RU2799084C2 - Treatment of respiratory disorders using arachidonate 15-lipoxygenase (alox15) inhibitors - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates specifically to new methods of treating patients suffering from a respiratory disorder selected from nasal polyp, allergic rhinitis, asthma, or aspirin-induced respiratory disease (AIRD). The invention involves the identification in a patient of a variant nucleic acid with a predictable loss of function of the enzyme arachidonate 15-lipoxygenase (ALOX15) encoding a human ALOX15 polypeptide, where the ALOX15 polypeptide is a variant of Thr560Met, Tyr139Cys, Leu651fs, Pro565Leu, Asn658Lys, Gly283Arg, Val474Ala, Gly 422Arg or Leu106fs, and providing the patient with an ALOX15 inhibitor or other therapeutic agent capable of treating the said diseases in the event that a detectable nucleic acid is not detected in a biological sample obtained from the patient.

EFFECT: obtaining new methods of treating patients suffering from a respiratory disorder selected from nasal polyp, allergic rhinitis, asthma, or aspirin-induced respiratory disease (AIRD).

92 cl, 1 ex, 1 tbl, 8 dwg

Description

Link to sequence listing

This application includes a sequence listing submitted electronically as a text file named "18923802102SEQ", created on November 24, 2019, with a size of 63 kilobytes. This sequence listing is incorporated herein by reference.

Field of invention

The present invention relates generally to the treatment of patients having a respiratory disorder with an arachidonate 15-lipoxygenase (ALOX15) inhibitor, methods for identifying subjects at increased risk of developing a respiratory disorder, and methods for detecting ALOX15 variant nucleic acid molecules and variant polypeptides.

State of the art invention

Asthma may result from aeroallergen-induced inflammation mediated by T-helper type 2 (Th2) activity and mediated by cytokines including interleukin (IL)-4, IL-5 and IL-13. IL-13 is a Th2 pleiotropic cytokine produced by activated T cells, basophils, eosinophils, and mast cells and has been found to be actively involved in the pathogenesis of asthma in preclinical models. Elevated levels of IL-13 have been found in the airways of a group of patients with asthma. Although asthma is often characterized by eosinophilic airway infiltration, there is increasing evidence that other subtypes of the disease exist, driven by alternative forms of inflammation. For example, studies of the cellular components of airway inflammation in asthma provide evidence for distinct eosinophilic and non-eosinophilic asthma phenotypes. It would be useful to identify and develop asthma biomarkers.

Nasal polyps are often soft, painless, noncancerous growths on the lining of the nasal passages or sinuses. Nasal polyps can result from chronic inflammation caused by asthma, recurrent infection, allergies, drug sensitivities, or certain immune disorders. Large growths or groups of nasal polyps can block the nasal passages and possibly lead to breathing problems, loss of smell, and frequent infections. Medications can often shrink or eliminate nasal polyps, but sometimes surgery is required to remove them. Even after successful treatment, nasal polyps often recur.

Allergic rhinitis usually causes symptoms in the nose, throat, eyes, ears, skin, and/or palate. Seasonal allergic rhinitis (such as hay fever) is most commonly caused by pollen carried into the air at different times of the year in different parts of the country. Allergic rhinitis, such as persistent allergic rhinitis, can also be caused by indoor allergens such as dry skin flakes, urine and saliva found on pet dander, mold, dust mite waste, and cockroach particles, with symptoms often occurring during the entire of the year. In addition to allergenic triggers, symptoms can also be triggered by irritants such as smoke and strong odors, or changes in air temperature and humidity.

Aspirin-induced respiratory disease (AIRD) is characterized by swelling of the mucous membranes of the sinuses and nasal membranes, nasal polyps, and asthma in association with respiratory reactions to aspirin/NSAIDs. AIRD is an acquired disease that begins on average at age 30. Approximately 50% of patients develop AIRZ after infection with a respiratory virus. AIRD can cause severe asthma and airway remodeling, and is often diagnosed by a history of respiratory reactions to COX1 inhibitors. The prevalence of this disease is estimated at 7.2% in general among asthmatics (1.3 million in the US), 14.9% among asthmatics with severe asthma, 9.7% among patients with nasal polyps, 8.7% among patients with chronic sinusitis. However, about 20-40% of patients with nasal polyps, asthma, and chronic sinusitis are sensitive to aspirin without prior exposure to COX1 inhibitors.

ALOX15 (also known as 15-LO and 15-LOX) is a non-heme iron dioxygenase that catalyses the stereospecific peroxidation of free and esterified polyunsaturated fatty acids, generating a spectrum of biologically active lipid mediators. In addition, ALOX15 converts arachidonic acid to 12-hydroperoxyeicosatetraenoic acid/12-HPETE and 15-hydroperoxyeicosatetraenoic acid/15-HPETE. ALOX15 also converts linoleic acid to 13-hydroperoxyoctadecadienoic acid. ALOX15 can also act on (12S)-hydroperoxyeicosatetraenoic acid/(12S)-HPETE to form hepoxilin A3.

The essence of the invention

The present invention provides methods for treating a patient having a respiratory disorder, a method comprising administering an ALOX15 inhibitor to the patient. In some embodiments, the patient has a nasal polyp, allergic rhinitis, asthma, and/or AIRZ.

The invention also provides methods for treating a patient with a therapeutic agent that treats or inhibits a respiratory disorder, wherein the patient is suffering from a respiratory disorder, a method comprising the steps of: determining if the patient has a variant nucleic acid molecule with predicted loss of function ALOX15, encoding a human ALOX15 polypeptide by: obtaining or receiving a biological sample from a patient; and performing or performing genotyping on a biological sample to determine if the patient has a genotype containing said variant nucleic acid molecule with predicted loss of ALOX15 function; and when the patient is an ALOX15 reference, then by administering or continuing to administer to the patient a therapeutic agent that treats or inhibits a respiratory disorder in a unit dose amount, and administering an ALOX15 inhibitor to the patient; and when the patient is heterozygous for the predicted loss of ALOX15 function variant, then by administering or continuing to administer to the patient a therapeutic agent that treats or inhibits a respiratory disorder in an amount equal to or less than the standard dose amount and administering to the patient an ALOX15 inhibitor; wherein the presence of a genotype having a variant ALOX15 loss-of-function nucleic acid molecule encoding a human ALOX15 polypeptide indicates that the patient has a reduced risk of developing a respiratory disorder.

The invention also provides methods for identifying a human subject at increased risk of developing a respiratory disorder, the method comprising: determining the presence or absence of an ALOX15 predictive loss of function nucleic acid molecule encoding a human ALOX15 polypeptide in a biological sample obtained from the patient; wherein: when a human subject is a reference for ALOX15, then said human subject has an increased risk of developing a respiratory disorder; and when the human subject is heterozygous for the ALOX15 predictive loss of function variant, or homozygous for the ALOX15 predictive loss of function variant, then said human subject has a reduced risk of developing a respiratory disorder.

The invention also provides methods for detecting an ALOX15 variant nucleic acid molecule in a human subject, comprising analyzing a sample obtained from a human subject to determine whether the nucleic acid molecule in the sample is: a genomic nucleic acid molecule containing a nucleotide sequence, containing thymine at the position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; an mRNA molecule containing a nucleotide sequence containing uracil at the position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; or a cDNA molecule containing a nucleotide sequence containing thymine at the position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence.

The invention also provides methods for detecting the presence of a variant human ALOX15 Thr560Met polypeptide, comprising analyzing a sample obtained from a human subject to determine if the ALOX15 protein in the sample contains methionine at position corresponding to position 560 according to SEQ ID NO : 8

The invention also provides therapeutic agents that treat or inhibit a respiratory disorder for use in the treatment of a respiratory disorder in a human subject having: a genomic nucleic acid molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing thymine in the position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; an mRNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing uracil at position corresponding to position 1693 according to SEQ ID NO:4 or its complementary nucleotide sequence; or a cDNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence.

The invention also provides ALOX15 inhibitors for use in the treatment of a respiratory disorder in a human subject having: a genomic nucleic acid molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; an mRNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; or a cDNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence.

Brief description of graphic materials

The accompanying figures, which are included in this description and are part of it, illustrate some of the features of this invention.

In FIG. 1 shows a table indicating that rs34210653 is significantly associated with a decrease in eosinophils in exomes from the UK Biobank 50K.

In FIG. 2 shows a table indicating that rs34210653 is significantly associated with a decrease in eosinophils in UK Biobank 500K genotyping.

In FIG. 3 shows a table indicating that rs34210653 is significantly associated with a reduced incidence of nasal polyp and allergic rhinitis, and is associated with physician-diagnosed asthma in UK Biobank 500K genotyping.

In FIG. 4 shows a table indicating that rs34210653 is significantly associated with a decrease in eosinophils in exomes from the GHS 90K biobank.

In FIG. 5 shows a table indicating that ALOX15 is associated with a reduced likelihood of nasal polyps in exomes from the GHS 90K biobank.

In FIG. 6 shows a plot of locus scaling for significant association between rs34210653 and eosinophils based on UKB 500K biobank genotyping data.

In FIG. 7 shows quantitative distributions of traits for eosinophil counts based on genotyping data from the UKB 500K biobank, showing a decrease in eosinophils among heterozygous and homozygous carriers of the rs34210653 variant (dashed line indicates the mean eosinophil count for carriers of the ALOX15 reference allele).

In FIG. 8 shows a plot of locus scaling for significant association between rs34210653 and nasal polyps based on UKB 500K biobank genotyping data.

Detailed Description of the Invention

Various terms relating to aspects of this invention are used throughout this description and claims. Such terms should be given their usual meaning in the art, unless otherwise indicated. Other specifically defined terms should be interpreted in accordance with the definitions given in this document.

Unless expressly stated otherwise, it is in no way intended that any method or aspect set forth herein be construed as requiring that their steps be performed in a specific order. Accordingly, unless a claim or method description specifically states that the steps are to be limited to a specific order, it is by no means intended to imply that the order is intended in any respect. This refers to any possible non-expressed basis for interpretation, including questions of logic regarding the organization of steps or workflow, simple meaning derived from grammatical organization or punctuation, or the number or type of aspects described in this disclosure.

In the context of this document, the singular forms also include the plural forms, unless the context clearly indicates otherwise.

In the context of this document, the term "about" means that the given numerical value is approximate, and small variations will not significantly affect the practice of the described embodiments. Where a numerical value is used, unless the context indicates otherwise, the term "about" means that the numerical value may vary by ±10% and remain within the described embodiments.

In the context of this document, the term "comprising(s)" can be replaced by "consisting(s) of" or "essentially consisting(s) of" in specific embodiments, the implementation is arbitrary.

In the context of this document, the term "isolated" in relation to a nucleic acid molecule or polypeptide means that the nucleic acid molecule or polypeptide is in a state other than its natural environment, for example, outside the blood and/or tissues of animals. In some embodiments, the isolated nucleic acid molecule or the isolated polypeptide is substantially free of other nucleic acid molecules or other polypeptides, in particular other nucleic acid molecules or polypeptides of animal origin. In some embodiments, the nucleic acid molecule or polypeptide may be in a highly purified form, i. be more than 95% pure or more than 99% pure. When used in this context, the term "isolated" does not exclude the presence of the same nucleic acid molecule or polypeptide in alternative physical forms, such as dimers or alternatively phosphorylated forms, or derivatized forms.

As used herein, the terms "nucleic acid", "nucleic acid molecule", "nucleic acid sequence", "polynucleotide", or "oligonucleotide" may include the polymeric form of nucleotides of any length, may include DNA and/or RNA, and may be single-stranded, double-stranded or multi-stranded. One strand of nucleic acid also refers to its complementary sequence.

In the context of this document, the terms "subject" and "patient" are used interchangeably. The subject may include any animal, including mammals. Mammals include, but are not limited to, farm animals (such as, for example, horse, cow, pig), domestic animals (such as, for example, dog, cat), laboratory animals (such as, for example, mouse, rat, rabbits) and non-human primates. In some embodiments, the subject is a human.

A rare variant in the ALOX15 gene associated with a reduced risk of developing respiratory disorders such as nasal polyps, allergic rhinitis, asthma and AIRZ has been identified in humans in accordance with the present invention. For example, a genetic change (rs34210653) has been found that replaces the cytosine nucleotide at position 9917 in the reference human ALOX15 (see SEQ ID NO: 1) with thymine, indicating that a person having such a change may be at reduced risk of developing respiratory disorder such as nasal polyps, allergic rhinitis, asthma, and AIRZ. No variants of the ALOX15 gene or protein are believed to have any known association with respiratory disorders such as nasal polyps, allergic rhinitis, asthma, and AIRD. Overall, the genetic analyzes described herein unexpectedly indicate that the ALOX15 gene, and in particular a variant in the ALOX15 gene, is associated with a reduced risk of developing respiratory disorders such as nasal polyps, allergic rhinitis, asthma, and AIRZ. Therefore, human subjects that are ALOX15 references that have an increased risk of developing a respiratory disorder such as nasal polyps, allergic rhinitis, asthma, and/or AIRZ can be treated to prevent, reduce symptoms, and/or suppress the respiratory disorder. development of symptoms. Accordingly, the present invention provides methods for using the identification of such variants in subjects to identify or stratify such subjects at risk of developing a respiratory disorder, such as nasal polyps, allergic rhinitis, asthma, and/or AIRD, or to diagnose subjects at increased risk of developing a respiratory disorder. such as nasal polyps, allergic rhinitis, asthma, and/or AIRZ, so that subjects at risk, or subjects with active disease, can be treated appropriately.

For the purposes of this invention, any particular individual may be classified as having one of three ALOX15 genotypes: i) ALOX15 reference; ii) heterozygous for the predicted loss of function ALOX15 variant; or iii) homozygous for the predicted loss of ALOX15 function variant. An individual is an ALOX15 reference when that individual does not have a copy of the variant nucleic acid molecule with predicted loss of ALOX15 function. An individual is heterozygous for an ALOX15 loss-of-function predicted variant when that individual has a single copy of the ALOX15 predicted loss of function variant nucleic acid molecule. An ALOX15 predictive loss-of-function variant nucleic acid molecule is any ALOX15 nucleic acid molecule (e.g., a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule) encoding an ALOX15 polypeptide having partial loss of function, complete loss of function, predictive partial loss of function, or predictable complete loss of function. An individual having an ALOX15 polypeptide with partial loss of function (or predicted partial loss of function) is ALOX15 hypomorphic. A variant nucleic acid molecule with predicted loss of ALOX15 function can be any nucleic acid molecule encoding ALOX15 Thr560Met, Tyr139Cys, Leu651fs, Pro565Leu, Asn658Lys, Gly283Arg, Val474Ala, Gly422Arg, or Leu106fs. In some embodiments, the ALOX15 loss-of-function variant nucleic acid molecule encodes for ALOX15 Thr560Met. An individual is homozygous for an ALOX15 loss-of-function predicted variant when the individual has two copies of the ALOX15 predicted loss of function variant nucleic acid molecule.

With respect to human subjects or patients that are genotyped or identified as reference for ALOX15, such human subjects or patients are at increased risk of developing respiratory disorders such as nasal polyps, allergic rhinitis, asthma, and/or AIRZ. For human subjects or patients that are genotyped or determined to be either ALOX15 reference or heterozygous for a predicted loss of ALOX15 function variant, such human subjects or patients can be treated with an ALOX15 inhibitor.

In any of the embodiments described herein, the ALOX15 loss-of-function variant nucleic acid molecule may be any ALOX15 nucleic acid molecule (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule) encoding an ALOX15 polypeptide having a partial loss of function, total loss of function, predicted partial loss of function, or predicted total loss of function. For example, a variant nucleic acid molecule with predicted loss of ALOX15 function can be any nucleic acid molecule encoding ALOX15 Thr560Met, Tyr139Cys, Leu651fs, Pro565Leu, Asn658Lys, Gly283Arg, Val474Ala, Gly422Arg, or Leu106fs. In some embodiments, the ALOX15 loss-of-function variant nucleic acid molecule encodes for ALOX15 Thr560Met.

In any of the embodiments described herein, an ALOX15 predictive loss of function polypeptide can be any ALOX15 polypeptide having partial loss of function, complete loss of function, predictive partial loss of function, or predictive complete loss of function. In any of the embodiments described herein, the ALOX15 predicted loss of function polypeptide can be any of the ALOX15 polypeptides described herein, including, but not limited to, e.g. Val474Ala, Gly422Arg or Leu106fs. In some embodiments, the ALOX15 predicted loss of function polypeptide is an ALOX15 Thr560Met polypeptide.

In any of the embodiments described herein, the respiratory disorder is a nasal polyp, allergic rhinitis, asthma, and/or AIRD. In any of the embodiments described herein, said respiratory disorder is a nasal polyp. In any of the embodiments described herein, said respiratory disorder is allergic rhinitis. In any of the embodiments described herein, said respiratory disorder is asthma. In any of the embodiments described herein, the respiratory disorder is AIRZ.

The present invention provides methods for treating a patient having a respiratory disorder comprising administering an ALOX15 inhibitor to the patient.

The present invention provides methods for treating a patient having a nasal polyp comprising administering an ALOX15 inhibitor to the patient.

The present invention provides methods for treating a patient having allergic rhinitis, comprising administering an ALOX15 inhibitor to the patient. In some embodiments, the implementation of allergic rhinitis is an allergic rhinitis with a high level of eosinophils.

The present invention provides methods for treating a patient having asthma, comprising administering an ALOX15 inhibitor to the patient. In some embodiments, the asthma is allergic asthma, moderate to severe asthma, oral corticosteroid dependent asthma, eosinophilic asthma, or eosinophil high eosinophilic asthma. In some embodiments, the asthma is allergic asthma. In some embodiments, the asthma is moderate to severe asthma. In some embodiments, the asthma is oral corticosteroid dependent asthma. In some embodiments, the asthma is eosinophilic asthma. In some embodiments, the asthma is high eosinophil eosinophilic asthma. In some embodiments, the asthma is an overlapping syndrome of eosinophilic asthma and chronic obstructive pulmonary disease (COPD). In some embodiments, the PSAC is an eosinophilic PSAC with a high level of eosinophils.

The present invention provides methods for treating a patient having PSAH, comprising administering an ALOX15 inhibitor to the patient.

The present invention provides methods for treating an atopic patient, comprising administering an ALOX15 inhibitor to the patient. In some embodiments, the atopy is allergic rhinitis, asthma, and/or atopic dermatitis.

In some embodiments, the respiratory disorder is chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, allergic pneumonia, and/or allergic respiratory disease.

In some embodiments, the ALOX15 inhibitor comprises an antisense molecule. Examples of antisense molecules include, but are not limited to, antisense nucleic acid molecules, small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). Such antisense molecules can be designed to target any region of the ALOX15 mRNA. In some embodiments, the antisense RNA, siRNA, or shRNA hybridizes to a sequence in an ALOX15 genomic nucleic acid molecule or mRNA molecule and reduces expression of the ALOX15 polypeptide in a subject's cell. In some embodiments, the ALOX15 inhibitor comprises an antisense RNA that hybridizes to an ALOX15 genomic nucleic acid molecule or mRNA molecule and reduces the expression of an ALOX15 polypeptide in a subject's cell. In some embodiments, the ALOX15 inhibitor comprises an antisense siRNA that hybridizes to an ALOX15 genomic nucleic acid molecule or mRNA molecule and reduces the expression of an ALOX15 polypeptide in a subject's cell. In some embodiments, the ALOX15 inhibitor comprises an antisense shRNA that hybridizes to an ALOX15 genomic nucleic acid molecule or mRNA molecule and reduces the expression of an ALOX15 polypeptide in a subject's cell. In some embodiments, shRNA contains: a) CC

GGGAAACTGGAAGGACGGGTTAACTCGAGTTAACCCGTCCTTCCAGTTTCTTTTTTG (SEQ ID NO:9); b) CCGGGCTATCAAAGACTCTCTAAATCTCGAGATTTAGAGAGTCTTTGATAGCTTTTTG (SEQ ID NO:10); c) CCGGTGGGAAATCATCTATCGGTATCTCGAGATACCGATAGATGATTTCCCATTTTTG (SEQ ID NO:11); d) CCGGCCTGGAAGGAAGATGCCTTATCTCGAGATAAGGCATCTTCCTTCAGGTTTTTG (SEQ ID NO:12); e) CCGGCCAGTTTCTTAATGGCGCCAACTCGAGTTGGCGCCATTAAGAAACTGGTTTT

TG (SEQ ID NO:13); f) CCGGGCCGTCGATACATCCTATCTTCTCGAGAAGATAGGATGTATCGACGGCT

TTTTG (SEQ ID NO:14); g) CCGGTAGATGACTTCAACCGGATTTCTCGAGAAATCCGGTTGAAGTCATCT

ATTTTTTG (SEQ ID NO:15); or h) CCGGTGGTACTCTTGGGTGCCTAATCTCGAGATTAGGCACCCAAGA

GTACCATTTTTTG (SEQ ID NO: 16).

