of its lower respiratory tract and examined for MAP3K9 expression using RT-PC. In these two patients, a 10-fold increased expression of the β-isoform b of? 3 9 9 was observed (see FIG 9) compared to the controls. EXAMPLE 3. Evaluation of the expression of ??? 3? 9 in peripheral blood mononuclear cells (PBM): The expression of ??.? 3? 9 in PBM cells from patients with asthma versus controls was examined by the methods described above and a significantly increased expression was observed for isoform b (variant b) of the gene in patients compared to controls (numbers are indicated in FIG 10). In conclusion, the evidence from linkage and association studies with case-controls shows that the gene of ??.? 3? 9 is the gene responsible for asthma, judging by positional cloning. In addition, tissue tests of the airways of an asthmatic patient and PBM cells of patients with asthma demonstrate that the expression of isoform b (variant b) of the MAP3K9 gene is increased with respect to the control samples. Collectively, these tests confirm the role of the ??? 3? 9 gene as a therapeutic target for asthma.lotype analysis Haplotype Marker type haplotype Haplotype hapl DG14S205 microsatellite -4 hapl DG14S428 microsatellite 0 hapl microsatellite D14S1002 e 10 hapl DG14399 microsat lite 13 hapl DG14S404 microsatellite 0 hap2 DG14S428 microsatellite 0 hap2 D14S1002 microsatellite 10 hap2 DG14S399 microsatellite 13 hap2 DG14S404 microsatellite 0 ha D14S251 microsatellite 2 hap3 DG14S1300 microsatellite 0 hap3 DG14S420 microsatellite 4 hap3 DG14S1266 microsatellite 2 hap4 DG14S1266 microsatellite -2 hap4 DG14S462 microsatellite 6 hap4 DG14S448 microsatellite 14 hap4 DG14S205 microsatellite 4 ha 5 D14S1002 microsatellite 10 hap5 DG14S399 microsatellite 13 hap5 DG14S404 microsatellite 0 hap6 DG14S399 microsatellite 13 hap6 DG14S404 microsatellite 0 hap6 DG14S406 microsat lite 4 hap7 DG14S399 microsatellite 13 hap7 DG14S404 microsatellite 4 No. of Alleles: For the microsatellite alleles: the CEPH samples (CEPH genomic deposit No. 1347-02) are used as references, the minor allele of each microsatellite in this sample is set to 0 and the other alleles in other samples are List in relation to this reference. Thus, allele 1 is a larger bp than the lower allele in the CEPH sample, allele 2 is 2 bp larger than the lower allele in the CEPH sample, allele 3 is 3 bp larger than the lower allele in the CEPH sample, the 4 allele is 4 bp higher than the lower allele in the CEPH sample, the -1 allele is a shorter bp than the lower allele in the CEPH sample, the -2 allele is 2 bp shorter than the lower allele in the CEPH sample and so on. Table 2 Frequencies of alleles and meaning of 'haplotypes that capture in the relative risk of the asthma gene,? 3? 9. Hap value N ° freq. Frequency frec. X2 info No. of p r af af with H0 with hap 0, 001 5, 913 169 0, 067 134 0, 01 0, 042 10, 3 0, 813 1 2 49 hap 0, 000 10, 400 179 0, 062 135 0, 00 0, 039 12, 9 0, 810 2 3 6 54 hap 0.001 11598, 5 111 0, 032 120 0.00 0, 013 9.74 0.939 3 8 00 0 4 ap 0.002 9819.48 162 0, 028 107 0, 00 0, 017 9,20 0, 999 4 4 0 0 3 hap 0,000 150,592 185 0, 060 139 0, 00 0, s40 14, 9 0,606 5 1 0 79 hap 0, 001 2, 784 184 0,135 138 0, 05 0,103 10,4 0, 832 6 2 3 78 hap 0.000 2, 83183 196 0, 1458 141 0, 05 0, 1103 11, 9 0, 829 7 6 26 6858 77 352 311 8 ? ° Hap - Haplotype number val-p - value of p r - relative risk No. af - number of affected (patients) frec. af - frequency of (haplotype) in affected N ° with - number of controls frec. with - frequency (haplotype) in frequency controls. H0- frequency (of the haplotype) under the null hypothesis (in affected and controls) X2 - chi square Info - information content Table 3 MarcaPos. of the Primer Pair SEC sequencers in ID NCBI Build 33 N °: DG14S205 chrl4: F: CATGGGTAAGAGAAAGGGAACA 3 69.250345- R.: AGCTCCCAGCATAGTTCCAG 4 69.250499 DG14428 chrl: F: GGCAACGTTGACTTCCAGTA 5 69.267406-: CAGCCCAGAGTTCAAGACG 6 69.267644 D14S1002 Chx: F: AGATTTTGGATGTATCAGGC 7 69. 291050- R: CAGAAGCAATAGGATGGATG 8 69.291217 DG14S399 c r: F: GTGTCAGCAACTGCACGATT 9 69. 316671- R: GGCATGGTGGTACATGTCTG 10 69.317039 DG14S404 Chr1: F: AAAGCTCAGCCAGAGTCTCAA 11 69. 3400520- R: GGCCTTACAGTGCCTAGCAA 12 69. 340691 D14S251 CHR14: F: AAAGGATGAACTATTGGTGC 13 69. 115521- R-. TTTACTTGTACCCAGTATG NTCTG 14 69. 115940 DG14S1300 Chrl4: F: TGAAAGGGAGCCTACGTCTG 15 69.134571- R: TGAATGCGGGAGTAAATAAATG 16 69.134971 DG14S420 Chr: F: AGGGTGAGAGACTGCTCTGG 17 69. 167270- R: GGAGGGAGGGAAGAAAGAGA 69.167488 DG14S1266 Chrl4: F: GCCAAAGAGAGAGGCAGGTA 19 69. 182501- R: CCAGATTGCTTCCCTTGGT 20 69. 182636 DG14S462 Chrl: F: CCAGGGAAACTAATTCATTCACA 21 69.196223- R: TCCTAAGGAAACTTGCCATATACTTT 22 69.196387 DG14S448 Chrl4: F: CAAAGGATTAGCTTTACGGTATGT_ 23 69. 216835- R: TCATGGCTGTGGGACAGTAG_24_69217046 ÜG14S406 Chrl4:: CAAAGGATTAGCTTTACGGTATGT_ 25 69. 216835- R: TCATGGCTGTGGGACAGTAG_26_69. 