In some embodiments, the ALOX15 inhibitor comprises a nuclease agent that induces one or more notches or double-strand breaks in the recognition sequence(s) or DNA-binding protein that binds to the recognition sequence in the ALOX15 genomic nucleic acid molecule. The recognition sequence may be located in the coding region of the ALOX15 gene or in regulatory regions that affect the expression of this gene. The recognition sequence of a DNA binding protein or nuclease agent may be located in an intron, exon, promoter, enhancer, regulatory region, or any region that does not code for a protein. The recognition sequence may include or be located near the start codon of the ALOX15 gene. For example, the recognition sequence may be located about 10, about 20, about 30, about 40, about 50, about 100, about 200, about 300, about 400, about 500, or about 1000 nucleotides from the start codon. As another example, two or more nuclease agents can be used, each targeting a nuclease recognition sequence including or adjacent to a start codon. As another example, two nuclease agents can be used, one targeting a nuclease recognition sequence including or near a start codon, and one targeting a nuclease recognition sequence including or near a stop codon, wherein cleavage with nuclease agents can remove the coding region between the two nuclease recognition sequences. Any nuclease agent that induces a notch or double-strand break in the desired recognition sequence can be used in the methods and compositions described herein. Any DNA binding protein that binds to the desired recognition sequence can be used in the methods and compositions described herein.

Suitable nuclease agents and DNA binding proteins for use in the present invention include, but are not limited to, zinc finger protein or a pair of zinc finger nucleases (ZFNs), a transcription activator-like effector protein (TALE), or an effector nuclease like transcription activators (TALEN), or regularly spaced short palindromic repeats (CRISPR)/CRISPR-associated systems (Cas). The length of the recognition sequence may vary and includes, for example, recognition sequences that are about 30-36 bp. for a zinc finger protein or ZFN pair, about 15-18 bp. for each ZFN, about 36 bp for the TALE or TALEN protein and about 20 bp. for CRISPR/Cas guide RNA.

In some embodiments, CRISPR/Cas systems can be used to modify the ALOX15 genomic nucleic acid molecule in a cell. The methods and compositions disclosed herein can utilize CRISPR-Cas systems by using CRISPR complexes (comprising a guide RNA (gRNA) complexed with a Cas protein) to site-directly cleave ALOX15 nucleic acid molecules.

Cas proteins typically contain at least one RNA recognition or binding domain that can interact with gRNA. Cas proteins may also contain nuclease domains (such as, for example, DNase or RNase domains), DNA binding domains, helicase domains, protein-protein interaction domains, dimerization domains, and other domains. Suitable Cas proteins include, for example, wild-type Cas9 protein and wild-type Cpf1 protein (eg, FnCpf1). The Cas protein may have full cleavage activity to create a double-strand break in the ALOX15 genomic nucleic acid molecule, or it may be a nickase that creates a single-strand break in the ALOX15 genomic nucleic acid molecule. Additional examples of Cas proteins include, but are not limited to, Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas5e (CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8a1, Cas8a2, Cas8b, Cas8c, Cas9 (Csn1 or Csx12), Cas10, Cas10d, CasF, CasG, CasH, Csy1, Csy2, Csy3, Cse1 (CasA), Cse2 (CasB), Cse3 (CasE), Cse4 (CasC), Csc1, Csc2, Csa5, Csn2, Csm2, Csm3 , Csm4, Csm5, Csm6, Cmr1 , Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx15, Csf1, Csf2, Csf3, Csf4 and Cu1966 as well also their homologues or modified versions. Cas proteins can also be operably linked to heterologous polypeptides as fusion proteins. For example, a Cas protein can be fused to a cleavage domain, an epigenetic modification domain, a transcriptional activation domain, or a transcriptional repression domain. The Cas proteins may be provided in any form. For example, the Cas protein may be provided in the form of a protein, such as a Cas protein complexed with gRNA. Alternatively, the Cas protein may be provided as a nucleic acid molecule encoding a Cas protein, such as RNA or DNA.

In some embodiments, targeted genetic modifications of ALOX15 genomic nucleic acid molecules can be obtained by contacting a cell with a Cas protein and one or more gRNAs that hybridize to one or more gRNA recognition sequences at the target genomic locus in the ALOX15 genomic nucleic acid molecule. . For example, the gRNA recognition sequence may be located within the region of SEQ ID NO: 1. The gRNA recognition sequence may also include or be located near the position corresponding to position 9917 according to SEQ ID NO: 1. For example, the gRNA recognition sequence may be located at a distance of about 1000, about 500, about 400, about 300, about 200, about 100, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10 or about 5 nucleotides from the position corresponding to position 9917 according to SEQ ID NO: 1. The gRNA recognition sequence includes or is located near the start codon of the ALOX15 genomic nucleic acid molecule or the stop codon of the ALOX15 genomic nucleic acid molecule. For example, the gRNA recognition sequence may be located about 10, about 20, about 30, about 40, about 50, about 100, about 200, about 300, about 400, about 500, or about 1000 nucleotides from said start codon or stop codon.

The gRNA recognition sequences within the target genomic locus in the ALOX15 genomic nucleic acid molecule are located next to the protospacer adjacent motif (PAM) motif sequence, which is a DNA sequence that immediately follows after 2-6 base pairs the DNA sequence targeted by Cas9 nuclease. The canonical PAM is the sequence 5'-NGG-3', where "N" is any nucleobase followed by two guanine ("G") nucleobases. gRNAs can transport Cas9 anywhere in the genome for gene editing, but no editing can occur at any site other than the one where Cas9 recognizes PAM. In addition, 5'-NGA-3' may be a highly effective non-canonical PAM for human cells. Typically, the PAM is located about 2-6 nucleotides downstream (in the 3' direction) of the DNA sequence targeted by the gRNA. PAM can flank the gRNA recognition sequence. In some embodiments, the gRNA recognition sequence may be flanked by PAM at the 3' end. In some embodiments, the gRNA recognition sequence may be flanked by a PAM at the 5' end. For example, the cleavage site of Cas proteins can be located 1 to 10 base pairs, 2 to 5 base pairs, or three base pairs upstream (in the 5' direction) or downstream (in the 3' direction) of the PAM sequence. In some embodiments (for example, when Cas9 from S. pyogenes or a closely related Cas9 is used), the PAM sequence of the non-complementary strand may be 5'-NGG-3', where "N" is any DNA nucleotide and is located directly at the 3' position to the gRNA recognition sequence of the non-complementary strand of the target DNA. Thus, the complementary strand PAM sequence will be 5'-CCN-3', where "N" is any DNA nucleotide and is located immediately 5' to the gRNA recognition sequence of the complementary strand of the target DNA.

gRNA is an RNA molecule that binds to the Cas protein and targets the Cas protein to a specific location in the ALOX15 genomic nucleic acid molecule. An exemplary gRNA is a gRNA that effectively directs the Cas enzyme to bind or cleave an ALOX15 genomic nucleic acid molecule, wherein said gRNA contains a DNA targeting segment that hybridizes to a gRNA recognition sequence in an ALOX15 genomic nucleic acid molecule that includes or is adjacent to position corresponding to position 9917. For example, the gRNA can be chosen such that it hybridizes to a gRNA recognition sequence that is about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40 , about 45, about 50, about 100, about 200, about 300, about 400, about 500, or about 1000 nucleotides from the position corresponding to position 9917 according to SEQ ID NO: 1. Other exemplary gRNAs contain a DNA targeting segment that hybridizes to a gRNA recognition sequence present in the ALOX15 genomic nucleic acid molecule that includes or is located near said start codon or said stop codon. For example, the gRNA can be chosen such that it hybridizes to a gRNA recognition sequence that is about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50 , about 100, about 200, about 300, about 400, about 500 or about 1000 nucleotides from the specified start codon, or located at a distance of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 100, about 200, about 300, about 400, about 500, or about 1000 nucleotides from said stop codon. Suitable gRNAs may be about 17 to about 25 nucleotides, about 17 to about 23 nucleotides, about 18 to about 22 nucleotides, or about 19 to about 21 nucleotides. In some embodiments, the implementation of gRNA may contain 20 nucleotides.

Examples of suitable gRNA recognition sequences located within the human ALOX15 reference gene are shown in Table 1 as SEQ ID NOs: 19-43.

Table 1: Guide RNA recognition sequences near ALOX15 variant(s)

Chain Guide RNA recognition sequence SEQID NO: - TACCAAGCACGCGAGCCCCGTGG 19 + GACCACGGGGCTCCGTGTGCTTGG 20 + ACGGGGCTCGCGTGCTTGGTAGG 21 - GCATCCTTGGTGGTTGGCGGGGG 22 - CGGGGGCAGCCGCATCGTGCAGG 23 + TTAGCTGGACTGGTACTCTTGGG 24 - GGGGGCAGCCGCATCGTGCAGGG 25 + CTTAGCTGGACTGGTACTCTTGG 26 - TGCATCCTTGGTGGTTGGCGGGG 27 - CAAGAGTACCAGTCCAGCTAAGG 28 + GATGTCCATCACTTGGCAGCTGG 29 - GTACCAGTCCAGCTAAGGAAGGG thirty - TTGCATCCTTGGTGGTTGGCGGG 31 + CTGTGTGCAGGTGGACCACGGGG 32 + TCTGTGTGCAGGTGGACCACGGG 33 + TGCTTGGTAGGCACTGACTCTGG 34 - AGTACCAGTCCAGCTAAGGAAGG 35 + CTGCCCTTCCTTAGCTGGACTGG 36 + GACACTGCCCAACTTCCACCAGG 37 - AGAGAAGCCTGGTGGAAGTTGGG 38 + GATCCCTGCCCTTCCTTAGCTGG 39 + GTCTGTGTGTCAGGTGGACCACGG 40 - CAGTCCAGCTAAGGAAGGGCAGG 41 - GCTGCCAAGTGATGGACATCTGG 42 - TCTGCCCAGCTGCCAAGTGATGG 43

The Cas protein and gRNA form a complex, and the Cas protein cleaves the target ALOX15 genomic nucleic acid molecule. The Cas protein can cleave a nucleic acid molecule at a site within or outside the nucleic acid sequence present in the target ALOX15 genomic nucleic acid molecule to which the DNA targeting gRNA segment will bind. For example, formation of a CRISPR complex (comprising gRNA hybridized to the gRNA recognition sequence and complexed to the Cas protein) can result in cleavage of one or both strands within or near (e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50 or more bp) nucleic acid sequence present in the ALOX15 genomic nucleic acid molecule to which the DNA targeting gRNA segment will bind.

Such methods may result, for example, in an ALOX15 genomic nucleic acid molecule in which the region of SEQ ID NO: 1 is disrupted, a start codon is disrupted, a stop codon is disrupted, or a coding sequence is disrupted or deleted. Optionally, the cell may further be contacted with one or more additional gRNAs that hybridize to additional gRNA recognition sequences at a target genomic locus in the ALOX15.beta. genomic nucleic acid molecule. By bringing the cell into contact with one or more additional gRNAs (such as, for example, a second gRNA that hybridizes to a second gRNA recognition sequence), cleavage with the Cas protein can create two or more double-strand breaks, or two or more single-strand breaks.

In some embodiments, the ALOX15 inhibitor is a small molecule. In some embodiments, the ALOX15 inhibitor is 6,11-dihydro[1]benzothiopyrano[4,3-b]indole (PD146176), 2-bromophenol, 2,4-dibromophenol, 2-(1-thienyl)ethyl-3, 4-dihydroxybenzylidenecyanoacetate (TEDC), 4,4'-(2,3-dimethyl-1,4-butandiyl)bis-1,2-benzenediol (nordihydroguaiaretic acid) or cinnamyl-3,4-dihydroxy-a-cyanocinnamate (CDC ). In some embodiments, the ALOX15 inhibitor is 2-bromophenol, 2,4-dibromophenol, 2-(1-thienyl)ethyl-3,4-dihydroxybenzylidenecyanoacetate (TEDC), or 4,4'-(2,3-dimethyl-1, 4-butandiyl)bis-1,2-benzenediol (nordihydroguaiaretic acid).

In some embodiments, the methods of treatment further comprise detecting the presence or absence of a variant nucleic acid molecule with predicted loss of function ALOX15 encoding a human ALOX15 polypeptide in a biological sample from a patient. As used throughout this disclosure, "an ALOX15 predictive loss of function variant nucleic acid molecule" is any ALOX15 nucleic acid molecule (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule) encoding an ALOX15 polypeptide having a partial loss of function. function, total loss of function, predicted partial loss of function, or predicted total loss of function.

The invention also provides methods of treating a patient with a therapeutic agent that treats or inhibits a respiratory disorder, wherein the patient is suffering from a respiratory disorder. In some embodiments, the methods include determining whether a patient has a variant ALOX15 loss-of-function nucleic acid molecule encoding a human ALOX15 polypeptide by obtaining or obtaining a biological sample from the patient and performing or performing genotyping on said biological sample to determine whether whether the patient has a genotype containing said variant nucleic acid molecule with predicted loss of ALOX15 function. When the patient is an ALOX15 reference, then the therapeutic agent that treats or inhibits the respiratory disorder is administered or continues to be administered to the patient in a unit dose amount, and the ALOX15 inhibitor is administered to the patient. When the patient is heterozygous for the predicted loss of ALOX15 function variant, then the therapeutic agent that treats or inhibits the respiratory disorder is or continues to be administered to the patient in an amount equal to or less than the standard dose amount, and the ALOX15 inhibitor is administered to the patient. The presence of a genotype having a variant ALOX15 loss-of-function nucleic acid molecule encoding a human ALOX15 polypeptide indicates that the patient has a reduced risk of developing a respiratory disorder. In some embodiments, the patient is an ALOX15 reference. In some embodiments, the patient is heterozygous for the predicted loss of ALOX15 function variant.

For human subjects or patients that are genotyped or determined to be either ALOX15 reference or heterozygous for a predicted loss of ALOX15 function variant, such human subjects or patients can be treated with an ALOX15 inhibitor as described herein.

Detecting the presence or absence of an ALOX15 predictive loss of function nucleic acid molecule in a biological sample from a patient and/or determining whether a patient has an ALOX15 predictive loss of function nucleic acid molecule can be performed by any of the methods described herein. In some embodiments, these methods can be performed in vitro. In some embodiments, these methods can be performed in situ. In some embodiments, these methods can be performed in vivo. In any of these embodiments, the nucleic acid molecule may be present in a cell derived from a human subject.

In some embodiments, when the patient is an ALOX15 reference, the patient is also administered a therapeutic agent that treats or inhibits a respiratory disorder in a unit dose amount. In some embodiments, when the patient is heterozygous for the predicted loss of function ALOX15 variant, the patient is also administered a therapeutic agent that treats or inhibits a respiratory disorder in an amount equal to or less than the standard dose amount.

In some embodiments, the methods of treatment further comprise detecting the presence or absence of a loss-of-function predictive ALOX15 polypeptide in a biological sample from a patient. In some embodiments, when the patient does not have a predicted loss of function ALOX15 polypeptide, the patient is also administered a therapeutic agent that treats or inhibits the respiratory disorder in a unit dose amount. In some embodiments, when the patient has an ALOX15 polypeptide with predicted loss of function, the patient is also administered a therapeutic agent that treats or inhibits a respiratory disorder in an amount equal to or less than the standard dose amount.

The invention also provides methods of treating a patient with a therapeutic agent that treats or inhibits a respiratory disorder, wherein the patient is suffering from a respiratory disorder. In some embodiments, the method includes determining if a patient has an ALOX15 polypeptide with predicted loss of function by obtaining or obtaining a biological sample from said patient and performing or performing an analysis on said biological sample to determine if the patient has an ALOX15 polypeptide with predictive loss of function. loss of function. When a patient does not have an ALOX15 polypeptide with predicted loss of function, then a therapeutic agent that treats or inhibits a respiratory disorder is administered or continues to be administered to the patient in a unit dose amount, and the ALOX15 inhibitor is administered to the patient. When a patient has an ALOX15 polypeptide with predicted loss of function, then the therapeutic agent that treats or inhibits the respiratory disorder is or continues to be administered to the patient in an amount equal to or less than the standard dose amount, and the ALOX15 inhibitor is administered to the patient. The presence of an ALOX15 polypeptide with predicted loss of function indicates that the patient has a reduced risk of developing a respiratory disorder. In some embodiments, the patient has an ALOX15 polypeptide with predicted loss of function. In some embodiments, the patient does not have an ALOX15 polypeptide with predicted loss of function.

Detecting the presence or absence of an ALOX15 predictive loss of function polypeptide in a biological sample from a patient and/or determining whether a patient has an ALOX15 predictive loss of function polypeptide can be performed by any of the methods described herein. In some embodiments, these methods can be performed in vitro. In some embodiments, these methods can be performed in situ. In some embodiments, these methods can be performed in vivo. In any of these embodiments, said polypeptide may be present in a cell derived from a human subject.

Examples of therapeutic agents that treat or inhibit a respiratory disorder include, but are not limited to, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, anti-proliferative agents, anti-macrophage agents, muscle relaxants, narcotic analgesics, non-opioid analgesics, local anesthetics, and other agents. An additional example of a therapeutic agent that treats or inhibits a respiratory disorder is an interleukin-4 receptor (IL-4Rα) antagonist such as, for example, DUPIXENT® (dupilumab).

Examples of steroidal anti-inflammatory agents include, but are not limited to, glucocorticoids and corticosteroids such as, for example, 21-acetoxypregnenolone, alklomethasone, algeston, amycinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone , cortisone, cortivazole, deflazacort, desonide, deoxymethasone, dexamethasone, diflorazone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortine butyl, fluocortolone, fluorometholone , fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide , fluticasone, formocortal, halcinonide, halobetasol priopionate, halomethasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisone sodium phosphate, prednisone, prednival, prednilidene, rimexolone, thixocortal, triamcinolone, triamcinolone acetonide, triamcinolone benetonide and triamcinolone hexacetonide.

Examples of non-steroidal anti-inflammatory agents include, but are not limited to, aminoarylcarboxylic acid derivatives such as, for example, enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, and tolfenamic acid; arylacetic acid derivatives such as, for example, acemetacin, alklofenac, amfenac, bufexamac, cinmethacin, clopirac, diclofenac, etodolac, felbinac, fenclofenac, fenclorac, fenclosic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac , methiasinic acid , oxamethacin, proglumethacin, sulindac, thiaramide, tolmetin and zomepirak; arylbutyric acid derivatives such as, for example, bumadison, butibufen, fenbufen and xenbucin; arylcarboxylic acids such as, for example, clidanac, ketorolac and tinoridin; arylpropionic acid derivatives such as, for example, alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miroprofen, naproxen, oxaprozin, piketoprofen, pyrprofen, pranoprofen, pro tisic acid, supprofen and thiaprofenic acid; pyrazoles such as, for example, diphenamisole and epirizole; pyrazolones such as, for example, apazone, benzpiperilone, feprazone, mofebutazone, morazone, oxyphenbutazone, phenibutazone, pipebusone, propyphenazone, ramiphenazone, suxibuzone and thiazolinobutazone; salicylic acid and its derivatives, such as, for example, acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, estersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl salicylate lat, olsalazin , parsalmid, phenylacetylsalicylate, phenyl salicylate, salacetamide, salicylamine o-acetic acid, sulfosalicylic acid, salsalate and sulfasalazine; thiazinecarboxamides such as, for example, droxicam, isoxicam, piroxicam and tenoxicam; and other agents such as e.g. , paranilin, perizoxal, pifoxime, proquasone, proxazole and tenidap.

Examples of antiproliferative agents include, but are not limited to, anthracyclines, alkyl sulfonates, agents that affect microtubule dynamics, agents that affect various growth factors, including IGF pathway agents such as somatostatin analogs, angiotensin-converting enzyme inhibitors, antimetabolites (e.g., purine analogs), cytotoxic agents, cytostatic agents, cell proliferation affectors, caspase activators, proteasome inhibitors, angiogenesis inhibitors, ethyleneimines, intercalating agents, metal coordination complexes, nitrogen mustard, nitrosoureas, nucleic acid damaging agents such as alkylating agents, purine analogs , pyrimidine analogs, pyrimidine biosynthesis inhibitors, vinca alkaloids. Additional examples include, but are not limited to, adriamycin, alitretinoin (9-cis-retinoic acid), amifostine, angiopeptin, angiostatin, arabinosyl 5-azacytosine, arabinosylcytosine, 5-aza-2'-deoxycytidine, 6-azacytidine, 6-azauridine, azaribin, bexarotene (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoic acid), bleomycin, BCNU, CCNU, captopril, capecitabine (5'-deoxy-5-fluorocytidine), chlorambucil, colchicine, cilazapril, cisplatin, cladribine (chlorinated purine nucleoside analogue), cytarabine, cyclocytidine, cyclophosphamide, daunorubicin, 3-deazauridine, 2'-deoxy-5 -fluorouridine, 5'-deoxy-5-fluorouridine, docetaxel, doxorubicin, endostatin, epirubicin, epothilone, estramustine, etoposide, exemestane, flutamide, fludarabine, fludarabine phosphate, fluorocytosine, 5-fluorouracil, 5-fluorouridine, 5-fluoro-2 '-doxyuridine, hemcitabin, hydroxymochevin, Idarubicin, irinothens, analogues of LhRH, Lisinopril, Melfalan, Metrexate, 6-Merkaptopurin, Mitoxantron, Paclitaksel, Pentostatin, N-Fosphonoacethyl-L-Acparagina, Perenimustin, Piraisophy Rin, Squlam, streptozocin, tamoxifen, temozolomide, teniposide, 6-thioguanine, tomodex, thiotepa, topotecan, 5-trifluoromethyl-2'-deoxyuridine, valrubicin, vincristine, vinblastine, and vinarelbine.

Examples of anti-macrophage agents include, but are not limited to, bisphosphonates and clodronate compounds such as, for example, dichloromethylene diphosphonate (CL2MDP).

Examples of muscle relaxants include, but are not limited to: anticholinergic agents (e.g., adifenin, alverin, ambutonomy, aminopentamide, amixetrine, amprotropine phosphate, anisotropine methyl bromide, apoatropine, atropine, atropine n-oxide, benactizine, benaprisine, benzethimide, benzylone ii, benztropine mesylate, bevonium methyl sulfate, biperiden, butropium, n-butylscopolammonium bromide, busepid, camilofin, caramiphene, chlorobenzoxamine, chlorophenoxamine, cimetropium, clidinium, cyclodrin, cyclonium, cycrimine, deptropine, dexetimide, dibutolin sulfate, dicyclomine, dietazine, diphemerin, dihexiverin, diphemanylmethylsulfate, n-(1,2-diphenylethyl)nicotinamide, dipiverin, diponium, emepronium, endobenziline, etopropazine, ethbenztropine, ethylbenzhydramine, etomidoline, eucatropine, fenpiverinium, fentonium, flutropium, glycopyrrolate, heteronium, hexocyclium methyl sulfate, homatropine, hyoscia min, ipratropium, isopropamide, levomepat, mecloxamine, mepenzolate, methcarafen, methantheline, methixene, metscopolamine, octylamine, oxybutynin, oxyphencyclimine, oxyphenonium, pentapiperide, pentienate, phencarbamide, fenglutarimide, pipenzolate, piperidolate, piperylate, halfdine methysulfate, pridinol, prifinium, procyclidine, propanteline, propenzolate , propiverine, propyromazine, scopolamine, scopolamine n-oxide, stramonium, sultroponium, tifenamil, thiemonium, timepidium, tikvizium, tridihexetyl iodide, trihexyphenidyl hydrochloride, trimebutine, tropacin, tropenzil, tropicamide, trospium, valetamate, vamimide and xenitropium); alcuronium, atracurium, baclofen, benzodiazepines (eg clozapine or diazepam), botulinum toxin (BOTOX), 4-amino-3-(4-chlorophenyl)butanoic acid, carbolonium, carisoprodol, chlorphenesin, chlorzoxazon, cyclobenzaprine, cyclandelate, dantrolene, decamethonium bromide, diazepam, hydralazine, fazadinium, gallamine, guaifenesin, hexafluorenium, isoxsuprine, meladrazine, mefenzine, metaxalone, methocarbamol, nilidrine, methocurine iodide, orphenadrine, pancuronium, papaverine, pridinol, styramate, suxamethonium, suxetonium, thiocolchi cozid, tizanidine, suxamethonium, tolperisone, and tubocurarine; bronchodilators (ephedrine derivatives such as, for example, albuterol, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenaline, dioxetedrine, ephedrine, epiniphrine, eprosinol, ephedrine, ethylnorepinephrine, fenoterol, hexoprenaline, isoetarine, isoproterenol, mabuterol, metaproterenol, n -methylephedrine, pirbuterol, procaterol, protokilol, reproterol, rimiterol, salmeterol, soterenol, terbutaline and tulobuterol; quaternary ammonium compounds such as, for example, bevonium methyl sulfate, clatropium bromide, ipratropium bromide; and oxitropium bromide; xanthine derivatives, such as, for example, acephylline, acephylline piperazine, ambuphylline, aminophylline, bamiphylline, choline theophyllinate, doxophylline, difillin, enprofylline, etamifillin, etophylline, guaityllin, proxyfillin, theobromine, 1-theobrominoacetic acid and theophylline; and other bronchodilators such as, for example, fenspiride, medibazine, monteculast, methoxyphenanim, tretoquinol, zafirkulast and catecholamine analogues such as formoterol); antispasmodic agents (eg, alibendol, ambucetamide, aminopromazine, apoatropine, bevonium methyl sulfate, bietamiverine, butaverine, butropium bromide, n-butylscopolammonium bromide, caroverine, cimetropium bromide, cinnamedrine, cleboprid, coniine hydrobromide, coniine hydrochloride, cyclo nia iodide, difemerin, diisopromine, dioxafetyl butyrate, diponium bromide, drofenin, emepronium bromide, etaverine, feclemin, phenalamide, fenoverine, fenpipran, fenpiverinium bromide, fentonium bromide, flavoxate, flopropion, gluconic acid, guaiactamine, hydramitrazine, hymecromone, leiopyrrole, mebe verin, moxaverin, nafiverin, octamylamine, octaverine, oxybutynine chloride, pentapiperide, fenamacid hydrochloride, phloroglucinol, pinaverium bromide, piperylate, pipoxolane hydrochloride, pramiverine, prifinium bromide, properidin, propivane, propyromazine, prozapine, racefemin, rociverin, spasmolitol, stilonium iodide, sultroponium, thiemonium iodide, tikwizia bromide, tiropramide, trepibutone, tricromyl, trifolium, trimebutine, n, n-1-trimethyl-3,3-diphenylpropylamine, tropenzil, trospium chloride, and xenitropium bromide); and anticholinergic agents (eg, adifenin, alverin, ambutonomy, aminopentamide, amixetrine, amprotropine phosphate, anisotropine methyl bromide, apoatropine, atropine, atropine n-oxide, benactizine, benaprisine, benzethimide, benzyloniium, benztropine mesylate, bevonium methyl sulfate, biperiden, butropium, n -butylscopolammonium bromide, busepid, camilofin, caramiphene, chlorobenzoxamine, chlorophenoxamine, cimetropium, clidinium, cyclodrin, cyclonium, cycrimin, deptropine, dexetimide, dibutolin sulfate, dicyclomine, diethazine, diphemerin, dihexiverine, diphemanyl methyl sulfate, n-(1,2-diphenylethyl ) nicotinamide, dipiverin, diponium, emepronium, endobenziline, etopropazine, ethbenztropine, ethylbenzhydramine, etomidoline, eucatropine, fenpiverinium, fentonium, flutropium, glycopyrrolate, heteronium, hexocyclium methyl sulfate, homatropine, hyoscyamine, ipratropium, isopropamide, levomepat, mek loxamine, mepenzolate, methcarafen, methantheline , methixene, metscopolamine, octamylamine, oxybutynine, oxyphencyclimine, oxyphenonium, pentapiperide, pentienate, phencarbamide, fenglutarimide, pipenzolate, piperidolate, piperylate, halfdine methisulfate, pridinol, prifinium, procyclidine, propanteline, propenzolate, propiverine, propyromazine, scop olamine, scopolamine n-oxide , stramonium, sultroponium, tifenamil, thiemonium, timepidium, tikvizium, tridihexetyl iodide, trihexyphenidyl hydrochloride, trimebutine, tropacine, tropenzil, tropicamide, trospium, valetamate, vamicamide, and xenitropium).

Examples of narcotic analgesics include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, besytramid, buprenorphine, butorphanol, clonitazen, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, desomorphine, dextromoramide, dezocin, diampromide, dihydrocodeine, dihydrocodeinone enolacetate, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafetyl butyrate, dipipanone, eptazocine, etoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol , lofentanil, meperidine, meptazinol, methazocine, methadone hydrochloride, metopone, morphine, myrofin, nalbuphine, narcein, nycomorphine, norlevorphanol, normetadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveret, pentazocine, fenadoxone, phenazocine, feoperidine, piminodine, pyrithramide, proheptazine, promedol, properidin, propyram , propoxyphene, rumifentanil, sufentanil and tilidine.

Examples of non-narcotic analgesics include the following, but are not limited to them: aceklofenac, acetaminophene, ascetaminosalol, acetalide, acetylsalicylic acid, alminopenac, aloxyprofen, aloxyprin, aluminum BIS (acetylsalcilate), aminochlortenzazin, 2-amino-picolin Propilo, aminopyrine, Ammonium Salicylate, Amtolmetin Guacyl, Antipyrine, Antipyrine Salicylate, Anthrafenin, Apazon, Aspirin, Benorylate, Benoxaprofen, Benzpiperylone, Benzydamine, Bermoprofen, Brofenac, p-Bromoacetanilide, 5-Bromosalicylic Acid Acetate, Bucetin, Bufeksamak, Bumadizon, But acetin, calcium acetylsalicylate, carbamazepine, carbifen, carsalam, chloralantipyrine, chlortenoxazine, choline salicylate, cinchofen, cyramadol, clomethacin, cropropamide, crometamide, dexoxadrol, difenamizole, diflunisal, dihydroxyaluminum acetylsalicylate, dipyrocetyl, dipyrone, emorphazone, enfenamic acid, epirizole, etersa lat, etenzamide, ethoxazene, etodolac , felbinac, fenoprofen, floktafenin, flufenamic acid, fluoreson, flupirtine, fluproquasone, flurbiprofen, phosphosal, gentisic acid, glafenin, ibufenac, imidazole salicylate, indomethacin, indoprofen, isofezolac, isoladol, isonixin, ketoprofen, ketorolac, p-lactofenetide, lephetamine, loxoprofen, lysine acetylsalicylate, magnesium acetylsalicylate, methotrimeprazine, metholine, miroprofen, morazone, morpholine salicylate, naproxen, nefopam, niphenazone, 5'-nitro-2'-propoxyacetanilide, parsalmid, perizoxal, phenacetin, phenazopyridine hydrochloride, phenocol, fe nopyrazone, phenylacetylsalicylate, phenyl salicylate, pheniramidol, pipebuson, piperilone, prodylidine, propacetamol, propyphenazone, proxazole, quinine salicylate, ramiphenazone, rimazolium methyl sulfate, salacetamide, salicin, salicylamide, salicylamide-o-acetic acid, sulfosalicylic acid, salsalate, salverin, simetride, sodium salicylate, sulfamipyrine , Suprofen, Talniflumate, Tenoxicam, Terofenamate, Tetradrine, Tinoridine, Tolfenamic Acid, Tolpronin, Tramadol, Viminol, Xenbucin, and Zomepirac.

Examples of local anesthetics include, but are not limited to, amukaine, amolanon, amylocaine hydrochloride, benoxinate, benzocaine, betoxicaine, biphenamine, bupivacaine, butacaine, butabene, butanylycaine, butetamine, butoxycaine, carcaine, chloroprocaine hydrochloride, cocaethylene, cocaine, cyclomethicaine , dibucaine hydrochloride, dimetisoquine, dimethocaine, diperadone hydrochloride, cyclonine, ecgonidine, ecgonine, ethyl chloride, beta-eucaine, euprocin, phenalcomine, fomocaine, hexylcaine hydrochloride, hydroxytetracaine, isobutyl-p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepiva kain, meprilkain , metabutoxycaine, methyl chloride, mirtecaine, naepaine, octacaine, orthocaine, oxetazaine, paretoxycaine, phenacaine hydrochloride, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine hydrochloride, pseudococaine, pyrrocaine, ropavacaine, salicylic alcohol, tetracaine hydrochloride, tolikain, trimekain and zolamine.

Examples of other agents include, but are not limited to, amlexanox, aminophylline, azelastine, beclomethasone dipropionate, cromolyn, dexamethasone, ephedrine, fenoterol, flatropium, hydrocortisone, ibudilast, ipratropium, isoprenaline, ZAJITEN™ (ketotifen), leukotriene modifiers such as montelukast, zafirlukast and zileuton, ZESURAN™ (mequitazine), nedocromil, orciprenaline, oxytomide, oxitropium, pranlukasta hydrate, prednisolone, procaterol, repyrinast, salbutamol, seratrodast, sodium chromoglycate, suplatast tosylate, terbutaline, terfenadine, theophylline, thiaramide , tranilast, traxanox, trimethoquinol and tubobuterol.

Examples of therapeutic agents that treat or inhibit a respiratory disorder that are suitable for use in the treatment of nasal polyps include, but are not limited to, periostin antagonists, PP1 antagonists, MET antagonists, PIP agonists, and AZGP1 agonists.

Examples of periostin antagonists include, but are not limited to, anti-human periostin polyclonal antibodies (BioVendor Laboratory Medicine, Inc, Modrice, Czech Republic, Cat #: RD-181045050) and anti-periostin monoclonal antibodies (see Tai et al. , Carcinogenesis, 2005, 26, 908-15) and valsartan.

Examples of PP1 antagonists (such as, for example, PP1c antagonists, PPP1R9B antagonists, and PPP1R6 antagonists) include, but are not limited to, anti-human neurabin 2 (also known as PPP1R9B) polyclonal antibody (Abcam, Inc, Cambridge, MA, USA). , catalog #: AB18561), an anti-PPP1R9B antibody (Novus Biological, Inc., Littleton, Colorado, USA, catalog #: H00084687-A01), inhibitory peptides specific for PP1 (such as, for example, a peptide having the amino acid sequence MEPDNSPRKIQFTVPLLEPHLDPEAAEQIRRRRPTPATLVLTSDQSSPEIDEDRIPNSLLKSTLS

MSPRQRKKMTRTTPTMKELQTMVEHHLGQKQGEEPEGATESTGNQESCPPGIPDTGSASRPDTPGTAQKSAESNPKTQEQCGVEPRTEDSSAHMLPLDSQGASLV) (SEQ ID NO: 17), and a peptide having the amino acid sequence MAASTASHRPIKGILKNKTSSTSSRVASAEQPRGSVDEELSKKSQKWDEMNILA

(SEQ ID NO: 18)); and dopamine and cyclic AMP regulated phosphoprotein (DARPP-32) (EMD Calbiochem, Inc., Gibbstown, NJ, USA, cat#: 251755); protein phosphatase inhibitors such as, for example, okadaic acid and caliculin A.

Examples of MET antagonists include, but are not limited to, polyclonal anti-human MET antibodies (Santa Cruz Biotechnology, Inc, Santa Cruz, CA, USA, catalog #: SC-10) and anti-MET antibodies (Sigma-Aldrich, St. Louis, Missouri, USA, P/N: C7115); tyrosine kinase inhibitors such as, for example, (3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrole-2 -yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide (SU11274) and 1,3-dihydro-3-((3,5-dimethyl-1H-pyrrole -2-yl)methylene)-2H-indol-2-one (SU5416).

Examples of PIP agonists include, but are not limited to, the PIP protein, recombinant PIP protein (Abnova, Taipei, Taiwan, Cat #: H00005304-P01), and PIP expression stimulators such as, for example, interleukin-4 and interleukin- 13; and tamoxifen.

Examples of AZGP1 agonists include, but are not limited to: AZGP1 protein, recombinant AZGP1 protein (Abnova, Taipei, Taiwan, cat#: 1100000563-P01); rosiglitazone, dexamethasone and (RR+SS)-(±)-4-(2-(2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)phenoxyacetate (BRL 37344).

Examples of therapeutic agents that treat or inhibit a respiratory disorder that are suitable for use in the treatment of allergic rhinitis include, but are not limited to, corticosteroids, H1 antagonists/antiallergic agents, histamine receptor antagonists, chemical mediator release inhibitors, thromboxane receptor antagonists A2, thromboxane A2 synthesis inhibitors, leukotriene antagonists, Th2 cytokine inhibitors, TNF-alpha antagonists, PDE4 inhibitors, JAK3 inhibitors, and p38 kinase inhibitors.

Examples of corticosteroids include, but are not limited to, beclomethasone esters (KONAZE™, ARUDESHIN™, RHINOCORT™, SARUKOTO™ (17-propionate ester or 17,21-dipropionate ester), Furunaze™ (fluticasone propionate), budesonide, flunisolide, mometasone esters (eg, furoate ester), triamcinolone acetonide, rofleponide, and ciclesonide.

Examples of H1 antagonists/antiallergic agents (antihistamines) include, but are not limited to, first generation H1 antihistamines such as e.g. piperoxam, ethylenediamine (e.g. , doxylamine, clemastine, and dimenhydrinate), alkylamines (eg, pheniramine, curorenamine (chlorpheniramine), cycloalkylnaphthoylmethyl Na Min dextrose, brompheniramine, and triprolidine), piperazines (eg, cyclizine, hydroxyzine, and meclizine), and tricyclics (eg, promethazine, alimemazine (trimeprazine) , cyproheptadine and azatadine); second-generation antihistamines such as, for example, systemic drugs (eg, acrivastine, astemizole, cetirizine, loratadine, mizolastine, and terfenadine) and topical drugs (eg, azelastine, levocabastine, and olopatadine (olopatidine); and third-generation antihistamines such as, for example, (levocetirizine, desloratadine (desloratidine) and ALLEGRA® (fexofenadine).

Examples of histamine receptor antagonists include, but are not limited to, ZAJITEN™ (ketotifen), ZESURAN™ (mequitazine), ALLEGRA® (fexofenadine), EBASUTERU™ (ebastine), TALION™ (bepotastine), ALLELOCK™ (olopatadine), and CLARITIN ® (loratadine).

Examples of chemical mediator release inhibitors include, but are not limited to, INTAL™ (cromoglycate) and RIZABEN™ (tranilast).

Examples of thromboxane A2 receptor antagonists include, but are not limited to, BRONICA™ (seratrodast) and BAINASU™ (ramatroban).

Examples of thromboxane A2 synthesis inhibitors include, but are not limited to, DOMENAN™ (fired).