217046 Table 4 SEC ID CEPH (pb) N °: Amplifier 165/165 27 CATGGGTAAGAGAAAGGGAACATTTACATTTTGGGATCACGTAAGTAAAC CAGTTCACATGATATttcattcattcattcattcattcattcattcCTTT TATCTATacatttattgaggaccctactatgcacctggaactatgctggg agct 244/244 28 GGCAACGTTGACTTCCAGTAAGAAAGGTTCTCTGATCTTTTTTTCTCTTT TCTTTTCTTTTCTTTTCTTTTCCTTTCTTTTCTTTTCTTTTCTTCCAGGG TCTCAGTTTGTTGTCCAGGCCAGAGTGCAGTGGCGCAATCTCGGCTCACT GCAGCCTCAACATCCTAGGCTCAAGCCATCCTCCCACCTCACCCTCCCGA GTAGCTGGAAGTACAGGCTCGTCTTGAACTCTGGGCTG 157/157 29 AGCTCTNCCTGGTTCACTAGCAGACTGTCTTTGGACTTGAACTGAAACCC TTTCCTACATCTCTGGCCAGTNAGCCTÍICCGTGTCAGATTTTGGATGTAT CAGGCTTCCACAATTGGGTGAGGCGATTCCTTTAGAATAAATCTCTTTTA CACACACACACACACACACACACGTGTACCCACACACACGTGCATATGCA CACACACACACGNACACATCCATCCTATTGCTTCTGTTTCTNTGGAGA1TC CCTKATACAAATTNGCATGTCATTAAATATCACTAGTGTTGTAGCT 375/379 30 gcaattctattatctagtacaactttagcaagagaatttaaagtctgtta gtgtcagcaactgcacgatttctccctattcagccagtagggaatctaga tgcaaccatagcctttgcaatagaatctgctatagagatgattataagga atttccttccttccttccttccttccttccttccttccttccttctttct ttctttctttctttctttctttctttctttctttctttctttcttctttc tttttctttctttctttccttctttGAGACAGGGTCTTGctcaacctccc aggctcaagcaattctccctacctcagtctcccaagtggctgggagtaca gacatgtaccaccatgcc 174/178 31 AAAGCTCAGCCAGAGTCTCAATTCCTATAACCTCCTTCccatccatccat tcatccatccatctatccatccatccatccatccatccatccatccatcc aGCTGATGGAttaataaatttatatcaagcacttactctgagcaaggcat tttgctaggcactgtaaggcc 298/300 32 CTACAGAGCAATTAAAAAAGGATGAACTATTGGTGCATTTAACAACTTGG ATGCATTGCAAGGAAATTATGCTGAGTGTAAAAAGCGCCTTCCAAAGGAT TTCATGCTATGTGATTCCATTTATATAATATTTTCAAAATGACAAAATTT TAAAAATAGAGAACAGGTTAGCAGTTGTCAGGGGTTAAAGAGGAAGTGGT GGGACAGGAAGGAGATGATAGAGGAACCTACACACGATAAAACTGTATAT AACTAAACACACACACGCACACACACACACACACACACANACAGANACAT ACTGGGTACAAGTAAAGCT 407/407 33 TGAAAGGGAGCCTACGTCTGACCCCTAGACTTGCCTTGTTTTCCAAGTCt cacagaatattagggctggacagaagcttgaagctcagtagttcaaccct cttttctttcagatgagagatcaagtccagagatgattaagagatttatt caaggtcacacagatagtaagcagcaaatctgaactggaactcaggtcag tttcctgacaacaaacaatactctttccactgaaccaAAGTATACTTCCA AAatatatatacacacatatatgtatatgtgtgtacgtgtgtgtatatat atatatatgtgtgtgtgtgtgtatatatatatatGCTGTAAAATTGTTCT CTTCTAAAGAAAGAAGGAGCATAGTACTCATTTATTTACTCCCGCATTCA 243/243 34 AGGGTGAGAGACTGCTCTGGAGCTCAGTGAGGGACCTCAGGGTTACACAA GAAGGGACTCTGCGCTGGGTTCCAGGCCTGATTCTTTTATTTTCTCTTTT TCTTTCTTTCTCTTTCTTTTTCTTTCTTTCTTTTCTTTCTTTCTTTCTTT CTTTCTTTTCTTTCTTTCTTTCTTXCTTTCTTTCTTTCTTTCTTTCTCTC TCTTTCTTCCCTCCCTCC 144/144 35 GCCAAAGAGAGAGGCAGGTACAttagggtgaaccatatgaaatagctgat attcgactgtttttgacgtaaaaCCGTACGTATATTTcacacacacacac acacacacTTTTCTGCACCAAGGGAAGCAATCTGG 171/171 36 CCAGGGAAACTAATTCATTCACATATAGGTGTATGTTCACACACACACACACACACACACACTTACATGTATGTGTGAGTATTTTTTTTAAGCAAATACT GTAGCAAAGATAAAATTGGTCCAGATTTGGCTTATTATAAAGTATATGGC AAGTTTCCTTAGGA 210/210 37 CAAAGGATTAGCTTTACGGTATGTGAATAATAGCTCAATAAAGCTATTAT TTAAAATAAAC6TGCACACACACACACACACACACACACACACACATACA CAGCTCACTTTACAACACATCAGGACAATAACTCCATGGACTGATATATA ATGATAAACTACAGTCCTTTCTTTTGTATACTAAGGTGATGCTACTGTCC CACAGCCATGA 38 CAAAGGATTAGCTTTACGGTATGTGAATAATAGCTCAATAAAGCTATTAT TTAAAATAAACGTGCACACACACACACACACACACACACACATACA CAGCTCACTTTACAACACATCAGGACAATAACTCCATGGACTGATATATA ATGATAAACTACAGTCCTTTTTTTTTGTATACTAAGGTGATGCTACTGTCC CACAGCCATGA Table 5 MAP3K9 SNP on Chromosome 14q24.2 Position1 Marker Name Public Name 69186428 rs2286054 rs2286054 rs2286053 69187796 69186468 SG14S94 SNP14MAP3K9MD174E1213 rsl476610 69189493 69189852 SNP14 rs3829955 rs3814874 rs3814874 A.P3K9Y609E805 69190615 69189871 rs3814873 rs3814873 SNP14MAP3K9MD59E41 NEW2 69191845 rs4899367 rs4899367 rs4141095 69193272 69192691 SNP14MAP3K9RU28E68 rsl859465 rsl859465 69197135 69199037 SG14S93 rs2286052 rs4899368 SNP14MAP3K9YU72E240 69199066 69199320 SNP14MAP3 9KU43E240 rs4902843 rs3081458 rs3081458 rsl990032 69199696 69202427 rsl990032 rs4902844 rs4902844 69202855 SG14S92 rs2269946 69203912 rs2332455 rs2332455 69204821 rs4902845 rs4902845 69204879 rs4899369 rs4899369 69204881 rs4899370 rs4899370 69205272 rs2332456 rs2332456 69205421 SNP14MAP3 K9MU166E175 rs2332457 69205568 rs5809495 rs5809495 69205576 rs5809496 rs5809496 69205770 SNP14MAP3K9YD8E175 new3 69207818 rsll60880 rsll60880 69209251 rs4902846 rs4902846 69210078 rs4902847 rs4902847 69210257 rs4902848 rs4902848 69212106 rsl476609 rsl476609 69212484 rs2877693 rs2877693 69217954 SNP14MA.P3K9KD14E180 rs3814872 69217954 rs3814872 rs3814872 69218041 SNP14MAP3K9YD101E180 new3 69219322 rs886600 rs886600 69219322 rs4612997 rs4612997 69220250 rs3081478 rs3081478 69220761 rs3889682 rs3889682 69220771 rs3889683 rs3889683 69220869 rsll42243 rsll42243 69221773 rs4902849 rs4902849 69222957 rs4902852 rs4902852 Rs2332458 rs2332458 69223699 69224637 69224705 rsl548585 rsl548585 rs4902853 rs4902853 SG14S83 rsl548584 69235648 69236948 69237009 rs2107666 rs2107666 rs2158531 rs2158531 rs2158530 rs2158530 69237036 69238432 69244156 rs4902854 rs4902854 rsl9.87652 rsl987652 69244739 69244995 rs4902855 rs4902855 rsl034769 rsl034769 69249713 rs2107665 rs2107665 rs2158529 69249922 69251671 rs4528504 rs4528504 SG14S90 69253468 rs2051857 rs2051857 rs4902856 rs4902856 69254165 69257386 SNP14MAP3K9RU39E413 rs4902857 rs4899371 rs4899371 69,259,152 69,261,096 69,261,390 rs731571 rs731571 SG14S89 rs2023955 rs2023954 rs2023954 69,261,417 69,261,451 69,261,452 rs3081535 rs5809497 rs5809497 rs3081535 rs4902858 rs4902858 69,265,364 69,262,833 69,265,815 rs3832971 rs3832971 rs4902859 SNP14MAP3K9YU160E201 1 Position numbering with respect to the Build (name of the database) 2 Detected by sequencing 3 Genotyped in TaqMan BIBLIOGRAPHY American Thoracic Society, Standardization of Spiroraetry, 1994. 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The teachings of all publications cited in this document are incorporated by reference in their entirety. Although this invention has been particularly demonstrated and described with reference to preferred aspects thereof, it will be understood by those skilled in the art that various changes in shape and detail may be made without departing from the scope of the invention limited by the appended claims.