Examples of leukotriene antagonists include, but are not limited to, SINGULAIR® and KIPRES™ (montelukast) and ONON™ (pranlukast).

Examples of Th2 cytokine inhibitors include, but are not limited to, IPD™ (suplatast).

Examples of TNF-alpha antagonists include, but are not limited to, ENBREL® (etanercept), REMICADE® (infliximab), and HUMIRA® (adalimumab).

Examples of PDE4 inhibitors include, but are not limited to, oliram, piclamylast, CDP-840, ariflo, pentoxifylline, denbuphylline, theophylline, substituted 8-arylquinoline phosphodiesterase-4 inhibitors (see U.S. Patent No. 6,740,666), alkynaryl phosphodiesterase-4 inhibitors (see US patent No. 6743802), 1-aryl-1,8-naphthyridin-4-one phosphodiesterase inhibitors (see US patent No. 6677351 and 6541480), hydroxyindoles (see US patent No. RE38624, 6613794 and 6602890), derivatives phthalazine (see U.S. Patent No. 6,589,951), tricyclic phthalazine derivatives (see U.S. Patent No. 6,525,055), benzazine derivatives (see U.S. Patent No. 6,358,973), benzamides with tetrahydrofuranyloxy substituents (see U.S. Patent No. 6,303,789), diazepinoindolones (see U.S. Patent No. 6,239,130), 1-oxo-1-3-substituted phenyl-1,4-dihydro-1,8-naphthyridine-3-carboxamide phosphodiesterase-4 inhibitors (see U.S. Patent Publication No. 2006/0058316), N -substituted diarylamines (see U.S. Patent Publication No. 2005-0222207), allin-arylphosphodiesterase-4 inhibitors (see U.S. Pat. US Patent Publication No. 2005-0070569) and naphthyridine derivatives (see US Patent Publication No. 2004-0254212).

Examples of JAK3 inhibitors include, but are not limited to, tacrolimus, CP-690550, WHI-P131, WHIP-97, WHIP-154, AG490, PS-608504, and PNU156804. Additional examples include, but are not limited to: 2-(1H-benzimidazol-1-yl)-9-[1(R)-(3-pyridyl)ethyl]-8,9-dihydro-7H-purine- 8-he; 2-(1H-benzimidazol-1-yl)-9-[4-oxo-1,2,3,4-tetrahydronaphthalen-1(R)-yl]-8,9-dihydro-7H-purin-8-one ; 1-[9-[6-fluoro-3,4-dihydro-2H-1-benzopyran-4(R)-yl]-8-oxo-8,9-dihydro-7H-purin-2-yl]-1H -benzimidazole-6-carbonitrile; 1-[9-[7-fluoro-3,4-dihydro-2H-1-benzopyran-4(R)-yl]-8-oxo-8,9-dihydro-7H-purin-2-yl]-1H -benzimidazole-6-carbonitrile; and 2-(1H-benzimidazol-1-yl)-9-[5,8-difluoro-3,4-dihydro-2H-1-benzopyran-4(R)-yl]-8,9-dihydro-7H- purine-8-one).

Examples of p38 kinase inhibitors include, but are not limited to, 3(5)-heteroaryl-substituted pyrazoles (see US Pat. No. 5,932,425). Additional examples of p38 kinase inhibitors include, but are not limited to, 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholine-4- yl-ethoxy)naphthalen-1-yl]urea (BIRB 796); SB202190; SB203580; VX-745; and VX-702.

Examples of therapeutic agents that treat or inhibit a respiratory disorder that are suitable for use in the treatment of AIRD include, but are not limited to, high dose aspirin therapy, P2Y12 inhibitors, leukotriene receptor antagonists, thromboxane receptor antagonists, and 5-lipoxygenase inhibitors.

Examples of P2Y12 inhibitors include, but are not limited to, PLAVIX™ (clopidogrel), cangrelor, ticagrelor, TICLID™ (ticlopidine), EFFIENT™ (prasugrel), and elinogrel (PRT060128 and PRT128).

Examples of leukotriene receptor antagonists include, but are not limited to, SINGULAIR™ and ACCOLATE™ (zafirlukast).

Examples of thromboxane receptor antagonists include, but are not limited to: HEPATOREN™ (iretroban), SERATRODAST™ (AA-2414), S18886 (terutroban), PTA2, 13-APA, GR-32191, BM-13177 (sulotroban), SQ-29,548, SQ-28,668, ONO-3708, Bay U3405, EP-045, BMS-180,291, S-145, I-BOP ([1S-[1-alpha,2-alpha(Z),3-beta( 1E,3S*),4-alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]5 -heptenoic acid), U46619 (9,11-dideoxy-9-alpha,11-alpha-methanoeroxy-prosto-5Z,13E-diene-1-oic acid), PBT-3 [10(S)-hydroxy-11, 12-cyclopropyl-eicose-5Z,8Z,14Z-trienoic acid methyl ester], hepoxillin cyclopropane, BM-531 (N-tert-butyl-N′-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), EV -077, L0655 and ICI 192.605.

Examples of 5-lipoxygenase inhibitors include, but are not limited to, ASTELIN™ and ASTELPRO™ (azelastine), diethylcarbamazine, nordihydroguaiaretic acid, and ZYFLO™ (zileuton).

In some embodiments, the dose of therapeutic agents that treat or inhibit a respiratory disorder may be reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% for patients or human subjects who are heterozygous for the predicted loss of ALOX15 function variant (i.e., lower than the standard dose amount) compared to human patients or subjects, who are ALOX15 reference (who can receive a standard dose amount). In some embodiments, the dose of therapeutic agents that treat or inhibit a respiratory disorder may be reduced by about 10%, about 20%, about 30%, about 40%, or about 50%. In addition, the dose of therapeutic agents that treat or inhibit respiratory distress in patients or human subjects who are heterozygous for the predicted loss of function ALOX15 variant may be administered less frequently compared to patients or human subjects that are ALOX15 reference.

Administration of therapeutic agents that treat or inhibit respiratory distress and/or ALOX15 inhibitors may be repeated, for example, one day, two days, three days, five days, one week, two weeks, three weeks, one month, five weeks , six weeks, seven weeks, eight weeks, two months or three months. Repeated administration can be carried out at the same dose or at a different dose. The introduction can be repeated once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times or more times. For example, in accordance with certain dosing regimens, the patient may receive therapy for an extended period of time, such as, for example, 6 months, 1 year, or longer.

Administration of therapeutic agents that treat or inhibit a respiratory disorder and/or ALOX15 inhibitors may be by any suitable route, including but not limited to: parenterally, intravenously, orally, subcutaneously, intra-arterially, intracranially, intrathecally, intraperitoneally, topically, intranasally, or intramuscularly. Pharmaceutical compositions for administration are preferably sterile and substantially isotonic, and are manufactured under the terms of the Good Manufacturing Practice (GMP). Pharmaceutical compositions may be presented in unit dosage form (ie dosage form for single administration). Pharmaceutical compositions may be formulated using one or more physiologically and pharmaceutically acceptable carriers, diluents, excipients or excipients. The appropriate formulation depends on the route of administration chosen. The term "pharmaceutically acceptable" means that the carrier, diluent, excipient or excipient is compatible with the other ingredients of the formulation and is not substantially harmful to their recipient.

The terms "treat", "treat" and "treatment", and "prevent", "prevention" and "prevention" as used herein, refer to inducing a desired biological response, such as a therapeutic and prophylactic effect, respectively. In some embodiments, the therapeutic effect includes one or more of the following: amelioration/reduction of the respiratory disorder, amelioration/reduction of the severity of the respiratory disorder (such as, for example, amelioration or inhibition of the development of the respiratory disorder), amelioration/reduction of symptoms and effects associated with respiratory distress, delayed onset of symptoms and effects associated with respiratory distress, reduced severity of symptoms of respiratory effects, reduced severity of acute episode, reduced number of symptoms and effects associated with respiratory distress, reduced latency of symptoms and effects associated with respiratory amelioration of symptoms and effects associated with a respiratory disorder, amelioration of secondary symptoms, amelioration of secondary infections, prevention of recurrence of a respiratory disorder, reduction in the number or frequency of relapse episodes, increased latency between symptomatic episodes, increased time to sustained progression, accelerated remission, induction of remission, enhancing remission, accelerating recovery, or increasing the effectiveness of alternative therapy, or reducing resistance to alternative therapy, and/or increased survival time of the affected host animal after administration of an agent or composition containing said agent. The prophylactic effect may include total or partial prevention/inhibition or delay in the development/progression of a respiratory disorder (eg, total or partial prevention/inhibition or delay) and an increase in the survival time of the affected host after the implementation of the therapeutic protocol. Treatment of a respiratory disorder includes treatment of patients already diagnosed with any form of respiratory disorder at any clinical stage or manifestation, delaying the onset or development of, or exacerbation of, or worsening of symptoms or signs of a respiratory disorder, and/or prevention and/or reduction in severity. respiratory disorder.

The invention also provides methods for identifying a human subject at increased risk of developing a respiratory disorder. In some embodiments, the method includes determining, in a biological sample obtained from a patient, the presence or absence of an ALOX15 predictive loss of function variant nucleic acid molecule (e.g., genomic nucleic acid molecule, mRNA molecule, and/or cDNA molecule) encoding a human ALOX15 polypeptide . When a human subject lacks a variant nucleic acid molecule with predicted loss of ALOX15 function (i.e., the human subject is genotypically characterized as ALOX15 reference), then said human subject has an increased risk of developing a respiratory disorder. When a human subject has an ALOX15 predictive loss of function nucleic acid molecule (i.e., the human subject is heterozygous for the ALOX15 predictive loss of function variant, or homozygous for the ALOX15 predictive loss of function variant), then said human subject has a reduced the risk of developing a respiratory disorder.

The presence of a single copy of the variant nucleic acid molecule with predicted loss of ALOX15 function is more protective of the human subject from the development of a respiratory disorder than the absence of copies of the variant nucleic acid molecule with predicted loss of ALOX15 function. Without intending to be bound by any particular theory or mechanism of action, it is believed that a single copy of the ALOX15 predictive loss-of-function variant nucleic acid molecule (i.e., heterozygosity for the ALOX15 predictive loss-of-function variant) protects the human subject from developing a respiratory disorder, and it is also believed that having two copies of the ALOX15 predictive loss-of-function variant nucleic acid molecule (i.e., homozygosity for the ALOX15 predictive loss-of-function variant) may better protect a human subject from developing a respiratory disorder compared to a human subject with a single copy . Therefore, in some embodiments, a single copy of the ALOX15 predicted loss of function variant nucleic acid molecule may not provide complete protection, but may instead partially or incompletely protect the human subject from developing a respiratory disorder. Without wishing to be bound by any particular theory, there may be additional factors or molecules involved in the development of a respiratory disorder that are still present in a human subject having a single copy of a variant nucleic acid molecule with predicted loss of ALOX15 function, resulting in incomplete protection. from the development of a respiratory disorder.

Detecting whether a human subject has an ALOX15 predictive loss of function nucleic acid molecule in a biological sample from a patient and/or determining whether a patient has an ALOX15 predictive loss of function nucleic acid molecule can be performed by any of the methods described in this document. In some embodiments, these methods can be performed in vitro. In some embodiments, these methods can be performed in situ. In some embodiments, these methods can be performed in vivo. In any of these embodiments, the nucleic acid molecule may be present in a cell derived from a human subject.

In some embodiments, when a human subject is identified as having an increased risk of developing a respiratory disorder, then said human subject is further treated with a therapeutic agent that treats or inhibits the respiratory disorder and/or with an ALOX15 inhibitor, as described herein. . For example, when a human subject is an ALOX15 reference and therefore has an increased risk of developing a respiratory disorder, then an ALOX15 inhibitor is administered to said human subject. In some embodiments, such a patient is also administered a therapeutic agent that treats or inhibits a respiratory disorder. In some embodiments, when the patient is heterozygous for the predicted loss of ALOX15 function variant, the patient is also administered a therapeutic agent that treats or inhibits a respiratory disorder in an amount equal to or less than the standard dose amount, and an ALOX15 inhibitor is also administered. In some embodiments, the patient is an ALOX15 reference. In some embodiments, the patient is heterozygous for the predicted loss of ALOX15 function variant.

The invention also provides methods for detecting the presence or absence of an ALOX15 predictive loss of function variant genomic nucleic acid molecule in a biological sample from a human subject and/or an ALOX15 predictive loss of function variant mRNA molecule in a biological sample from a human subject, and/or a molecule a variant cDNA with predicted loss of ALOX15 function derived from an mRNA molecule in a biological sample from a human subject. It should be understood that the gene sequences within a population and the mRNA molecules encoded by such genes may vary due to polymorphisms, such as single nucleotide polymorphisms. The sequences of the ALOX15 variant genomic nucleic acid molecule, the ALOX15 variant mRNA molecule, and the ALOX15 variant cDNA molecule shown herein are illustrative sequences only. Other sequences of the ALOX15 variant genomic nucleic acid molecule, variant mRNA molecule, and variant cDNA molecule are also possible.

The biological sample can be obtained from any cell, tissue or biological fluid of the subject. The sample may contain any clinically relevant tissue, such as a bone marrow sample, a tumor biopsy, a fine needle aspirate, or a body fluid sample such as blood, periodontal fluid, plasma, serum, lymph, ascitic fluid, cystic fluid, or urine. In some cases, the sample contains an oral swab. The sample used in the methods described herein will vary depending on the assay format, the nature of the detection method, and the tissues, cells, or extracts used as the sample. A biological sample may undergo different processing depending on the analysis used. For example, when a ALOX15 variant nucleic acid molecule is detected, pretreatment can be used to isolate or enrich the genomic DNA sample. For this purpose, various techniques can be applied. When detecting the level of any ALOX15 variant mRNA, different techniques can be used to enrich the biological mRNA sample. Various methods can be used to detect the presence or level of an mRNA molecule or the presence of a particular variant genomic DNA locus.

In some embodiments, detecting a variant nucleic acid molecule with a predictive loss of human ALOX15 function in a human subject includes analyzing or genotyping a biological sample obtained from said human subject to determine whether the ALOX15 genomic nucleic acid molecule contains ALOX15 in the biological sample, and/or an ALOX15 mRNA molecule in a biological sample and/or an ALOX15 cDNA molecule derived from an mRNA molecule in a biological sample one or more variations that cause loss of function (partial or complete) or are predicted to cause loss of function (partial or complete).

In some embodiments, methods for detecting the presence or absence of an ALOX15 predictive loss of function nucleic acid molecule (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, and/or a cDNA molecule derived from an mRNA molecule) in a human subject include performing analyzing a biological sample obtained from a human subject. Said analysis determines whether a nucleic acid molecule in a biological sample contains a particular nucleotide sequence.

In some embodiments, the nucleotide sequence contains: thymine at position corresponding to position 9917 according to SEQ ID NO: 2 (for genomic nucleic acid molecules); uracil at position corresponding to position 1693 according to SEQ ID NO: 4 (for mRNA molecules); or thymine at the position corresponding to position 1693 according to SEQ ID NO: 6 (for cDNA molecules derived from mRNA molecules). In some embodiments, the nucleotide sequence contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence. In some embodiments, the nucleotide sequence contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence. In some embodiments, the nucleotide sequence contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence.

In some embodiments, the biological sample contains a cell or cell lysate. Such methods may further include, for example, obtaining from the subject a biological sample containing the ALOX15 genomic nucleic acid molecule or mRNA molecule, and, in the case of mRNA, optionally reverse transcribing the mRNA into cDNA. Such assays may include, for example, identifying designated positions of a particular ALOX15 nucleic acid molecule. In some embodiments, the method is an in vitro method.

In some embodiments, the detection step, detection step, or genotyping comprises sequencing at least a portion of the nucleotide sequence of an ALOX15 genomic nucleic acid molecule, an ALOX15 mRNA molecule, or an ALOX15 cDNA molecule in a biological sample, wherein the sequenced portion contains one or more variations that cause loss of function (partial or complete) or are predicted to cause loss of function (partial or complete).

In some embodiments, the detection step, detection step, or genotyping comprises sequencing at least a portion of: the nucleotide sequence of an ALOX15 genomic nucleic acid molecule in a biological sample, wherein the sequenced portion contains a position corresponding to position 9917 according to SEQ ID NO: 2, or its complementary nucleotide sequence; the nucleotide sequence of the ALOX15 mRNA molecule in the biological sample, wherein the sequenced portion contains the position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and/or the nucleotide sequence of the ALOX15 cDNA molecule derived from the mRNA in the biological sample, wherein the sequenced portion contains the position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence. When the sequenced portion of the ALOX15 nucleic acid molecule in the biological sample contains thymine at the position corresponding to position 9917 according to SEQ ID NO: 2, uracil at the position corresponding to position 1693 according to SEQ ID NO: 4, or thymine at the position corresponding to position 1693 according to SEQ ID NO: 6, then the ALOX15 nucleic acid molecule in the biological sample is a variant nucleic acid molecule with predicted loss of ALOX15 function.

In some embodiments, the identification step, detection step, or genotyping comprises sequencing at least a portion of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule in a biological sample, wherein the sequenced portion contains a position corresponding to position 9917 according to SEQ ID NO: 2 or complementary her nucleotide sequence. When the sequenced portion of the ALOX15 nucleic acid molecule in the biological sample contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2, then the ALOX15 nucleic acid molecule in the biological sample is a variant nucleic acid molecule with predicted loss of ALOX15 function.

In some embodiments, the detection step, detection step, or genotyping comprises sequencing at least a portion of the nucleotide sequence of an ALOX15 mRNA molecule in a biological sample, wherein the sequenced portion contains a position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence. sequence. When the sequenced portion of the ALOX15 nucleic acid molecule in the biological sample contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4, then the ALOX15 nucleic acid molecule in the biological sample is a variant nucleic acid molecule with predicted loss of ALOX15 function.

In some embodiments, the detection step, detection step, or genotyping comprises sequencing at least a portion of the nucleotide sequence of an ALOX15 cDNA molecule in a biological sample, wherein the sequenced portion contains a position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence. sequence. When the sequenced portion of the ALOX15 nucleic acid molecule in the biological sample contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6, then the ALOX15 nucleic acid molecule in the biological sample is a variant nucleic acid molecule with predicted loss of ALOX15 function.

In some embodiments, the identification step, detection step, or genotyping comprises: a) contacting a biological sample with a primer that hybridizes to a portion of the ALOX15 nucleotide sequence: a genomic nucleic acid molecule located near the position corresponding to position 9917 according to SEQ ID NO : 2; mRNA molecules located near the position corresponding to position 1693 in accordance with SEQ ID NO: 4; and/or cDNA molecules located near the position corresponding to position 1693 in accordance with SEQ ID NO: 6; b) extending the primer at least inclusive to the position of the nucleotide sequence of ALOX15: genomic nucleic acid molecule corresponding to position 9917 in accordance with SEQ ID NO: 2; mRNA molecules corresponding to position 1693 according to SEQ ID NO: 4; and/or a cDNA molecule corresponding to position 1693 according to SEQ ID NO: 6; and c) determining whether the primer extension product contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2; uracil at position corresponding to position 1693 according to SEQ ID NO: 4; and/or thymine at position 1693 according to SEQ ID NO: 6.

In some embodiments, the detection step, detection step, or genotyping comprises: a) bringing the biological sample into contact with a primer that hybridizes to a portion of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule located near the position corresponding to position 9917 according to SEQ ID NO: 2; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule corresponding to position 9917 in accordance with SEQ ID NO: 2; and c) determining if the primer extension product contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2.

In some embodiments, the detection step, detection step, or genotyping comprises: a) bringing the biological sample into contact with a primer that hybridizes to a portion of the nucleotide sequence of the ALOX15 mRNA molecule located near the position corresponding to position 1693 according to SEQ ID NO: 4; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 mRNA molecule corresponding to position 1693 in accordance with SEQ ID NO: 4; and c) determining if the primer extension product contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4.