Claims (147)

1. Use of a kinase inhibitor of the MLK family for the manufacture of a medicament for the treatment of asthma in an individual in need, where the individual has at least one risk factor selected from the group consisting of: a risk haplotype for asthma; a haplotype of risk in the gene of ??? 3? 9; a polymorphism in a nucleic acid of ??? 3? 9; dysregulation of the expression of ??? 3? 9 mRNA, deregulation of an isoform of ??? 3? 9 mRNA; increased expression of the MLK1 protein; increase in the biochemical activity of MLK1; and increased expression of an isoform of the MLK1 protein.

2. The use of claim 1, wherein the kinase inhibitor of the MLK family is an inhibitor of MLK1.

3. The use of claim 2, wherein the MLK1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

4. The use of claim 2, wherein the MLK1 inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

5. The use of claim 1, wherein the isoform of the protein is variant b.

6. Use of a first nucleic acid molecule to diagnose asthma or an asthma susceptibility in a sample of an individual in which it is desired to diagnose the disease, which comprises detecting the presence or absence of a second nucleic acid molecule of at least one marker of a risk haplotype associated with the MAP3K9 gene selected from the group consisting of: haplotypes 1, 2, 3, 4, 5, 6, 7 of Table 1 and combinations thereof in the sample by contact with the first nucleic acid, where the presence of one more markers indicates asthma or an asthma susceptibility.

7. The use of claim 6, wherein the determination of the presence or absence of one or more markers comprises the enzymatic amplification of nucleic acids.

8. The use of claim 6, wherein the determination of the presence or absence of one or more markers further comprises an electrophoretic analysis.

9. The use of claim 6, wherein determining the presence or absence of one or more markers comprises restriction fragment length polymorphism analysis.

10. The use of claim 6, wherein the determination of the presence or absence of one or more markers comprises a sequence analysis.

11. A method for diagnosing and identifying asthma susceptibility in an individual, comprising: investigating in a sample of the individual in which it is desired to diagnose the disease at least one risk haplotype associated with ??? 3? 9 that is present with more often in an individual susceptible to asthma, than in an individual who is not susceptible to asthma, where the risk haplotype significantly increases the risk.

12. The method of claim 11, wherein the significant increase is at least about 20%.

13. The method of claim 11, wherein the significant increase is identified as a prevalence ratio of at least about 1.2.

1 . A method for diagnosing asthma or an asthma susceptibility in an individual, which comprises detecting in a sample of the individual in which the disease is to be diagnosed the presence or absence of at least one marker of a risk haplotype associated with the gene of? ?? 3? 9, comprising a risk haplotype selected from the group consisting of: haplotypes 1, 2, 3, 4, 5, S, 7 of Table 1 and combinations thereof, where the presence of one or more markers indicates asthma or a susceptibility to asthma.

15. A method for diagnosing asthma or an asthma susceptibility in an individual, which comprises detecting in a sample of the individual in which the disease is to be diagnosed the presence or absence of at least one marker of a risk haplotype associated with the gene of? ?.? 3? 9 selected from the group consisting of: DG14S205, DG14S428, D14S1002, DG14S4399, DG14S404, D14S251, DG14S1300, DG14S266, DG14S462, DG14S448 and DG14S406, where the presence of one or more markers indicates asthma or an asthma susceptibility .

16. A method of treating asthma in an individual, comprising administering a kinase inhibitor of the ML family to the individual in need thereof, in a therapeutically effective amount, wherein the individual has at least one risk factor selected from the group consisting of: a haplotype of risk for asthma; a haplotype of risk in the MAP3K9 gene; a polymorphism in a nucleic acid of ??? 3 9; dysregulation of MAP3K9 mRNA expression, deregulation of an MAP3K9 mRNA isoform; an increase in the expression of the MLK1 protein; an increase in the biochemical activity of MLK1; and an increase in the expression of an isoform of the MLK1 protein.

17. The method of claim 16, wherein the kinase inhibitor of the MLK family is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

18. The method of claim 16, wherein the kinase inhibitor of the MLK family is "an inhibitor of MLK1.

19. The method of claim 18, wherein the MLK1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

20. The method of claim 18, wherein the MLKI inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

21. The method of claim 16, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the JTsTK pathway.

22. The method of claim 21, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the MLK kinase pathway.

23. A method for evaluating the response to treatment with a nucleic acid inhibitor of a kinase of the MLK family by an individual in a target population, comprising: a) evaluating the level of MLK1 protein in the individual before treatment with acid inhibitor kinase nucleic of the MLK family; b) evaluating the level of the MLK1 protein in the individual during or after treatment with the nucleic acid inhibitor; c) comparing the level of the MLK1 protein before treatment with the MLK1 level during or after treatment, where a level of MLK1 during or after treatment that is significantly lower than the MLK1 level before treatment indicates efficacy of treatment with the nucleic acid inhibitor.

24. The method of claim 23, wherein the nucleic acid inhibitor is RNAi.

25. The method of claim 23, wherein the level of MLK1 in steps a) and b) is evaluated by measuring the ex vivo production of MLK1 in a sample of the individual.

26. A method of treating asthma in an individual with an asthma risk haplotype, comprising administering a kinase inhibitor of the MLK family to the individual in need thereof, in a therapeutically effective amount.

27. The method of claim 26, wherein the kinase inhibitor of the MLK family is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

28. The method of claim 26, wherein the kinase inhibitor of the MLK family is an inhibitor of MLK1.

29. The method of claim 28, wherein the MLK1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

30. The method of claim 28, wherein the MLK1 inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

31. The method of claim 26, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the ÜTsTK pathway.

32. The method of claim 31, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the MLK kinase pathway.

33. A method for evaluating the response to treatment with a kinase nucleic acid inhibitor of the MLK family by an individual with an asthma risk haplotype, comprising: a) assessing the level of MLK1 protein in the individual prior to inhibitor treatment of kinase nucleic acid from the MLK family; b) evaluating the level of the MLK1 protein in the individual during or after treatment with the nucleic acid inhibitor; c) comparing the level of the MLK1 protein before treatment with the MLK1 level during or after treatment, where a level of MLK1 during or after treatment that is significantly lower than the level of MLK1 before treatment indicates efficacy of treatment with the nucleic acid inhibitor.

34. The method of claim 33, wherein the nucleic acid inhibitor is ARWi.

35. The method of claim 33, wherein the level of MLK1 in steps a) and b) is evaluated by measuring the ex vivo production of MLK1 in an individual sample.

36. A method of treating asthma in an individual with a haplotype of risk in the gene of ??? 3? 9, which comprises administering a kinase inhibitor of the MLK family to the individual in need, in a therapeutically effective amount.