In some embodiments, the identification step, detection step, or genotyping comprises: a) bringing the biological sample into contact with a primer that hybridizes to a portion of the nucleotide sequence of the ALOX15 cDNA molecule located near the position corresponding to position 1693 according to SEQ ID NO: 6; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 cDNA molecule corresponding to position 1693 in accordance with SEQ ID NO: 6; and c) determining if the primer extension product contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6.

In some embodiments, the analysis includes sequencing the entire nucleic acid molecule. In some embodiments, only the ALOX15 genomic nucleic acid molecule is analyzed. In some embodiments, only ALOX15 mRNA is analyzed. In some embodiments, only ALOX15 cDNA derived from ALOX15 mRNA is analyzed.

In some embodiments, the detection step, detection step, or genotyping comprises: a) amplifying at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the amplified portion contains: i) a thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; ii) uracil at position corresponding to position 1693 according to SEQ ID NO:4 or its complementary nucleotide sequence; and/or iii) thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing a substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that, under stringent conditions, hybridizes with the nucleic acid sequence of the amplified nucleic acid molecule containing: i) thymine at the position corresponding to position 9917 in according to SEQ ID NO: 2 or its complementary nucleotide sequence; ii) uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and/or iii) thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and d) detecting a detectable label.

In some embodiments, the detection step, detection step, or genotyping comprises: a) amplifying at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the amplified portion contains thymine at position corresponding to position 9917 according to SEQ ID NO : 2 or its complementary nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing the substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; and d) detecting a detectable label.

In some embodiments, the detection step, detection step, or genotyping comprises: a) amplifying at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the amplified portion contains uracil at position corresponding to position 1693 according to SEQ ID NO :4 or its complementary nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing a substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and d) detecting a detectable label.

In some embodiments, the detection step, detection step, or genotyping comprises: a) amplifying at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the amplified portion contains thymine at position corresponding to position 1693 according to SEQ ID NO : 6 or its complementary nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing the substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and d) detecting a detectable label.

In some embodiments, the nucleic acid molecule is mRNA, and the determination step further comprises performing reverse transcription of the mRNA into cDNA prior to the amplification step.

In some embodiments, the detection step, detection step, or genotyping includes: bringing a nucleic acid molecule in a biological sample into contact with a substitution-specific probe containing a detectable label, wherein the substitution-specific probe contains a nucleotide sequence that, under stringent conditions, hybridizes to the nucleotide sequence of the amplified molecule a nucleic acid containing: thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and/or thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and detecting a detectable label.

In some embodiments, the detection step, detection step, or genotyping includes: bringing a nucleic acid molecule in a biological sample into contact with a substitution-specific probe containing a detectable label, wherein the substitution-specific probe contains a nucleotide sequence that, under stringent conditions, hybridizes to the nucleotide sequence of the amplified molecule a nucleic acid containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; and detecting a detectable label.

In some embodiments, the detection step, detection step, or genotyping includes: bringing a nucleic acid molecule in a biological sample into contact with a substitution-specific probe containing a detectable label, wherein the substitution-specific probe contains a nucleotide sequence that, under stringent conditions, hybridizes to the nucleotide sequence of the amplified molecule a nucleic acid containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and detecting a detectable label.

In some embodiments, the detection step, detection step, or genotyping includes: bringing a nucleic acid molecule in a biological sample into contact with a substitution-specific probe containing a detectable label, wherein the substitution-specific probe contains a nucleotide sequence that, under stringent conditions, hybridizes to the nucleotide sequence of the amplified molecule a nucleic acid containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and detecting a detectable label.

Substitution-specific polymerase chain reaction techniques can be used to detect mutations, such as SNPs, in a nucleic acid sequence. Substitution-specific primers can be used because DNA polymerase will not extend the nucleotide product in the presence of a template mismatch.

In some embodiments, the nucleic acid molecule in the sample is an mRNA, and said mRNA is reverse transcribed into cDNA prior to the amplification step. In some embodiments, the nucleic acid molecule is present in a cell derived from a human subject.

In some embodiments, the assay may include contacting a biological sample with a primer or probe, such as a substitution-specific primer or a substitution-specific probe, that specifically hybridizes to a variant ALOX15 genomic sequence, a variant mRNA sequence, or a variant cDNA sequence, but not to the corresponding reference sequence. ALOX15 under stringent conditions and determining if hybridization has occurred.

In some embodiments, the analysis includes RNA sequencing (RNA sequencing). In some embodiments, the assays also include performing reverse transcription of mRNA into cDNA, for example, using reverse transcriptase polymerase chain reaction (RT-PCR).

In some embodiments, the methods use probes and primers of sufficient nucleotide length to bind to a target nucleotide sequence and, in particular, to detect and/or identify a polynucleotide containing an ALOX15 variant genomic nucleic acid molecule, a variant mRNA molecule, or a variant cDNA molecule. Hybridization conditions or reaction conditions may be determined by the experimenter to achieve a given result. The nucleotide length can be any length sufficient for use in the chosen detection method, including any assay described or exemplified herein. Such probes and primers can specifically hybridize to a target nucleotide sequence under highly stringent hybridization conditions. The probes and primers may be completely identical to the sequence of adjacent nucleotides within the target nucleotide sequence, although conventional methods can design probes that differ from the target nucleotide sequence but retain the ability to specifically detect and/or identify the target nucleotide sequence. Probes and primers can be about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100% identical or complementary to the nucleotide sequence of the target nucleic acid molecule.

In some embodiments, to determine whether an ALOX15 nucleic acid molecule (genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) or its complementary nucleic acid molecule in a biological sample contains a nucleotide sequence containing thymine at a position corresponding to position 9917 according to SEQ ID NO: 2 (genomic nucleic acid molecule), or uracil at position corresponding to position 1693 according to SEQ ID NO: 4 (mRNA molecule), or thymine at position corresponding to position 1693 according to SEQ ID NO: 6 (molecule cDNA), the biological sample can be subjected to an amplification method using a primer pair that includes a first primer derived from a 5' flanking sequence adjacent to thymine at position corresponding to position 9917 according to SEQ ID NO: 2, or uracil at position corresponding to position 1693 according to SEQ ID NO: 4, or thymine at position corresponding to position 1693 according to SEQ ID NO: 6, and a second primer derived from a 3' flanking sequence adjacent to thymine at position, corresponding to position 9917 according to SEQ ID NO: 2, or uracil at position corresponding to position 1693 according to SEQ ID NO: 4, or thymine at position corresponding to position 1693 according to SEQ ID NO: 6, to obtain an amplicon, which indicates the presence of SNPs at positions encoding thymine at position corresponding to position 9917 according to SEQ ID NO: 2, or uracil at position corresponding to position 1693 according to SEQ ID NO: 4, or thymine at position corresponding to position 1693 according to SEQ ID NO: 6. In some embodiments, said amplicon may vary in length from the combined length of primer pairs plus one base pair to the length of any amplicon produced by a DNA amplification protocol. This distance may range from one base pair to the limit of the amplification reaction, or up to about twenty thousand base pairs. Optionally, the primer pair flanks a region including positions containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2, or uracil at position corresponding to position 1693 according to SEQ ID NO: 4, or thymine at position corresponding to position 1693 in accordance with SEQ ID NO 6, and at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleotides on each side of the positions containing thymine in the position corresponding to position 9917 according to SEQ ID NO: 2, or uracil at position corresponding to position 1693 according to SEQ ID NO: 4, or thymine at position corresponding to position 1693 according to SEQ ID NO: 6.

Similar amplicons can be generated from mRNA and/or cDNA sequences. PCR primer pairs can be generated from a known sequence, for example, using computer programs designed for this purpose, such as the Vector NTI PCR Primer Analysis Tool, Version 10 (Informax Inc., Bethesda, MD, USA); PrimerSelect (DNASTAR Inc., Madison, WI, USA); and Primer3 (version 0.4.0.COPYRGT., 1991, Whitehead Institute for Biomedical Research, Cambridge, MA, USA). In addition, the sequence can be assessed visually and primers can be manually determined using known guidelines.

Illustrative examples of nucleic acid sequencing techniques include, but are not limited to, strand terminator (Sanger) sequencing and dye terminator sequencing. Other methods include nucleic acid hybridization methods other than sequencing, including the use of labeled primers or probes directed against purified DNA, amplified DNA, and fixed cell preparations (fluorescence in situ hybridization (FISH)). In some methods, the target nucleic acid molecule can be amplified prior to or simultaneously with detection. Illustrative examples of nucleic acid amplification techniques include, but are not limited to, polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (CDS) and nucleotide sequence based amplification (SANP). Other methods include, but are not limited to, ligase chain reaction, strand displacement amplification, and thermophilic ACC (tCDA).

Hybridization techniques can apply stringent conditions so that the probe or primer specifically hybridizes to its target. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target sequence to a detectably greater extent than to other non-target sequences, e.g., at least 2-fold, at least 3-fold, at least 4 times or more above background, including more than 10 times background. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater extent, at least 2-fold, than to other nucleotide sequences. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater extent, at least 3-fold, than to other nucleotide sequences. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater extent, at least 4-fold, than to other nucleotide sequences. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater extent than to other nucleotide sequences, at least 10 times background. Stringent conditions are sequence dependent and will be different in different circumstances.

Appropriate stringency conditions that promote DNA hybridization, such as 6X sodium chloride/sodium citrate (SSC) at about 45°C followed by a 2X SSC wash at 50°C, are known or can be found in Current Protocols in Molecular Biology , John Wiley & Sons, NY (1989), 6.3.1-6.3.6. Typically, stringent conditions for hybridization and detection will be those where the salt concentration is less than about 1.5 M Na ⁺ ions, typically Na ⁺ ion (or other salt) concentrations from about 0.01 to about 1, 0 M at pH 7.0 to 8.3 and the temperature is at least about 30°C for short probes (eg, 10 to 50 nucleotides) and at least about 60°C for longer probes (eg, more than 50 nucleotides). Stringent conditions can also be achieved by adding destabilizing agents such as formamide. Optionally, wash buffers may contain 0.1% to 1% SDS. The duration of hybridization is generally less than about 24 hours, typically from about 4 hours to about 12 hours. The duration of the flushing time will be at least the amount of time needed to reach equilibrium.

The invention also provides methods for detecting the presence of a human ALOX15 polypeptide with a predictive loss of function, comprising analyzing a sample obtained from a human subject to determine if the ALOX15 polypeptide in the subject contains one or more variations that result in loss of function of said human subject. polypeptide (partial or complete) or predicted loss of function (partial or complete) of said polypeptide. The ALOX15 predicted loss of function polypeptide can be any of the variant ALOX15 polypeptides described herein. In some embodiments, these methods detect the presence of ALOX15 Thr560Met, Tyr139Cys, Leu651fs, Pro565Leu, Asn658Lys, Gly283Arg, Val474Ala, Gly422Arg, or Leu106fs. In some embodiments, these methods detect the presence of ALOX15 Thr560Met.

In some embodiments, these methods include analyzing a sample obtained from a human subject to determine if the ALOX15 polypeptide in said sample contains methionine at position corresponding to position 560 according to SEQ ID NO: 8.

In some embodiments, the discovery step includes sequencing at least a portion of the polypeptide that contains the position corresponding to position 560 according to SEQ ID NO: 8 or SEQ ID NO: 7.

In some embodiments, the detection step includes an immunoassay to determine the presence of a polypeptide that contains a position corresponding to position 560 according to SEQ ID NO: 8 or SEQ ID NO: 7.

In some embodiments, when a human subject does not have an ALOX15 predictive loss of function polypeptide, then said human subject has an increased risk of developing a respiratory disorder such as nasal polyp, allergic rhinitis, asthma, and/or AIRZ. In some embodiments, when a human subject has an ALOX15 polypeptide with predicted loss of function, then said human subject has a reduced risk of developing a respiratory disorder such as nasal polyp, allergic rhinitis, asthma and/or AIRD, and/or atopy.

The invention also provides isolated nucleic acid molecules that hybridize to ALOX15 variant genomic nucleic acid molecules, ALOX15 variant mRNA molecules, and/or ALOX15 variant cDNA molecules (such as any of the variant genomic nucleic acid molecules, variant mRNA molecules, and/or variant cDNA disclosed in this document). In some embodiments, isolated nucleic acid molecules hybridize to a portion of an ALOX15 nucleic acid molecule that contains a position corresponding to position 9917 according to SEQ ID NO: 2, position 1693 according to SEQ ID NO: 4, or position 1693 according to SEQ ID NO:6.

In some embodiments, such isolated nucleic acid molecules comprise or consist of at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50 , at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 2000, at least about 3000, at least about 4000, or at least about 5000 nucleotides. In some embodiments, such isolated nucleic acid molecules comprise or consist of at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, or at least about 25 nucleotides. In some embodiments, said isolated nucleic acid molecules contain or consist of at least about 18 nucleotides. In some embodiments, said isolated nucleic acid molecules contain or consist of at least about 15 nucleotides. In some embodiments, said isolated nucleic acid molecules comprise or consist of about 10 to about 35, about 10 to about 30, about 10 to about 25, about 12 to about 30, about 12 to about 28, about 12 to about 24, about 15 to about 30, about 15 to about 25, about 18 to about 30, about 18 to about 25, about 18 to about 24, or about 18 to about 22 nucleotides. In some embodiments, said isolated nucleic acid molecules contain or consist of at least about 18 to about 30 nucleotides. In some embodiments, said isolated nucleic acid molecules contain or consist of at least about 15 to about 35 nucleotides.

In some embodiments, such isolated nucleic acid molecules are hybridized to ALOX15 variant nucleic acid molecules (such as genomic nucleic acid molecules, mRNA molecules, and/or cDNA molecules) under stringent conditions. Such nucleic acid molecules can be used, for example, as probes, primers, substitution-specific probes, or substitution-specific primers as described or illustrated herein, and include, but are not limited to, primers, probes, antisense RNAs, shRNAs, and siRNAs, each of which is described in more detail in other parts of this document and can be used in any of the ways described in this document.

In some embodiments, said isolated nucleic acid molecules hybridize to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or 100% identical to ALOX15 variant genomic nucleic acid molecules, ALOX15 variant mRNA molecules and/or ALOX15 variant cDNA molecules. In some embodiments, said isolated nucleic acid molecules comprise or consist of at least about 15 to about 100 nucleotides, or at least about 15 to about 35 nucleotides. In some embodiments, said isolated nucleic acid molecules contain or consist of at least about 15 to about 100 nucleotides. In some embodiments, said isolated nucleic acid molecules contain or consist of at least about 15 to about 35 nucleotides.

In some embodiments, said isolated substitution-specific probes or substitution-specific primers comprise at least about 15 nucleotides, wherein said substitution-specific probe or substitution-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence encoding a human ALOX15 polypeptide, wherein said portion contains a position corresponding to : position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; or position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence. In some embodiments, said substitution-specific probe or substitution-specific primer comprises a nucleotide sequence that is complementary to a portion of the nucleotide sequence containing positions corresponding to: positions 9916 to 9918 according to SEQ ID NO: 2 or its complementary nucleotide sequence; positions 1692 to 1694 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and/or positions 1692 to 1694 according to SEQ ID NO: 6 or its complementary nucleotide sequence.

In some embodiments, said substitution-specific probes and substitution-specific primers comprise DNA. In some embodiments, said substitution-specific probes and substitution-specific primers comprise RNA.

In some embodiments, said probes and primers described herein (including substitution-specific probes and substitution-specific primers) have a nucleotide sequence that specifically hybridizes to any of the nucleic acid molecules described herein or their complementary nucleotide sequences. In some embodiments, said probes and primers specifically hybridize to any of the nucleic acid molecules described herein under stringent conditions.

In some embodiments, these primers, including substitution-specific primers, can be used in second generation sequencing or high throughput sequencing. In some cases, these primers, including replacement-specific primers, may be modified. In particular, these primers may contain various modifications that are used at different stages, for example, massively parallel recognition sequencing (MPSS), polony sequencing and 454 pyrosequencing. Modified primers can be used in several steps of the process, including biotinylated primers in the cloning step and fluorescently labeled primers used in the microbead loading step and detection step. Polony sequencing is usually performed using a library of paired end tags, in which the length of each DNA template molecule is about 135 bp. Biotinylated primers are used in the microbead loading and emulsion PCR steps. Fluorescently labeled degenerate nomeric oligonucleotides are used in the discovery step. The adapter may contain a 5'-biotin tag for immobilizing the DNA library onto streptavidin-coated microbeads.

The probes and primers described herein can be used to detect nucleotide variations in any of the ALOX15 variant genomic nucleic acid molecules, ALOX15 variant mRNA molecules, and/or ALOX15 variant cDNA molecules described herein. The primers described herein can be used to amplify ALOX15 variant genomic nucleic acid molecules, ALOX15 variant mRNA molecules and/or ALOX15 variant cDNA molecules or fragments thereof.

The invention also provides primer pairs containing any of the primers described above. For example, if the 3' end of one of the primers hybridizes to a cytosine at position corresponding to position 9917 according to SEQ ID NO: 1 (and not to thymine) in a particular ALOX15 nucleic acid molecule, then the presence of an amplified fragment would indicate the presence of a reference molecule. ALOX15 genomic nucleic acid. Conversely, if the 3' end of one of the primers hybridizes to thymine at position corresponding to position 9917 according to SEQ ID NO: 2 (and not to cytosine) in a particular ALOX15 nucleic acid molecule, then the presence of the amplified fragment will indicate the presence of the molecule ALOX15 variant genomic nucleic acid. In some embodiments, the primer nucleotide complementary to thymine at position corresponding to position 9917 according to SEQ ID NO: 2 may be at the 3' end of said primer. In addition, if the 3' end of one of the primers hybridizes to a cytosine at position corresponding to position 1693 according to SEQ ID NO: 3 (and not to uracil) in a particular ALOX15 nucleic acid molecule, then the presence of an amplified fragment will indicate the presence of the ALOX15 reference mRNA molecule. Conversely, if the 3' end of one of the primers hybridizes to uracil at position corresponding to position 1693 according to SEQ ID NO: 4 (and not to cytosine) in a particular ALOX15 mRNA molecule, then the presence of an amplified fragment will indicate the presence of a variant molecule. ALOX15 mRNA. In some embodiments, the primer nucleotide complementary to uracil at position corresponding to position 1693 according to SEQ ID NO: 4 may be at the 3' end of said primer. In addition, if the 3' end of one of the primers hybridizes to a cytosine at position corresponding to position 1693 according to SEQ ID NO: 5 (rather than thymine) in a particular ALOX15 nucleic acid molecule, then the presence of an amplified fragment will indicate the presence of the reference cDNA molecule ALOX15. Conversely, if the 3' end of one of the primers hybridizes to thymine at position corresponding to position 1693 according to SEQ ID NO: 6 (and not to cytosine) in a particular ALOX15 cDNA molecule, then the presence of an amplified fragment will indicate the presence of a variant molecule. cDNA of ALOX15. In some embodiments, the primer nucleotide complementary to thymine at position corresponding to position 1693 according to SEQ ID NO: 6 may be at the 3' end of said primer.

As used herein, the phrase "specifically hybridizes" means that a probe or primer (such as, for example, a substitution-specific probe or a substitution-specific primer) does not hybridize to a nucleic acid sequence encoding an ALOX15 reference genomic nucleic acid molecule, an ALOX15 reference mRNA molecule, and/or a reference cDNA ALOX15.

In some embodiments, the probes (such as, for example, a substitution probe) contain a label. In some embodiments, said label is a fluorescent label, a radioisotope label, or biotin.

The invention also provides substrates containing a substrate to which one or more of the probes described herein are attached. Solid supports are solid phase substrates or supports to which molecules can bind, such as any of the probes described herein. The solid support is in the form of a matrix. Another form of solid substrate is the array detector. A matrix detector is a solid substrate with which various probes have been coupled in the form of a matrix, lattice, or other ordered structure. A form of solid phase substrate is a microtiter plate, such as a standard 96-well type plate. In some embodiments, multiwell glass slides can be used, which typically contain one matrix per well.