37. The method of claim 36, wherein the kinase inhibitor of the MLK family is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

38. The method of claim 36, wherein the kinase inhibitor of the MLK family is an inhibitor of MLK1.

39. The method of claim 38, wherein the MLK1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

40. The method of claim 38, wherein the MLK1 inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

41. The method of claim 36, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the JK path.

42. The method of claim 41, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the MLK kinase pathway.

43. A method to evaluate the response to treatment with a kinase nucleic acid inhibitor of the MLK family by an individual with a risk haplotype in the MAP3K9 gene in a target population, comprising: a) assessing the level of MLK1 protein in the individual before treatment with kinase nucleic acid inhibitor of the MLK family; b) evaluating the level of the MLK1 protein in the individual during or after treatment with the nucleic acid inhibitor; c) comparing the level of the MLK1 protein before treatment with the MLK1 level during or after treatment, where a level of MLK1 during or after treatment that is significantly lower than the MLK1 level before treatment indicates efficacy of treatment with the nucleic acid inhibitor.

44. The method of claim 43 wherein the nucleic acid inhibitor is RNAi.

45. The method of claim 43, wherein the MLK1 level in steps a) and b) is evaluated by measuring the ex vivo production of the MLK1 in an individual sample.

46. A method of treating asthma in an individual having a polymorphism in a nucleic acid of ??? 3? 9, which comprises administering a kinase inhibitor of the MLK family to the individual in need thereof, in a therapeutically effective amount.

47. The method of claim 46, wherein the kinase inhibitor of the MLK family is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

48. The method of claim 46, wherein the kinase inhibitor of the MLK family is an inhibitor of MLK1.

49. The method of claim 48, wherein the MLK1 inhibitor is CEP-1347"(Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

50. The method of claim 46, wherein the MLK1 inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

51. The method of claim 46, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the JNK pathway.

52. The method of claim 51, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the MLK kinase pathway.

53. A method for evaluating the response to treatment with a nucleic acid inhibitor of the MLK family by an individual having a polymorphism in a nucleic acid of ??? 3? 9, comprising: a) evaluating the level of a protein LK1 in the individual before treatment with a nucleic acid inhibitor; b) evaluating the level of the MLK1 protein in the individual during or after treatment with the nucleic acid inhibitor; c) comparing the level of the ML 1 protein before treatment with the MLK1 level during or after treatment, where a level of MLK1 during or after treatment that is significantly lower than the MLK1 level before treatment indicates efficacy of the treatment with the nucleic acid inhibitor.

54. The method of claim 53 wherein the nucleic acid inhibitor is A i.

55. The method of claim 53, wherein the level of ML 1 in steps a) and b) is evaluated by measuring the ex vivo production of MLK1 in a sample of the individual.

56. A method of treating asthma in an individual having a deregulation of MAP3K9 mRNA expression, which comprises administering a kinase inhibitor of the MLK family to the individual in need thereof, in a therapeutically effective amount.

57. The method of claim 56, wherein the kinase inhibitor of the MLK family is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

58. The method of claim 56, wherein the kinase inhibitor of the MLK family is an inhibitor of MLK1.

59. The method of claim 58, wherein the MLK1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

60. The method of claim 58, wherein the MLK1 inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

61. The method of claim 58, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the JNK pathway.

62. The method of claim 61, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the MLK kinase pathway.

63. A method for evaluating the response to treatment with a kinase nucleic acid inhibitor of the MLK family by an individual having a deregulation of ??? 3? 9 mRNA expression, comprising: a) evaluating the level of a MLK1 protein in the individual before treatment with a nucleic acid inhibitor; b) evaluating the level of the MLK1 protein in the individual during or after treatment with the nucleic acid inhibitor; c) comparing the level of the MLK1 protein before treatment with the MLK1 level during or after treatment, where a level of MLK1 during or after treatment that is significantly lower than the MLK1 level before treatment indicates efficacy of treatment with the nucleic acid inhibitor.

64. The method of claim 63 wherein the nucleic acid inhibitor is RNAi.

65. The method of claim 63, wherein the MLK1 level in steps a) and b) is evaluated by measuring the ex vivo production of the MLK1 in an individual sample.

66. A method of treating asthma in an individual having a deregulation of an AENm isoform of ??? 3? 9, which comprises administering a kinase inhibitor of the MLK family to the individual in need thereof, in a therapeutically effective amount.

67. The method of claim 66, wherein the kinase inhibitor of the LK family is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

68. The method of claim 66, wherein the kinase inhibitor of the MLK family is an inhibitor of MLK1.

69. The method of claim 68, wherein the ML 1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

70. The method of claim 68, wherein the MLK1 inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

71. The method of claim 66, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the JISTK pathway.

72. The method of claim 71, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the MLK kinase pathway.

73. A method for evaluating the response to treatment with a kinase nucleic acid inhibitor of the MLK family by an individual having a deregulation of an MAP3K9 mRNA isoform, comprising: a) evaluating the level of an MLK1 protein in the individual before treatment with a nucleic acid inhibitor; b) evaluating the level of the L 1 protein in the individual during or after treatment with the nucleic acid inhibitor; c) comparing the level of MLK1 protein before treatment with the level of LK1 during or after treatment, where a level of MLK1 during or after treatment that is significantly lower than the MLK1 level before treatment indicates efficacy of treatment with the nucleic acid inhibitor.

74. The method of claim 73 wherein the nucleic acid inhibitor is RNAi.

75. The method of claim 73, wherein the MLK1 level in steps a) and b) is evaluated by measuring the ex vivo production of the MLK1 in an individual sample.