The invention also provides molecular complexes comprising or consisting of any of the ALOX15 nucleic acid molecules (genomic nucleic acid molecules, mRNA molecules, or cDNA molecules) or their complementary nucleotide sequences described herein, and any of the substitution-specific primers or substitution-specific probes, described in this document. In some embodiments, the ALOX15 nucleic acid molecules (genomic nucleic acid molecules, mRNA molecules, or cDNA molecules) or their complementary nucleotide sequences in said molecular complexes are single stranded. In some embodiments, the ALOX15 nucleic acid molecule is any of the genomic nucleic acid molecules described herein. In some embodiments, the ALOX15 nucleic acid molecule is any of the mRNA molecules described herein. In some embodiments, the ALOX15 nucleic acid molecule is any of the cDNA molecules described herein. In some embodiments, said molecular complex comprises or consists of any of the ALOX15 nucleic acid molecules (genomic nucleic acid molecules, mRNA molecules, or cDNA molecules) or their complementary nucleotide sequences described herein, and any of the replacement-specific primers described herein. . In some embodiments, said molecular complex comprises or consists of any of the ALOX15 nucleic acid molecules (genomic nucleic acid molecules, mRNA molecules, or cDNA molecules) or their complementary nucleotide sequences described herein and any of the replacement-specific probes described herein. .

In some embodiments, said molecular complex comprises or consists of a substitution-specific primer or substitution-specific probe hybridized to a genomic nucleic acid molecule containing a nucleotide sequence encoding a human ALOX15 polypeptide, wherein said substitution-specific primer or substitution-specific probe is hybridized to thymine at position corresponding to position 9917 according to SEQ ID NO: 2, or its complementary nucleotide sequence.

In some embodiments, said molecular complex comprises or consists of a substitution-specific primer or a substitution-specific probe that is hybridized to an ATG codon at positions corresponding to positions 9916 to 9918 according to SEQ ID NO: 2.

In some embodiments, said molecular complex comprises or consists of a genomic nucleic acid molecule that comprises SEQ ID NO: 2.

In some embodiments, said molecular complex comprises or consists of a substitution-specific primer or substitution-specific probe hybridized to an mRNA molecule containing a nucleotide sequence encoding a human ALOX15 polypeptide, wherein said substitution-specific primer or substitution-specific probe is hybridized to uracil at position corresponding to position 1693 according to with SEQ ID NO: 4, or its complementary nucleotide sequence.

In some embodiments, said molecular complex comprises or consists of a substitution-specific primer or a substitution-specific probe that is hybridized to an AUG codon at positions corresponding to positions 1692 to 1694 according to SEQ ID NO: 4.

In some embodiments, said molecular complex comprises or consists of an mRNA molecule that contains SEQ ID NO: 4.

In some embodiments, said molecular complex comprises or consists of a substitution-specific primer or substitution-specific probe hybridized to a cDNA molecule containing a nucleotide sequence encoding a human ALOX15 polypeptide, wherein said substitution-specific primer or substitution-specific probe is hybridized to thymine at position corresponding to position 1693 according to with SEQ ID NO: 6, or its complementary nucleotide sequence.

In some embodiments, said molecular complex comprises or consists of a substitution-specific primer or a substitution-specific probe that is hybridized to an ATG codon at positions corresponding to positions 1692 to 1694 according to SEQ ID NO: 6.

In some embodiments, said molecular complex comprises or consists of a cDNA molecule that contains SEQ ID NO: 6.

In some embodiments, said molecular complex comprises a replacement-specific probe and a replacement-specific primer containing a label. In some embodiments, said label is a fluorescent label, a radioisotope label, or biotin. In some embodiments, said molecular complex further comprises a non-human polymerase.

The nucleotide sequence of the ALOX15 reference genomic nucleic acid molecule is shown in SEQ ID NO: 1. Referring to SEQ ID NO: 1, the nucleotide at position 9917 is a cytosine.

There is a variant genomic nucleic acid molecule ALOX15 in which cytosine at position 9917 is replaced by thymine. The nucleotide sequence of this ALOX15 variant genomic nucleic acid molecule is shown in SEQ ID NO: 2.

The nucleotide sequence of the ALOX15 reference mRNA molecule is shown in SEQ ID NO: 3. Referring to SEQ ID NO: 3, the nucleotide at position 1693 is a cytosine.

There is a variant ALOX15 mRNA molecule in which the cytosine at position 1693 is replaced by uracil. The nucleotide sequence of this ALOX15 variant mRNA molecule is shown in SEQ ID NO: 4.

The nucleotide sequence of the ALOX15 reference cDNA molecule is shown in SEQ ID NO: 5. Referring to SEQ ID NO: 5, the nucleotide at position 1693 is a cytosine.

There is a variant ALOX15 cDNA molecule in which the cytosine at position 1693 is replaced by a thymine. The nucleotide sequence of this ALOX15 variant cDNA molecule is shown in SEQ ID NO: 6.

Also provided herein are functional polynucleotides that can interact with the disclosed nucleic acid molecules. Examples of functional polynucleotides include, but are not limited to, antisense molecules, aptamers, ribozymes, triple helixes, and external guide sequences. Functional polynucleotides may act as effectors, inhibitors, modulators, and promoters of a particular activity that the target molecule has, or functional polynucleotides may have a de novo activity independent of any other molecules.

The isolated nucleic acid molecules described herein may include RNA, DNA, or both RNA and DNA. Isolated nucleic acid molecules can also be linked or fused to a heterologous nucleotide sequence, such as a vector, or to a heterologous tag. For example, the isolated nucleic acid molecules described herein may be in a vector or an exogenous donor sequence containing an isolated nucleic acid molecule and a heterologous nucleic acid sequence. Isolated nucleic acid molecules may also be linked or fused to a heterologous tag. Said label may be directly detectable (such as, for example, a fluorophore) or indirectly detectable (such as, for example, a hapten, an enzyme, or a fluorophore quencher). Such labels can be detected by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Such labels include, for example, radioisotope labels, pigments, dyes, chromogens, spin labels, and fluorescent labels. The label can also be, for example, a chemiluminescent substance; metal-containing substance; or an enzyme where enzyme-dependent secondary signal generation occurs. The term "tag" may also refer to a "tag" or hapten that can selectively bind to a conjugated molecule such that the conjugated molecule, when subsequently added along with a substrate, is used to generate a detectable signal. For example, biotin can be used as a tag along with avidin or streptavidin horseradish peroxidate (HRP) conjugate to bind to the tag, and assayed using a calorimetric substrate (such as, for example, tetramethylbenzidine (TMB)) or a fluorogenic substrate to detect the presence of HRP. Exemplary labels that can be used as tags to facilitate purification include, but are not limited to, myc, HA, FLAG or 3XFLAG, 6XHis or polyhistidine, glutathione S-transferase (GST), maltose-binding protein, epitope tag, or Fc part of an immunoglobulin. Numerous labels include, for example, particles, fluorophores, haptens, enzymes and their calorimetric, fluorogenic and chemiluminescent substrates, and other labels.

The nucleic acid molecules described herein may contain, for example, nucleotides or non-naturally occurring nucleotides, or modified nucleotides such as nucleotide analogs or nucleotide substituents. Such nucleotides include a nucleotide that contains a modified base, sugar, or phosphate group, or that incorporates a non-naturally occurring moiety into its structure. Examples of non-naturally occurring nucleotides include, but are not limited to, dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and fluorophore-labeled nucleotides.

The nucleic acid molecules described herein may also contain one or more nucleotide analogs or substitutions. A nucleotide analog is a nucleotide that contains a modification either at the base or at the sugar or phosphate moieties. Modifications in the main fragment include, but are not limited to, natural and synthetic modifications A, C, G and T/U, as well as various purine or pyrimidine bases such as, for example, pseudouridine, uracil-5-yl, hypoxanthine- 9-yl (I) and 2-aminoadenin-9-yl. Modified nucleotide bases include, but are not limited to, 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine; pseudouracil), 4-thiouracil, 8-halo-, 8-amino-, 8-thiol-, 8-thioalkyl-, 8-hydroxyl- and other 8-substituted adenines and guanines, 5-halo- (such as, for example, 5-bromo-), 5-trifluoromethyl- and other 5-substituted uracils and cytosines, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine and 3-deazaadenine .

Nucleotide analogs may also contain modifications to the sugar moiety. Sugar moiety modifications include, but are not limited to, natural modifications of ribose and deoxyribose, as well as synthetic modifications. Sugar modifications include, but are not limited to, the following modifications at the 2' position: OH; F; O-, S- or N-alkyl; O-, S- or N-alkenyl;

O-, S- or N-alkynyl; or O-alkyl-O-alkyl, where alkyl, alkenyl and alkynyl may be substituted or unsubstituted C _1-10 alkyls or C _2-10 alkenyls and C _2-10 alkynyls. Exemplary 2' sugar modifications also include, but are not limited to, -O[(CH ₂ ) _n O] _m CH ₃ , -O(CH ₂ ) _n OCH ₃ , -O(CH ₂ ) _n NH ₂ , -O(CH ₂ ) _n CH ₃ ,

-O(CH ₂ ) _n -ONH ₂ and -O(CH ₂ ) _n ON[(CH ₂ ) _n CH ₃ )] ₂ where n and m are from 1 to about 10. Other modifications at the 2' position include themselves, but are not limited to, C _1-10 alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH ₃ , OCN, Cl, Br, CN, CF ₃ , OCF ₃ , SOCH ₃ , SO ₂ CH ₃ , ONO ₂ , NO ₂ , N ₃ , NH ₂ , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, RNA cleaving group, reporter group, intercalator, group for improving the pharmacokinetic properties of the oligonucleotide or a group for improving the pharmacodynamic properties of the oligonucleotide and other substituents having similar properties. Similar modifications can also be made at other sugar positions, in particular at the 3' position of the sugar in the 3'-terminal nucleotide or in 2'-5'-linked oligonucleotides and the 5' position of the sugar in the 5'-terminal nucleotide. Modified sugars may also include those containing modifications in the bridging oxygen of the ring, such as CH ₂ and S. Nucleotide sugar analogs may also contain sugar mimetics, such as cyclobutyl moieties, in place of the pentofuranose sugar.

Nucleotide analogs can also be modified in the phosphate moiety. Modified phosphate moieties include, but are not limited to, those that can be modified so that the bond between two nucleotides contains phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl and other alkyl phosphonates, including 3'-alkylene phosphonate and chiral phosphonates, phosphinates, phosphoramidates including 3'-aminophosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters and boranophosphates. These phosphate or modified phosphate bonds between two nucleotides may be formed via a 3'-5' bond or a 2'-5' bond, and the bond may have a reversed polarity such as 3'-5' to 5'-3' or from 2'-5' to 5'-2'. Also included are various salt, mixed salt, and free acid forms. Nucleotide substitutes also include peptide nucleic acids (PNAs).

Percent identity (or percent complementarity) between specific regions of nucleotide sequences in nucleic acid molecules or amino acid sequences in polypeptides can be determined according to common practice using BLAST programs (basic local alignment search tools) and PowerBLAST programs (Altschul et al., J. Mol Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656) or using the Gap program (Wisconsin Sequence Analysis Package, version 8 for Unix, Genetics Computer Group, University Research Park, Madison, WI, USA) using the default settings using the Smith and Waterman algorithm (Adv. Appl. Math., 1981, 2, 482-489). Herein, if percent sequence identity is indicated, higher percent sequence identity is preferred over lower ones.

The invention also provides compositions comprising any one or more of the isolated nucleic acid molecules, genomic nucleic acid molecules, mRNA molecules and/or cDNA molecules described herein. In some embodiments, said composition is a pharmaceutical composition. In some embodiments, the implementation of these pharmaceutical compositions contain a carrier and/or excipient. Examples of carriers include, but are not limited to, poly(lactic acid) (PLA) microspheres, poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres, liposomes, micelles, inverse micelles, lipid cochleates and lipid microtubules. The carrier may contain buffered saline such as PBS, HBSS, etc.

As used herein, the phrase "corresponding" or grammatical variations thereof, when used in the context of numbering a particular nucleotide or nucleotide sequence or position, refers to the numbering of a particular reference sequence when comparing a particular nucleotide or nucleotide sequence to a reference sequence (such as, for example, SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5). In other words, the residue number (such as, for example, a nucleotide or amino acid) or the position of a residue (such as, for example, a nucleotide or amino acid) of a particular polymer is referred to relative to the reference sequence, and not by the actual position number of the residue in the particular nucleotide or nucleotide sequence. For example, a particular nucleotide sequence can be aligned to a reference sequence by introducing gaps to optimize residue matching between the two specified sequences. In these cases, despite the presence of gaps, the numbering of the residue in a particular nucleotide or nucleotide sequence is relative to the reference sequence with which it was aligned.

For example, a nucleic acid molecule containing a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2, means that if said nucleotide sequence of the ALOX15 genomic nucleic acid molecule is aligned with SEQ ID NO: 2, said ALOX15 sequence has a thymine residue at position corresponding to position 9917 of SEQ ID NO: 2. The same applies to mRNA molecules containing a nucleotide sequence encoding a human ALOX15 polypeptide, wherein said nucleotide sequence contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4, and to cDNA molecules containing a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing thymine at position corresponding to position 1693 according to SEQ ID NO : 6. In other words, these phrases refer to a nucleic acid molecule encoding an ALOX15 polypeptide, wherein the genomic nucleic acid molecule has a nucleotide sequence that contains a thymine residue homologous to the thymine residue at position 9917 of SEQ ID NO: 2 (or the molecule The mRNA has a nucleotide sequence that contains a uracil residue homologous to the uracil residue at position 1693 according to SEQ ID NO: 4, or the cDNA molecule has a nucleotide sequence that contains a thymine residue homologous to the thymine residue at position 1693 according to SEQ ID NO: 6) . In this document, such a sequence is also referred to as "ALOX15 sequence with C9917T variation" or "ALOX15 sequence with C9917T variation", which refers to genomic nucleic acid molecules (or "ALOX15 sequence with C1693U variation" or "ALOX15 sequence with C1693U variation", which refers to mRNA molecules, and "ALOX15 sequence with C1693T variation" or "ALOX15 sequence with C1693 T variation", which refers to cDNA molecules).

As described herein, the position in the ALOX15 genomic nucleic acid molecule that corresponds to position 9917 according to SEQ ID NO: 2, for example, can be identified by performing a sequence alignment between the nucleotide sequence of the particular ALOX15 nucleic acid molecule and the nucleotide sequence of SEQ ID NO: 2. There are many computational algorithms that can be used to perform sequence alignments to identify a nucleotide position that corresponds to, for example, position 9917 in SEQ ID NO: 2. For example, sequence alignments can be performed using the NCBI BLAST algorithm (Altschul et al ., Nucleic Acids Res., 1997, 25, 3389-3402) or CLUSTALW software (Sievers and Higgins, Methods Mol. Biol., 2014, 1079, 105-116). However, sequences can also be manually aligned.

The amino acid sequence of the reference ALOX15 polypeptide is shown in SEQ ID NO: 7. Referring to SEQ ID NO: 7, the reference ALOX15 polypeptide is 662 amino acids long. Referring to SEQ ID NO: 7, the nucleotide at position 560 is threonine.

There is a variant ALOX15 polypeptide (Thr560Met or T560M) whose amino acid sequence is shown in SEQ ID NO: 8. Referring to SEQ ID NO: 8, the ALOX15 variant polypeptide is 662 amino acids long. Referring to SEQ ID NO: 8, the nucleotide at position 560 is methionine.

The nucleotide and amino acid sequences listed in the appended sequence listing are given using standard letter designations for nucleotide bases and a three-letter code for amino acids. Nucleotide sequences follow the standard system, starting at the 5' end of the specified sequence, continuing forward (i.e. from left to right on each line) to the 3' end. Only one strand of each nucleotide sequence is shown, but a complementary strand is intended to be included in any reference to the strand given. The amino acid sequences follow the standard system, starting at the amino terminus of the indicated sequence, continuing forward (ie, left to right on each line) to the carboxy terminus.

The invention also provides therapeutic agents that treat or inhibit a respiratory disorder for use in the treatment of a respiratory disorder (or for use in the preparation of a medicament for the treatment of a respiratory disorder) in a human subject, wherein said human subject has any of the genomic molecules nucleic acids, mRNA molecules and/or cDNA molecules encoding the human ALOX15 polypeptide described herein. Therapeutic agents that treat or inhibit a respiratory disorder can be any of the therapeutic agents that treat or inhibit a respiratory disorder described herein.

In some embodiments, the human subject comprises: a genomic nucleic acid molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein said nucleotide sequence contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; an mRNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; a cDNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; or an ALOX15 polypeptide which contains a methionine at position corresponding to position 560 according to SEQ ID NO: 8.

The invention also provides ALOX15 inhibitors for use in the treatment of a respiratory disorder (or for use in the preparation of a medicament for the treatment of a respiratory disorder) in a human subject, wherein said human subject has any of genomic nucleic acid molecules, mRNA molecules, and/or cDNA molecules encoding the human ALOX15 polypeptide described herein. ALOX15 inhibitors can be any of the ALOX15 inhibitors described herein.

In some embodiments, the human subject comprises: a genomic nucleic acid molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein said nucleotide sequence contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; an mRNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; a cDNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, said nucleotide sequence containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; or an ALOX15 polypeptide that contains a methionine at position corresponding to position 560 according to SEQ ID NO: 8. ALOX15 inhibitors can be any of the ALOX15 inhibitors described herein.

All patent documents, websites, other publications, account numbers, and the like cited above or below are incorporated herein by reference in their entirety and in all respects to the same extent as if each individual item were specifically and separately indicated its inclusion by reference. If different versions of the sequence are associated with an account at different times, the version associated with the access number at the time of the effective filing date of this application is assumed. Effective filing date means the earlier actual filing date or the filing date of the priority application referring to the account number, if applicable. Likewise, if different versions of a publication, website, etc. published at different times, the version published closest to the actual filing date is meant, unless otherwise indicated. Any feature, step, element, embodiment, or aspect of the present invention may be used in combination with any other feature, step, element, embodiment, or aspect, unless expressly stated otherwise. While the invention has been described in sufficient detail by way of illustration and example for purposes of clarity and understanding, it is apparent that certain changes and modifications may be made within the scope of the appended claims.

The following examples are provided to describe the embodiments in more detail. They are intended to illustrate and not limit the claimed embodiments. The following examples are provided to provide those of ordinary skill in the art with a disclosure and description of the making and evaluation of the compounds, compositions, articles, devices, and/or methods described herein, and are intended solely to illustrate, and not to limit the scope of, any claims. the appended claims. Efforts have been made to ensure accuracy with respect to the numbers used (eg amounts, temperatures, etc.), but some experimental errors and deviations must be taken into account. Unless otherwise indicated, parts are mass parts, temperatures are expressed in °C or equal to ambient temperature, and pressures are at or near atmospheric levels.

Examples

Example 1: Exome Sequencing Analysis

Sequencing and exome analysis at the Regeneron Genetic Center revealed that rs34210653 is significantly associated with a decrease in circulating eosinophils based on exome data from the UK Biobank 50K (see Figure 1) and genotyping data from the UK Biobank 500K (see Figure 1). 2) and is also associated with a decrease in circulating eosinophils based on exome data from the GHS 90K biobank (see Fig. 4). The analysis also showed that rs34210653 was significantly associated with a reduction in the incidence of nasal polyps, allergic rhinitis, and asthma based on UK Biobank 500K genotyping data (see Figure 3) and with a reduced incidence of nasal polyps based on exome data from the GHS Biobank 90K ( see Fig. 5). Locus scaling plot for significant association between rs34210653 and eosinophils based on UKB 500K biobank genotyping data (see Fig. 6). Quantitative distributions of traits for eosinophil counts based on UKB 500K biobank genotyping data showing a decrease in eosinophils among heterozygous and homozygous carriers of the rs34210653 variant (dashed line indicates the mean eosinophil count for carriers of the wild-type allele) (see Fig. 7). Locus scaling plot for significant association between rs34210653 and nasal polyps based on UKB 500K biobank genotyping data (see Fig. 8).