76. A method of treating asthma in an individual having an increased expression of the MLK1 protein, which comprises administering a kinase inhibitor of the MLK family to the individual in need thereof, in a therapeutically effective amount.

77. The method of claim 76, wherein the kinase inhibitor of the MLK family is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

78. The method of claim 76, wherein the kinase inhibitor of the MLK family is an inhibitor of MLK1.

79. The method of claim 78, wherein the MLK1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

80. The method of claim 76, wherein the MLKI inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

81. The method of claim 76, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the JNK pathway.

82. The method of claim 81, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the MLK kinase pathway.

83. A method for evaluating the response to treatment with a kinase nucleic acid inhibitor of the MLK family by an individual having an increased expression of the MLK1 protein, comprising: a) evaluating the level of a MLK1 protein in the individual before treatment with a nucleic acid inhibitor; b) evaluating the level of the MLK1 protein in the individual during or after treatment with the nucleic acid inhibitor; c) compare the level of the MLK1 protein before treatment with the MLK1 level during or after treatment, where a level of L1 during or after treatment that is significantly lower than the MLK1 level before treatment indicates efficacy of the treatment with the nucleic acid inhibitor.

84. The method of claim 83 wherein the nucleic acid inhibitor is RNAi.

85. The method of claim 83, wherein the level of MLK1 in steps a) and b) is evaluated by measuring the ex vivo production of the MLK1 in a sample of the individual.

86. A method of treating asthma in an individual having an increase in the biochemical activity of MLKl, which comprises administering a kinase inhibitor of the MLK family to the individual in need thereof, in a therapeutically effective amount.

87. The method of claim 86, wherein the kinase inhibitor of the MLK family is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

88. The method of claim 86, wherein the kinase inhibitor of the MLK family is an inhibitor of MLK1.

89. The method of claim 88, wherein the MLK1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

90. The method of claim 88, wherein the MLK1 inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

91. The method of claim 86, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the JNK pathway.

92. The method of claim 91, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the MLK kinase pathway.

93. A method for evaluating the response to treatment with a kinase nucleic acid inhibitor of the MLK family by an individual having an increase in the biochemical activity of MLK1, comprising: a) evaluating the level of a MLK1 protein in the individual before of the treatment with a nucleic acid inhibitor; b) evaluating the level of the MLK1 protein in the individual during or after treatment with the nucleic acid inhibitor; c) comparing the level of the MLK1 protein before treatment with the ML 1 level during or after treatment, where a level of MLK1 during or after treatment that is significantly lower than the MLK1 level before treatment indicates efficacy of the treatment with the nucleic acid inhibitor.

94. The method of claim 93 wherein the nucleic acid inhibitor is RNAi.

95. The method of claim 93, wherein the level of MLK1 in steps a) and b) is evaluated by measuring the ex vivo production of ML 1 in a sample of the individual.

96. A method of treating asthma in an individual having an increased expression of an MLK1 protein isoform, which comprises administering a kinase inhibitor of the MLK family. to the individual who needs it, in a therapeutically effective amount.

97. The method of claim 96, wherein the kinase inhibitor of the MLK family is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

98. The method of claim 96, wherein the kinase inhibitor of the MLK family is an inhibitor of MLK1.

99. The method of claim 98, wherein the MLK1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

100. The method of claim 98, wherein the MLK1 inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

101. The method of claim 96, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the JNK pathway.

102. The method of claim 101, wherein the kinase inhibitor of the MLK family is an inhibitor of a member of the MLK kinase pathway.

103. A method for evaluating the response to treatment with a kinase nucleic acid inhibitor of the MLK family by an individual having an increase in the expression of an MLK1 protein isoform, comprising: a) evaluating the level of a MLK1 protein in the individual before treatment with a nucleic acid inhibitor; b) evaluating the level of the MLK1 protein in the individual during or after treatment with the nucleic acid inhibitor; c) comparing the level of MLK1 protein before treatment with the MLK1 level during or after treatment, where a level of MLK1 during or after treatment that is significantly lower than the MLK1 level before treatment indicates efficacy of treatment with the nucleic acid inhibitor.

104. The method of claim 103 wherein the nucleic acid inhibitor is RNAi.

105. The method of claim 103, wherein the MLK1 level in steps a) and b) is evaluated by measuring the ex vivo production of the MLK1 in an individual sample.

106. A method for evaluating the response to treatment with a MLK1 inhibitor by an individual in a target population, comprising: a) evaluating the level of an inflammatory marker in the individual prior to treatment with a MLK1 inhibitor; b) evaluating the level of the inflammatory marker in the individual during or after treatment with the MLK1 inhibitor; c) comparing the level of the inflammatory protein before treatment with the level of the inflammatory protein during or after treatment, where a level of inflammatory marker during or after treatment that is significantly lower than the level of inflammatory marker before treatment indicates effectiveness of the treatment with the nucleic acid inhibitor.

107. The method of claim 106, wherein the inflammatory marker is IL-2 or TNF-.

108. The method of claim 106, wherein the individual has at least one risk factor for asthma selected from the group consisting of: a risk haplotype for asthma; a haplotype of risk in the MAP3K9 gene; a polymorphism in a nucleic acid of ??? 3? 9; dysregulation of MAPK3K9 AKNTm expression, deregulation of an AR isoform of ??? 3? 9; increased expression of the MLK1 protein; increase in the biochemical activity of MLK1; and increased expression of an isoform of the MLK1 protein.

109. The method of claim 106, wherein the MLK1 inhibitor is selected from the group consisting of: compounds of Formula I, Table A and Table B, and their optically pure stereoisomers, mixtures of stereoisomers and salts.

110. The method of claim 106, wherein the MLK1 inhibitor is CEP-1347 (Formula III) and its optically pure stereoisomers, mixtures of stereoisomers and salts.

111. The method of claim 106, wherein the MLK1 inhibitor is an indolocarbazole derivative and its optically pure stereoisomers, mixtures of stereoisomers and salts.

112. A method of treating asthma in an individual having an increased expression of a MAP3K9 splice variant, which comprises administering a kinase inhibitor of the MLK family to the individual in need thereof, in a therapeutically effective amount.

113. The method of claim 112, wherein the splicing variant is selected from the group consisting of variant a, variant b, variant c, variant d and variant e.

114. The method of claim 112, wherein the kinase inhibitor of the MLK family is a monoclonal antibody.

115. The method of claim 112, wherein the kinase inhibitor of the MLK family is a monoclonal antibody directed against a splice variant.

116. The method of claim 16, wherein the kinase inhibitor of the MLK family is selected from the group consisting of: compounds of Formula IV, their optically pure stereoisomers, mixtures of stereoisomers and salts wherein A represents O or S; W represents 0, NH, N 1; R4 and R5 are independently selected from the group represented by hydrogen, halogen, cyano, nitro, alk (in / in) ilo ¾_6, alk (in / in) iloxy Ci_G, alk (in / in) iloxy C; L_s-alk ( in / in) ilo Ci-6, alkyl (en / in) ilsulfañilo < ¾_6 / hydroxy, hydroxy-alk (in / in) ilo Ci_s, halo-alk (in / in) ilo Ci_6, halo-alk (in / in) iloxy Ci_6, cycloalk (en) ilo C3-8, cycloalk (en) C3_8-alkyl (en / y) ilo Ca.s, acyl, alk (en / in) ioxycarbonyl Cx-s, alk (en / in) ylsulphonyl Ci_6, - R7R8 and R7R8N-alk (en / in) yl Ci_6; R3 represents hydrogen, halogen, alk (en / in) yl Ci_s < cycloalk (en / in) yl C3_8, aryl, a heterocycle, hydroxy, hydroxyalk (en / in) yl Ca_6, alk (en / in) yloxy Ci-6, alk (en / in) yloxy Cx_6-alk (in / in) ilo Ca_6, cycloalk (in / in) oxy C3_8, alk (in / in) ilsulfañilo Ca-S / acyl, R7R8N-alk (en / in) ilo Cx-e or -NR7R8; or R3 represents a group of formula -R9-Ar2 where R9 represents O, H, NR1 ', S, -CONR1'-, -CO- or Cx_6 alkyl, C2_s alkenyl, which may be optionally substituted with OH, halogen, Ci_5 alkoxy or C3_B cycloalkyl; Rs represents alk (in / in) ilo s, cycloalk (in / in) yl C3_ 8, cycloalk (en) il C3_8-alk (en / in) yl or Ar1; Ar1 and Ar2 are independently selected from the group represented by aryl, a heterocycle or a carbocycle, all of which may be substituted one or more times with halogen, cyano, nitro, alk (en / in) yl Ci_6, alk (en / in) iloxy Ca_s, alk (en / in) iloxy Ci_e-alk (en / in) ilo Ci_e, alk (en / in) iloxy Ci_6-alqu (en / in) iloxi Ci_s-alqu (en / in) ilariloxi Ci_s, aril- alk (en / in) iloxy Ca_6, halo-alk (en / in) iloxy Ci_6 / alk (en / in) il-sulfañilo Ci_6, hydroxy, hydroxy-alk (en / in) ilo Ca-6, halo-alqu ( in / y) ilo C ± -6r cyano-alk (en / in) yl Ci_s, NR7R8, R7R8-alk (en / in) yl Ci_6, cycloalk (en) yl C3_8, cycloalk (en) yl C3_8-alk (in / in) ilo < ¾._ß, alkyl (in / in) ilsulfonyl Ci_s, aryl, acyl, alk (in / in) iloxycarbonyl 0? -6, alkyl (in / in) il Ci-6-CONR1-alk (in / in) ilo ¾ ._ß, alk (in / in) il Ci-s-CONR1 '-, -CO R7R8 or R7R8NCO-alk (en / in) yl Ci_6; R7 and R8 are independently selected from the group represented by hydrogen and alk (en / in) yl x-6 which may be further substituted with hydroxy, halogen, Ci_6 alkoxy, cyano, nitro, cycloalk (en) yl C3_8, cycloalk (en ) il C3_3-alk (en / in) yl Ci_6 / aryl or a heterocycle; or 7 and R8 together with the nitrogen to which they are attached form a 3-7 membered ring optionally containing one or more additional heteroatoms and may be optionally substituted with halogen, alkyl (en / in) yl ¾_6, hydroxy, hydroxy-alk (in / in) ilo CX-s or acyl; the aryls may be further substituted with halogen, cyano, nitro, alk (in / in) yl CX-6, alky (in / in) yloxy Ci_s, al (in / in) ilsulfañilo Ci_s, hydroxy, hydroxy-alk (in / in) ilo Ci_6, halo-alqu (en / in) ilo Cx_s, halo-alqu (en / in) iloxi Ci_s, cycloalqu (en) ilo C3.8, cycloalqu (en) il C3_B-alqu (en / in) ilo 0? _6? acyl, alk (in / in) iloxycarbonyl Ci_6, alk (in / in) ilsulfonyl Ci-s, or -NR7'R8 'where -NR7'R8' is as defined above for -NR7R8, with the proviso that any aryl substituent of -NR7R8 is not further substituted; and R1 and R1 'are independently selected from the group represented by alk (en / in) yl Ci_G, cycloalk (en) yl C3_8, aryl, hydroxy-alk (en / in) yl C -6l cycloalk (en) il C3_8- alkyl (en / in) yl Ci_s and acyl; or a pharmaceutically acceptable salt thereof.