Various modifications of the described subject matter, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also within the scope of the appended claims. Each reference (including, but not limited to, scientific journal articles, US and foreign patents, patent application publications, international patent application publications, genebank accession numbers, etc.) cited in this application is included in this document by reference in its entirety and for all purposes.

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SEQUENCE LIST

<110> Regeneron Pharmaceuticals, Inc.

<120> Treatment of respiratory disorders with inhibitors

15-lipoxygenase arachidonate (ALOX15)

<130> 189238.02102 (3145) (10524WO01)

<150> 62/785 899

<151> 12/28/2018

<160> 43

<170> PatentIn version 3.5

<210> 1

<211> 11017

<212> DNA

<213> homo sapiens

<400> 1

ctgcgtgttt tcggtccaaa tccttttctt tttctccctc ccgtcaagat agtggtttcc 60

actccctgct ctcgccagga caccgccttt tggactgggg ctgaattctg ccccttgaag 120

ctctgctcct tggagctggg ggccccagcg gtaggcggag ttgattggag acctgccacc 180

cacattccga ccccaagcga cctccgagag ggcggggtct caggctggggt tatttagctc 240

gtccaccctt ctccaccaga aggagcgaaa catctttgag caagatgggt ctctaccgca 300

tccgcgtgtc cactggggcc tcgctctatg ccggttccaa caaccaggtg cagctgtggc 360

tggtcggcca gcacggggag gcggcgctcg ggaagcgact gtggcccgca cggggcaagg 420

tgagctcccc agagccggggc ggggtggggct gcgcccctgg ctccgagtca gtcaaatacc 480

ggggaggaca tgcgcccccg ttggcctctg gccgattctc tttgccaagg gcccgcgcat 540

tgggctcaaa gcgcgcggag gccacggggg tggggggctt tagggcagtc ggtggcacac 600

agtaagcgct caataaatgt tgccgctacc cgatctcctt ggaattgagg gcatgctcct 660

gtgcgcccct cattgcacaa agctcccttg tctggaaact cagcagtcac tggagccgcc 720

gtcggtcctc tcgctttctc tattttaaaa accgtttcaa ccgctagcgc tgttggatct 780

ctacctttca ggctttatca cctggggtgg agtgggtggt gagagggaag ggatggggag 840

tcaagacagg agaacgctct cgatttcccg acccacctcc cgtcatatct catgtcacat 900

ctaccgggtg ttctacccgg tcctgttaac ttttttttctt ccgcgaaagc ccaaattccc 960

atcactgctc tagctctctc ccagatcccc aaatccggat gtctgtctca gggaacgtca 1020

aagcaacatg cccggatgag gtcctcccct ctccccacct cccagccctc tcctcctgcc 1080

tcccccggtg tcacccgcgc ctccttcctc tcttcacctc cctctaaaca agaatccggc 1140

gcagtcagtt ctagaccctg agcatctccc gcgtccctgc ccaatatccg tcccgccccc 1200

gaccgcccgc gtcctcttga acctgcggag ccctgctccc cgcactccac gcccttgctc 1260

cgagcttccg agaaagcggg gcaaagggag cggaagag agaaaatgcg cacggagcag 1320

gtggccccgc gactccatgg tgaggggacg gggcacggaa ggtggaaagg cgcgctccct 1380

ccctcccttttt ttcctcccta tggtggggcag ttggtgacac acagtaaagg ctcaataaat 1440

gttcccgcta ctcgatctcc ttggaattaa ggggatgctc ctgagcgccc ctcattccac 1500

acagctctgg tgcctggaaa ctgcggtcgc cggagcggtc gtcggtcctc ccggtttctc 1560

tattttaaaa gccatttcaa acctccagcg gcctcgccac ctctgctgca gaccttccaa 1620

gcccttctga agccggaatg atttctccct aattcactcc ccctgcttaa cacattcgaa 1680

cggctcccgc ttgttctcgg gaccaaatcc aaagcccctg gcgccacctt cgagagcctc 1740

cggacctgct gaccccccac acctgggctc tgagctccag ctccaagatg ctgctcgccc 1800

tcccttcccc gccgctctct ttctgcgcgc ctttcccctg ccttcccttt ctgtcactct 1860

ccctggctga gccctctccg cctccaggtc tccgggaagg ttgtccccag gccggtgggg 1920

cccctgcagg tcctcagcct cgggcggggt ggggtgggggg gtcgcacagc gggaattgcc 1980

accagcgcgt cggggctcca cagcgcgctc gtccagggcg cggcagcgct cagcccagcg 2040

cttggcacag tcagtgacca cagggaggag aaagtgaagg caggagcgca ccttcccacc 2100

tgccgtcccc gtcccctcag aaccgagtcc tggggccacc tgctcggcgc ggtccctctc 2160

tctctggctc agtccccgca ccccgatacg tctcctcctc tcagaggctc cgaggaaggg 2220

cgtgggcgct ggagggagca gggctcagcc gggtgcccct cccgccaggc cccaccgggg 2280

ctgagcctct tctgtcgccc gcaggagaca gaactcaagg tggaagtacc ggagtatctg 2340

gggccgctgc tgtttgtgaa actgcgcaaa cggcacctcc ttaaggacga cgcctggttc 2400

tgcaactgga tctctgtgca gggccccgga gccggggacg aggtcaggtt cccttgttac 2460

cgctgggtgg agggcaacgg cgtcctgagc ctgcctgaag gcaccggtaa gcgcggggct 2520

gagggtgtca ggaggcctct gggctgtgtg agaagctggg gggatgcgcg tgtggagaag 2580

agggcgcagg atgggggtgc tggaacctgg agcgccgggg tctttggggg tgtcgaaggg 2640

gcggtggctg cagctggcac aaagtggctg gagcctgggg gaggggcgtg atgctgaagg 2700

ggcagaggcc acacagaagg acggggtgct gaggctctcc tggcagagac aagaagaggc 2760

gctcaccaaa agtcactggc caagtcctcc tctgtccttc taggccgcac tgtgggcgag 2820

gaccctcagg gcctgttcca gaaacaccgg gaagaagagc tggaagagag aaggaagttg 2880

taccggtgag ccctcctccc ctgaccccac gtgagctgct gatgcttcca gcacccatac 2940

ttgatttcct tcctgcccca caggtggggga aactggaagg acggggttaat tctgaatatg 3000

gctggggcca aactatatga cctccctgtg gatgagcgat ttctggaaga caagagagtt 3060

3120

gtcctggtct agtggaagcc aaggggctta tgggctgcac tgcattggac tggccgga 3180

tcggtgcctg tggtcgtcat gttagagcct cagaatgatg ctcaaaccct ttgccccatc 3240

ctgccctgaa ggctggccga cctcgctatc aaagactctc taaatgttct gacttgctgg 3300

aaggatctag atgacttcaa ccggattttc tggtgtggtc agagcaagct ggctggtcag 3360

tcccccaccc cagtatgtct cccaaccccc cagatcccac cgatccca cccaacccag 3420

gggaattgaa agaagcaggg tggggagacc agagacttgg gtccctctgg tgggctggag 3480

tcaaggaggc atggttggtg gggttggaag gaccaagagc tcagatccca caacttgctc 3540

aacaactgcc ttccccagag cgcgtgcggg actcctggaa ggaagatgcc ttatttgggt 3600

accagtttct taatggcgcc aaccccgtgg tgctgaggcg ctctgctcac cttcctgctc 3660

gcctagtgtt ccctccaggc atggaggaac tgcaggccca gctggagaag gagctggagg 3720

tatggacatc agagccctga ggaagctcag cagtgaagtg gggtggccta gtgccaatga 3780

3840

aggagaggtc ctgagggacc ctggagaagc tcagctgctc ggcctccttc ctacacgaga 3900

gtagctgcgg agggagggcg tgcaagatgg aatggttgat agaaacaagg tcaaatgaag

aaatgtgact ggcccctggt gctagggatt cggggagtgt gcagagtaag agagtcagga 4020

tcagagtgct gtggctgttc atcaggaggc gatatggaac aacagagagg aaattcatgg 4080

gattaagggc agataggctt ggatgtgaat cctggttctg ctatttgtaa gctgtgtgac 4140

ctcaggcaaa atacccaacc tctctgatta tctgtttcct cttctgtaaa attgaggctc 4200

attcaactag gtataaaaat tataaggctg agcacagtga ctcacacctg taatcccagc 4260

actttgggag gctgcaggag gatcacctga gcccaggagt tggagaccag cctaggcaac 4320

4380

ggcatgcacc tgtagtccca gctacttggg aggctgaggt gggaggatca cctgggccca 4440

aggaagtcaa ggctgcagtg agccgtggtg atcctgccac gcactccagc ctgggcagca 4500

cggtaagacc ctgattaaaa aaaaaaatga tatgaggaag taagcacatg atccattacc 4560

tggtataaag tagatgatgg agacgagtta gctccactct cttccccctt ggaggaatcc 4620

gagtaggaag aagatgcttt atgttgatag cagcccttga cctcttcccc cacccaggga 4680

ggcacactgt tcgaagctga cttctccctg ctggatggga tcaaggccaa cgtcattctc 4740

tgtagccagc agcacctggc tgcccctcta gtcatgctga aattgcagcc tgatgggaaa 4800

ctcttgccca tggtcatcca ggtgagagga ctcaggattt ctgctcccag tctctggctt 4860

ttgagaaagc tcagcccctt atcaaaattt actgagcacc atctgcaaag gcactgggct 4920

aaggcacctg ggagacgcga aaggaggaaa tgcgccaagt ctctattcga aggccttgca 4980

gtgtagctgg agagacagac tgggccagtc tgcagaagct ccaggactga ggaagtccct 5040

gaggacagag acagcccagg agggattgggg gaggtggggt gtcacgagct ttggaggagg 5100

gccaggtctc agacaagcag gagggagagg aaggaccggt cctcaggggc aagacagact 5160

gggcagaggc tgaggtagag gagtcaggca attcctaggg gacagttgga ccagaagcca 5220

5280

tgtgggcacg cggtgtgggc agtggtgttt agggtggggtt ggagagggga gatgctagaa 5340

atagggactg gggcaacatg ccccagcact gaccccagga ggaggggagc tcggatgtgg 5400

gtagtgacca tcaggatgga gaggacaggt ggatgcgagt gcagagggag atcaaggaga 5460

ggggaaaggg gagccaggcc agttgcctgc agaaatagca ccgataaaga gaacagggtg 5520

cccaggtgga tttttgtctg gccaatgttg aggtaacggg aagacactta aattatccag 5580

caggcagctg agaacaagag attcagtcat ttgtgtagag gtggggccaa aagatgagtt 5640

ttcaaaaaac agtgtgggat ggaggaagca ggtggtttga atcttgtcca cactgtggga 5700

actgaaaggg gaagtggagg ctggaggagg caccagaaga gcagtttctg cagaatgctg 5760

gaggcaaagc agcttgcagg gtgctaatgc actgagcggg caggaagggg aggggaggaa 5820

5880

aagggtgagg ttaacatgca aggggggcgg gaatcgctga gtgcctggca ctcatgcctt 5940

ctctccccac acttgtccct gctccagctc cagctgcccc gcacaggatc cccaccacct 6000

6060

agctctgact tccagctcca tgagctgcag tctcatcttc tgaggggaca cttgatggct 6120

catgaggtgc ctgccgtcga tacatcctat cttcaaggta 6180

actccttatc cccttctctc ttgcctgcca ctatctctgc cccagggcac gttccgacct 6240

ctggaggctc cctctctgtg gggtctcggg gtacagagag aaacaatgaa tggacaatgt 6300

gagagcaaca gagaatgagc agggctggcc atgcattttc aaaggggata gcacctccca 6360

6420

tgaccaagga ttccatccaa caagaggaac ccgtgaaata acgttaaaaa gatcttttcc 6480

agacattgat tttttttttt tttttgagat ggagtctccc tttgcccaga ctggagtgca 6540

gtgatgcgat ctcggctcac tgcaacctct gcctcctggg tttaagcaat tctcccactt 6600

6660

tatttttaat agagacagga tttcaccatg ttggccaggc tggtctcgaa tgcctgacct 6720

cagatgatct gcttgtctag gtctcccaaa gtgctgggat tacaggcgtg agtcactgtg 6780

cctggtccaa gtttgtcttc tttaaagaac tgaaagaagc ctagtgtaat ggatgaagga 6840

gagagggagg agaccaggct ctggagggag gcagtggtta gaacatccat tctcagtggg 6900

ggcacaatgt cccccaaggg atgaagatgg ttggaaaatg tgtgtgaaaa atattattat 6960

tattattatt attattgctg cccaggctgg agtgcagtgt cacgatcttg gctcactgca 7020

acctctgcct cctgggttca agcaattctc ctgcttcagc ctcccgagta gctgggattc 7080

aggtgcctgc caccatgcct ggctaattttt tgtattttta gtagagatga ggttttgcca 7140

tgttggtcag gctggtctga aactcctgac ctcaggtgat ccgcccacct cggcctccca 7200

aagtgttggg attacaggcg tgagccaccg tggccggcca aatcttatta ctttatatag 7260

cacagatata atgtgatata tatctatata aagcacagat ataatgcaat acatagacag 7320

atatacagta tatatgtagc attaatattt aatgaggtgg agtgagatta ggaaaaaaca 7380

tctcaaaagg gtacttagtg ggtgattaaa aaaaaaaaag ttgagaaatc ttggtctaga 7440

cctatgaaaa aatatgaaaa gaaaaggagg ccaggcacgg tggttcacgc ctgtaatccc 7500

agctactcgg gaggctgagg caggagaatc gcgtgaaccc agaagacggga ggttgcagtg 7560

agccgagatc acaccactgt acttcagcct gggaaacaga gcaagactcc atctcaaaac 7620

aaaacaacaa caacaaagaa tgatttcttt caattatcat aaagcactaa gtctggtttg 7680

tggaatggaa atagttgatg caaatcaact gaaagctcag tggttttatt tttatgtatt 7740

tatttttaac tttaatttta ggttcaagga tacatgggca ggtttgttct gtaagtaaat 7800

tgtgtgtcat ggggcttggt gtacagatta ttttgtcacc aggtaataag catggtaccc 7860

cataggtagt ttttggatcc cctcactcct tccaccctct gtccacaagt agatgctggt 7920

gtctgttgtt cccttatttg tgtccatgtg tactcaatgt ttagctctca cttataagta 7980

agaacatacc atatttggct ttctgttcca gtgttagtgc acttaggatt atggcctcca 8040

gctccatcca tgttgctgca gagaacatga tcttgttctt cttcatggct gcatagtatt 8100

ccacagcata tgtctaccac attttcttta cctggtctat tgttgatggg catttaggtt 8160

gattccatat ctttgctatt gtgagtagtg ctggatgaac atccgtgagc atgtgtgttt 8220

atagtaaggc gatttatatt ttgggaggta tatatccagt aatgggattg ctgggttgaa 8280

tggtacttct gaaaactcac tgttgagagg ccactgaact ttacgtctgt gctttttctg 8340

aagacctggt gcctttcctg ctgtcagccc ttgtttcctg cagggatctt gcagctctcc 8400

tctgactctg cccttccctg tgtttctccc tctagcttat aattccccac ctgcgataca 8460

ccctggaaat taacgtccgg gccaggactg ggctggtctc tgacatggga attttcgacc 8520

aggtatggga agagaaaggg agattctgggg tctgtctttt ttccagctct ggattcaggg 8580

caggtcgatt cgcctgaccc tgctcaccct cacttctcag ataatgagca ctggtggggg 8640

aggccacgtg cagctgctca agcaagctgg agccttccta acctacagct ccttctgtcc 8700

ccctgatgac ttggccgacc gggggctcct gggagtgaag tcttccttct atgcccaaga 8760

tgcgctgcgg ctctgggaaa tcatctatcg gtgaggcaag cgggaaggcc agtgggggtg 8820

caagtggggg tggagaagac atgtaggaga gcaggaggtc tgcgtctggt tgggggcctg 8880

gggccctgac ctggccatgt gagcaggggc agagctggct tcagctccct ggccctgctc 8940

cgttggttgg taggtatgtg gaaggaatcg tgagtctcca ctataagaca gacgtggctg 9000

tgaaagacga cccagagctg cagacctggt gtcgagagat cactgaaatc gggctgcaag 9060

gggccgga ccgaggtaag aggagcccct gccctgagat ctcagacaca aagcccaaga 9120

gatcttccca gaatcccctg tgcttctgtg aaatctccca gaagcatttt caacacctat 9180

gagaactcca gaggccttct cagattccac tccctgtcac ctagagacag gtccccgtcc 9240

tacacactga gaacctctag gtgccagatg cagcgggacc agtggctgct cataaatgtt 9300

taacaactga ctctcgggaa gaaccgtcct gatttgtagc ttttgcacat ttccatggta 9360

taaatatttt tactgtgact acctaacgtga tgctgaccag cttgctaaac acctaacgtc 9420

atggactgac tcttgcgagc cagtgtgagt cagcagcagc accccactga gtgggaccct 9480

cccggcagag ctccccactc ccccacccca acctgctgtc atggtaattc ctgtaagagt 9540

taactgagca ttcctgccgc tctttctcgc ccttgttctc ctctcttggc ctcttcctct 9600

gagcgctgcc ctactcctgc cttcgcagct tctaactctc ttcacccctt gcagggtttc 9660

ctgtctcttt acaggctcgg gaccaggttt gccactttgt caccatgtgt atcttcacct 9720

gcaccggcca acacgcctct gtgcacctgg gccaggtact taccagagat gggcagctgg 9780

gaatttgggg cctggagtga gggaggggtc tgtgtgcagg tggaccacgg ggctcgcgtg 9840

cttggtaggc actgactctg gatccctgcc cttccttagc tggactggta ctcttgggtg 9900

cctaatgcac cctgcacgat gcggctgccc ccgccaacca ccaaggatgc aacgctggag 9960

acagtgatgg cgacactgcc caacttccac caggcttctc tccagatgtc catcacttgg 10020

cagctgggca gacgccagcc cgttatggtg agagctgagt gcccaggggcc ctaaggaagg 10080

aggcagctgt ggggacgtgt ggcatcccag actgggggtc ataaggctct cagccacctt 10140

ttcctctccc tcccaggtgg ctgtgggcca gcatgaggag gagtattttt cgggccctga 10200

gcctaaggct gtgctgaaga agttcaggga ggagctggct gccctggata aggaaattga 10260

gatccggaat gcaaagctgg acatgcccta cgagtacctg cggcccagcg tggtggaaaa 10320

cagtgtggcc atctaagcgt cgccaccctt tggttatttc agcccccatc acccaagcca 10380

caagctgacc ccttcgtggt tatagccctg ccctcccaag tcccaccctc ttcccatgtc 10440

ccaccctccc tagagggggca ccttttcatg gtctctgcac ccagtgaaca cattttactc 10500

tagaggcatc acctgggacc ttactcctct ttccttcctt cctcctttcc tatcttcctt 10560

cctctctctc ttcctctttc ttcattcaga tctatatggc aaatagccac aattatataa 10620

atcatttcaa gactagaata gggggatata atacatatta ctccacacct tttatgaatc 10680

10740

cagtggtgcc atcaccacgg ctcactgcag cctcagcgtc ctgggctcaa atgatcctcc 10800

10860

tttttatttt cgtggagacg gggcctcact atgttgccta ggctggaaat aggattttga 10920

acccaaattg agtttaacaa taataaaaag ttgttttacg ctaaagatgg aaaagaacta 10980