117. A method for diagnosing asthma or an asthma susceptibility in an individual, comprising detecting the presence or absence of at least one haplotype of risk comprising a haplotype selected from the group consisting of: haplotypes 1, 2, 3, 4, 5 , 6, 7 and combinations thereof, where the presence of the haplotype indicates asthma or susceptibility to asthma.

118. A method for testing the presence of a first nucleic acid molecule in a sample, comprising contacting said sample with a second nucleic acid molecule comprising the haplotype of claim 117.

119. The method of claim 117, wherein the determination of the presence or absence of the haplotype comprises enzymatic amplification of the nucleic acid of the individual.

120. The method of claim 119, wherein the determination of the presence or absence of the haplotype further comprises an electrophoretic analysis.

121. The method of claim 117, wherein the determination of the presence or absence of the haplotype comprises restriction fragment length polymorphism analysis.

122. The method of Claim 117, wherein the determination of the presence or absence of the haplotype comprises a sequence analysis.

123. A method for diagnosing asthma or an asthma susceptibility in an individual, comprising detecting the presence or absence of at least one haplotype of risk comprising haplotype 6, where the presence of the haplotype indicates asthma or susceptibility to asthma.

124. A method for testing the presence of a first nucleic acid molecule in a sample, comprising contacting said sample with a second nucleic acid molecule comprising the haplotype of claim 123.

125. The method of claim 123, wherein the determination of the presence or absence of the haplotype comprises enzymatic amplification of the nucleic acid of the individual.

126. The method of claim 125, wherein the determination of the presence or absence of the haplotype further comprises an electrophoretic analysis.

127. The method of claim 123, wherein the determination of the presence or absence of the haplotype comprises restriction fragment length polymorphism analysis.

128. The use of Claim 123, wherein the determination of the presence or absence of the haplotype comprises a sequence analysis.

129. A method for diagnosing asthma or an asthma susceptibility in an individual, comprising detecting the presence or absence of at least one haplotype of risk comprising haplotype 7, where the presence of the haplotype indicates asthma or susceptibility to asthma.

130. A method for testing the presence of a first nucleic acid molecule in a sample, comprising contacting said sample with a second nucleic acid molecule comprising the haplotype of claim 129.

131. The method of claim 129, wherein the determination of the presence or absence of the haplotype comprises enzymatic amplification of the nucleic acid of the individual.

132. The method of claim 131, wherein the determination of the presence or absence of the haplotype further comprises an electrophoretic analysis.

133. The method of claim 129, wherein the determination of the presence or absence of the haplotype comprises restriction fragment length polymorphism analysis.

134. The method of claim 129, wherein determining the presence or absence of one or more markers comprises a sequence analysis.

135. A kit for testing in a sample the presence of at least one haplotype associated with asthma, wherein the haplotype comprises two or more specific alleles, and wherein the kit comprises one or more nucleic acids capable of detecting the presence or absence of one or more of the specific alleles, indicating in this way the presence or absence of the haplotype in the sample.

136. The kit of claim 135, wherein the nucleic acid comprises at least one contiguous nucleotide sequence that is completely complementary to a region comprising at least one specific allele of the haplotype.

137. A kit of reagents for testing in a sample the presence of at least one haplotype associated with asthma, where the haplotype comprises two or more specific alleles, comprising in separate containers: a) one or more labeled nucleic acids capable of detecting one or more more specific alleles of the haplotype; and b) reagents for the detection of said marker.

138. The reagent kit of claim 137, wherein the labeled nucleic acid comprises at least one contiguous nucleotide sequence that is completely complementary to a region comprising at least one allele specific to the haplotype.

139. A kit of reagents for assaying in a sample the presence of at least one haplotype associated with asthma, wherein the haplotype comprises two or more specific alleles, wherein the kit comprises one or more nucleic acids comprising at least one nucleotide sequence that is at least partially complementary to a part of the MAP3K9 nucleotide sequence, and wherein the nucleic acid can act as a primer for a primer extension reaction capable of detecting two or more of the haplotype-specific alleles.

140. A method for diagnosing an asthma susceptibility in an individual, comprising determining the presence or absence in the individual of at least one haplotype comprising two or more alleles selected from the group consisting of: D14S251, DG14S1300, DG14S420, DG14S1266, DG14S462, DG14S448, DG14S205, DG14S428, D14S1002, DG14S399, DG14S404 and DG14S406, where the presence of the haplotype indicates susceptibility to asthma.

141. The method of claim 140, wherein the determination of the presence or absence of the haplotype comprises enzymatic amplification of the nucleic acid of the individual.

142. The method of claim 140, wherein determining the presence or absence of the haplotype further comprises electrophoretic analysis.

143. The method of claim 140, wherein the determination of the presence or absence of the haplotype further comprises restriction fragment length polymorphism analysis.

144. The method of claim 143, wherein the determination of the presence or absence of the haplotype further comprises analysis of the sequence.

145. A method for diagnosing an asthma susceptibility in an individual, comprising: obtaining a sample of the individual's nucleic acid; and analyzing in the nucleic acid sample the presence or absence of at least one haplotype comprising two or more alleles selected from the group consisting of: D14S251, DG14S1300, DG14S420, DG14S1266, DG14S462, DG14S448, DG14S205, DG14S428, D14S1002, DG14S399, DG14S404 and DG14S406, where the presence of the haplotype indicates susceptibility to asthma.

146. The method of claim 145, wherein the haplotype comprises two or more alleles selected from the group consisting of: DG14S399 and DG14S404.

147. The method of claim 145, wherein the haplotype further comprises DG14S406.