ggactgaact attttaaata aaatattggc aaaagaa 11017

<210> 2

<211> 11017

<212> DNA

<213> homo sapiens

<400> 2

ctgcgtgttt tcggtccaaa tccttttctt tttctccctc ccgtcaagat agtggtttcc 60

actccctgct ctcgccagga caccgccttt tggactgggg ctgaattctg ccccttgaag 120

ctctgctcct tggagctggg ggccccagcg gtaggcggag ttgattggag acctgccacc 180

cacattccga ccccaagcga cctccgagag ggcggggtct caggctggggt tatttagctc 240

gtccaccctt ctccaccaga aggagcgaaa catctttgag caagatgggt ctctaccgca 300

tccgcgtgtc cactggggcc tcgctctatg ccggttccaa caaccaggtg cagctgtggc 360

tggtcggcca gcacggggag gcggcgctcg ggaagcgact gtggcccgca cggggcaagg 420

tgagctcccc agagccggggc ggggtggggct gcgcccctgg ctccgagtca gtcaaatacc 480

ggggaggaca tgcgcccccg ttggcctctg gccgattctc tttgccaagg gcccgcgcat 540

tgggctcaaa gcgcgcggag gccacggggg tggggggctt tagggcagtc ggtggcacac 600

agtaagcgct caataaatgt tgccgctacc cgatctcctt ggaattgagg gcatgctcct 660

gtgcgcccct cattgcacaa agctcccttg tctggaaact cagcagtcac tggagccgcc 720

gtcggtcctc tcgctttctc tattttaaaa accgtttcaa ccgctagcgc tgttggatct 780

ctacctttca ggctttatca cctggggtgg agtgggtggt gagagggaag ggatggggag 840

tcaagacagg agaacgctct cgatttcccg acccacctcc cgtcatatct catgtcacat 900

ctaccgggtg ttctacccgg tcctgttaac ttttttttctt ccgcgaaagc ccaaattccc 960

atcactgctc tagctctctc ccagatcccc aaatccggat gtctgtctca gggaacgtca 1020

aagcaacatg cccggatgag gtcctcccct ctccccacct cccagccctc tcctcctgcc 1080

tcccccggtg tcacccgcgc ctccttcctc tcttcacctc cctctaaaca agaatccggc 1140

gcagtcagtt ctagaccctg agcatctccc gcgtccctgc ccaatatccg tcccgccccc 1200

gaccgcccgc gtcctcttga acctgcggag ccctgctccc cgcactccac gcccttgctc 1260

cgagcttccg agaaagcggg gcaaagggag cggaagag agaaaatgcg cacggagcag 1320

gtggccccgc gactccatgg tgaggggacg gggcacggaa ggtggaaagg cgcgctccct 1380

ccctcccttttt ttcctcccta tggtggggcag ttggtgacac acagtaaagg ctcaataaat 1440

gttcccgcta ctcgatctcc ttggaattaa ggggatgctc ctgagcgccc ctcattccac 1500

acagctctgg tgcctggaaa ctgcggtcgc cggagcggtc gtcggtcctc ccggtttctc 1560

tattttaaaa gccatttcaa acctccagcg gcctcgccac ctctgctgca gaccttccaa 1620

gcccttctga agccggaatg atttctccct aattcactcc ccctgcttaa cacattcgaa 1680

cggctcccgc ttgttctcgg gaccaaatcc aaagcccctg gcgccacctt cgagagcctc 1740

cggacctgct gaccccccac acctgggctc tgagctccag ctccaagatg ctgctcgccc 1800

tcccttcccc gccgctctct ttctgcgcgc ctttcccctg ccttcccttt ctgtcactct 1860

ccctggctga gccctctccg cctccaggtc tccgggaagg ttgtccccag gccggtgggg 1920

cccctgcagg tcctcagcct cgggcggggt ggggtgggggg gtcgcacagc gggaattgcc 1980

accagcgcgt cggggctcca cagcgcgctc gtccagggcg cggcagcgct cagcccagcg 2040

cttggcacag tcagtgacca cagggaggag aaagtgaagg caggagcgca ccttcccacc 2100

tgccgtcccc gtcccctcag aaccgagtcc tggggccacc tgctcggcgc ggtccctctc 2160

tctctggctc agtccccgca ccccgatacg tctcctcctc tcagaggctc cgaggaaggg 2220

cgtgggcgct ggagggagca gggctcagcc gggtgcccct cccgccaggc cccaccgggg 2280

ctgagcctct tctgtcgccc gcaggagaca gaactcaagg tggaagtacc ggagtatctg 2340

gggccgctgc tgtttgtgaa actgcgcaaa cggcacctcc ttaaggacga cgcctggttc 2400

tgcaactgga tctctgtgca gggccccgga gccggggacg aggtcaggtt cccttgttac 2460

cgctgggtgg agggcaacgg cgtcctgagc ctgcctgaag gcaccggtaa gcgcggggct 2520

gagggtgtca ggaggcctct gggctgtgtg agaagctggg gggatgcgcg tgtggagaag 2580

agggcgcagg atgggggtgc tggaacctgg agcgccgggg tctttggggg tgtcgaaggg 2640

gcggtggctg cagctggcac aaagtggctg gagcctgggg gaggggcgtg atgctgaagg 2700

ggcagaggcc acacagaagg acggggtgct gaggctctcc tggcagagac aagaagaggc 2760

gctcaccaaa agtcactggc caagtcctcc tctgtccttc taggccgcac tgtgggcgag 2820

gaccctcagg gcctgttcca gaaacaccgg gaagaagagc tggaagagag aaggaagttg 2880

taccggtgag ccctcctccc ctgaccccac gtgagctgct gatgcttcca gcacccatac 2940

ttgatttcct tcctgcccca caggtggggga aactggaagg acggggttaat tctgaatatg 3000

gctggggcca aactatatga cctccctgtg gatgagcgat ttctggaaga caagagagtt 3060

3120

gtcctggtct agtggaagcc aaggggctta tgggctgcac tgcattggac tggccgga 3180

tcggtgcctg tggtcgtcat gttagagcct cagaatgatg ctcaaaccct ttgccccatc 3240

ctgccctgaa ggctggccga cctcgctatc aaagactctc taaatgttct gacttgctgg 3300

aaggatctag atgacttcaa ccggattttc tggtgtggtc agagcaagct ggctggtcag 3360

tcccccaccc cagtatgtct cccaaccccc cagatcccac cgatccca cccaacccag 3420

gggaattgaa agaagcaggg tggggagacc agagacttgg gtccctctgg tgggctggag 3480

tcaaggaggc atggttggtg gggttggaag gaccaagagc tcagatccca caacttgctc 3540

aacaactgcc ttccccagag cgcgtgcggg actcctggaa ggaagatgcc ttatttgggt 3600

accagtttct taatggcgcc aaccccgtgg tgctgaggcg ctctgctcac cttcctgctc 3660

gcctagtgtt ccctccaggc atggaggaac tgcaggccca gctggagaag gagctggagg 3720

tatggacatc agagccctga ggaagctcag cagtgaagtg gggtggccta gtgccaatga 3780

3840

aggagaggtc ctgagggacc ctggagaagc tcagctgctc ggcctccttc ctacacgaga 3900

gtagctgcgg agggagggcg tgcaagatgg aatggttgat agaaacaagg tcaaatgaag

aaatgtgact ggcccctggt gctagggatt cggggagtgt gcagagtaag agagtcagga 4020

tcagagtgct gtggctgttc atcaggaggc gatatggaac aacagagagg aaattcatgg 4080

gattaagggc agataggctt ggatgtgaat cctggttctg ctatttgtaa gctgtgtgac 4140

ctcaggcaaa atacccaacc tctctgatta tctgtttcct cttctgtaaa attgaggctc 4200

attcaactag gtataaaaat tataaggctg agcacagtga ctcacacctg taatcccagc 4260

actttgggag gctgcaggag gatcacctga gcccaggagt tggagaccag cctaggcaac 4320

4380

ggcatgcacc tgtagtccca gctacttggg aggctgaggt gggaggatca cctgggccca 4440

aggaagtcaa ggctgcagtg agccgtggtg atcctgccac gcactccagc ctgggcagca 4500

cggtaagacc ctgattaaaa aaaaaaatga tatgaggaag taagcacatg atccattacc 4560

tggtataaag tagatgatgg agacgagtta gctccactct cttccccctt ggaggaatcc 4620

gagtaggaag aagatgcttt atgttgatag cagcccttga cctcttcccc cacccaggga 4680

ggcacactgt tcgaagctga cttctccctg ctggatggga tcaaggccaa cgtcattctc 4740

tgtagccagc agcacctggc tgcccctcta gtcatgctga aattgcagcc tgatgggaaa 4800

ctcttgccca tggtcatcca ggtgagagga ctcaggattt ctgctcccag tctctggctt 4860

ttgagaaagc tcagcccctt atcaaaattt actgagcacc atctgcaaag gcactgggct 4920

aaggcacctg ggagacgcga aaggaggaaa tgcgccaagt ctctattcga aggccttgca 4980

gtgtagctgg agagacagac tgggccagtc tgcagaagct ccaggactga ggaagtccct 5040

gaggacagag acagcccagg agggattgggg gaggtggggt gtcacgagct ttggaggagg 5100

gccaggtctc agacaagcag gagggagagg aaggaccggt cctcaggggc aagacagact 5160

gggcagaggc tgaggtagag gagtcaggca attcctaggg gacagttgga ccagaagcca 5220

5280

tgtgggcacg cggtgtgggc agtggtgttt agggtggggtt ggagagggga gatgctagaa 5340

atagggactg gggcaacatg ccccagcact gaccccagga ggaggggagc tcggatgtgg 5400

gtagtgacca tcaggatgga gaggacaggt ggatgcgagt gcagagggag atcaaggaga 5460

ggggaaaggg gagccaggcc agttgcctgc agaaatagca ccgataaaga gaacagggtg 5520

cccaggtgga tttttgtctg gccaatgttg aggtaacggg aagacactta aattatccag 5580

caggcagctg agaacaagag attcagtcat ttgtgtagag gtggggccaa aagatgagtt 5640

ttcaaaaaac agtgtgggat ggaggaagca ggtggtttga atcttgtcca cactgtggga 5700

actgaaaggg gaagtggagg ctggaggagg caccagaaga gcagtttctg cagaatgctg 5760

gaggcaaagc agcttgcagg gtgctaatgc actgagcggg caggaagggg aggggaggaa 5820

5880

aagggtgagg ttaacatgca aggggggcgg gaatcgctga gtgcctggca ctcatgcctt 5940

ctctccccac acttgtccct gctccagctc cagctgcccc gcacaggatc cccaccacct 6000

6060

agctctgact tccagctcca tgagctgcag tctcatcttc tgaggggaca cttgatggct 6120

catgaggtgc ctgccgtcga tacatcctat cttcaaggta 6180

actccttatc cccttctctc ttgcctgcca ctatctctgc cccagggcac gttccgacct 6240

ctggaggctc cctctctgtg gggtctcggg gtacagagag aaacaatgaa tggacaatgt 6300

gagagcaaca gagaatgagc agggctggcc atgcattttc aaaggggata gcacctccca 6360

6420

tgaccaagga ttccatccaa caagaggaac ccgtgaaata acgttaaaaa gatcttttcc 6480

agacattgat tttttttttt tttttgagat ggagtctccc tttgcccaga ctggagtgca 6540

gtgatgcgat ctcggctcac tgcaacctct gcctcctggg tttaagcaat tctcccactt 6600

6660

tatttttaat agagacagga tttcaccatg ttggccaggc tggtctcgaa tgcctgacct 6720

cagatgatct gcttgtctag gtctcccaaa gtgctgggat tacaggcgtg agtcactgtg 6780

cctggtccaa gtttgtcttc tttaaagaac tgaaagaagc ctagtgtaat ggatgaagga 6840

gagagggagg agaccaggct ctggagggag gcagtggtta gaacatccat tctcagtggg 6900

ggcacaatgt cccccaaggg atgaagatgg ttggaaaatg tgtgtgaaaa atattattat 6960

tattattatt attattgctg cccaggctgg agtgcagtgt cacgatcttg gctcactgca 7020

acctctgcct cctgggttca agcaattctc ctgcttcagc ctcccgagta gctgggattc 7080

aggtgcctgc caccatgcct ggctaattttt tgtattttta gtagagatga ggttttgcca 7140

tgttggtcag gctggtctga aactcctgac ctcaggtgat ccgcccacct cggcctccca 7200

aagtgttggg attacaggcg tgagccaccg tggccggcca aatcttatta ctttatatag 7260

cacagatata atgtgatata tatctatata aagcacagat ataatgcaat acatagacag 7320

atatacagta tatatgtagc attaatattt aatgaggtgg agtgagatta ggaaaaaaca 7380

tctcaaaagg gtacttagtg ggtgattaaa aaaaaaaaag ttgagaaatc ttggtctaga 7440

cctatgaaaa aatatgaaaa gaaaaggagg ccaggcacgg tggttcacgc ctgtaatccc 7500

agctactcgg gaggctgagg caggagaatc gcgtgaaccc agaagacggga ggttgcagtg 7560

agccgagatc acaccactgt acttcagcct gggaaacaga gcaagactcc atctcaaaac 7620

aaaacaacaa caacaaagaa tgatttcttt caattatcat aaagcactaa gtctggtttg 7680

tggaatggaa atagttgatg caaatcaact gaaagctcag tggttttatt tttatgtatt 7740

tatttttaac tttaatttta ggttcaagga tacatgggca ggtttgttct gtaagtaaat 7800

tgtgtgtcat ggggcttggt gtacagatta ttttgtcacc aggtaataag catggtaccc 7860

cataggtagt ttttggatcc cctcactcct tccaccctct gtccacaagt agatgctggt 7920

gtctgttgtt cccttatttg tgtccatgtg tactcaatgt ttagctctca cttataagta 7980

agaacatacc atatttggct ttctgttcca gtgttagtgc acttaggatt atggcctcca 8040

gctccatcca tgttgctgca gagaacatga tcttgttctt cttcatggct gcatagtatt 8100

ccacagcata tgtctaccac attttcttta cctggtctat tgttgatggg catttaggtt 8160

gattccatat ctttgctatt gtgagtagtg ctggatgaac atccgtgagc atgtgtgttt 8220

atagtaaggc gatttatatt ttgggaggta tatatccagt aatgggattg ctgggttgaa 8280

tggtacttct gaaaactcac tgttgagagg ccactgaact ttacgtctgt gctttttctg 8340

aagacctggt gcctttcctg ctgtcagccc ttgtttcctg cagggatctt gcagctctcc 8400

tctgactctg cccttccctg tgtttctccc tctagcttat aattccccac ctgcgataca 8460

ccctggaaat taacgtccgg gccaggactg ggctggtctc tgacatggga attttcgacc 8520

aggtatggga agagaaaggg agattctgggg tctgtctttt ttccagctct ggattcaggg 8580

caggtcgatt cgcctgaccc tgctcaccct cacttctcag ataatgagca ctggtggggg 8640

aggccacgtg cagctgctca agcaagctgg agccttccta acctacagct ccttctgtcc 8700

ccctgatgac ttggccgacc gggggctcct gggagtgaag tcttccttct atgcccaaga 8760

tgcgctgcgg ctctgggaaa tcatctatcg gtgaggcaag cgggaaggcc agtgggggtg 8820

caagtggggg tggagaagac atgtaggaga gcaggaggtc tgcgtctggt tgggggcctg 8880

gggccctgac ctggccatgt gagcaggggc agagctggct tcagctccct ggccctgctc 8940

cgttggttgg taggtatgtg gaaggaatcg tgagtctcca ctataagaca gacgtggctg 9000

tgaaagacga cccagagctg cagacctggt gtcgagagat cactgaaatc gggctgcaag 9060

gggccgga ccgaggtaag aggagcccct gccctgagat ctcagacaca aagcccaaga 9120

gatcttccca gaatcccctg tgcttctgtg aaatctccca gaagcatttt caacacctat 9180

gagaactcca gaggccttct cagattccac tccctgtcac ctagagacag gtccccgtcc 9240

tacacactga gaacctctag gtgccagatg cagcgggacc agtggctgct cataaatgtt 9300

taacaactga ctctcgggaa gaaccgtcct gatttgtagc ttttgcacat ttccatggta 9360

taaatatttt tactgtgact acctaacgtga tgctgaccag cttgctaaac acctaacgtc 9420

atggactgac tcttgcgagc cagtgtgagt cagcagcagc accccactga gtgggaccct 9480

cccggcagag ctccccactc ccccacccca acctgctgtc atggtaattc ctgtaagagt 9540

taactgagca ttcctgccgc tctttctcgc ccttgttctc ctctcttggc ctcttcctct 9600

gagcgctgcc ctactcctgc cttcgcagct tctaactctc ttcacccctt gcagggtttc 9660

ctgtctcttt acaggctcgg gaccaggttt gccactttgt caccatgtgt atcttcacct 9720

gcaccggcca acacgcctct gtgcacctgg gccaggtact taccagagat gggcagctgg 9780

gaatttgggg cctggagtga gggaggggtc tgtgtgcagg tggaccacgg ggctcgcgtg 9840

cttggtaggc actgactctg gatccctgcc cttccttagc tggactggta ctcttgggtg 9900

cctaatgcac cctgcatgat gcggctgccc ccgccaacca ccaaggatgc aacgctggag 9960

acagtgatgg cgacactgcc caacttccac caggcttctc tccagatgtc catcacttgg 10020

cagctgggca gacgccagcc cgttatggtg agagctgagt gcccaggggcc ctaaggaagg 10080

aggcagctgt ggggacgtgt ggcatcccag actgggggtc ataaggctct cagccacctt 10140

ttcctctccc tcccaggtgg ctgtgggcca gcatgaggag gagtattttt cgggccctga 10200

gcctaaggct gtgctgaaga agttcaggga ggagctggct gccctggata aggaaattga 10260

gatccggaat gcaaagctgg acatgcccta cgagtacctg cggcccagcg tggtggaaaa 10320

cagtgtggcc atctaagcgt cgccaccctt tggttatttc agcccccatc acccaagcca 10380

caagctgacc ccttcgtggt tatagccctg ccctcccaag tcccaccctc ttcccatgtc 10440

ccaccctccc tagagggggca ccttttcatg gtctctgcac ccagtgaaca cattttactc 10500

tagaggcatc acctgggacc ttactcctct ttccttcctt cctcctttcc tatcttcctt 10560

cctctctctc ttcctctttc ttcattcaga tctatatggc aaatagccac aattatataa 10620

atcatttcaa gactagaata gggggatata atacatatta ctccacacct tttatgaatc 10680

10740

cagtggtgcc atcaccacgg ctcactgcag cctcagcgtc ctgggctcaa atgatcctcc 10800

10860

tttttatttt cgtggagacg gggcctcact atgttgccta ggctggaaat aggattttga 10920

acccaaattg agtttaacaa taataaaaag ttgttttacg ctaaagatgg aaaagaacta 10980

ggactgaact attttaaata aaatattggc aaaagaa 11017

<210> 3

<211> 2707

<212> DNA

<213> homo sapiens

<400> 3

caucuuugag caagaugggu cucuaccgca uccgcguguc cacuggggcc ucgcucuaug 60

ccgguuccaa caaccaggug cagcuguggc uggucggcca gcacggggag gcggcgcucg 120

ggaagcgacu guggcccgca cggggcaagg agacagaacu caagguggaa guaccgggagu 180

aucuggggcc gcugcuguuu gugaaacugc gcaaacggca ccuccuuaag gacgacgccu 240

gguucugcaa cuggaucucu gugcagggcc ccggagccgg ggacgagguc agguucccuu 300

guuaccgcug gguggagggc aacggcgucc ugagccugcc ugaaggcacc ggccgcacug 360

ugggcgagga cccucagggc cuguuccaga aacaccggga agaagagcug gaagagagaa 420

ggaaguugua ccggugggga aacuggaagg acggguuaau ucugaauaug gcuggggcca 480

aacuauauga ccucccugug gaugagcgau uucuggaaga caagagaguu gacuuugagg 540

uuucgcuggc caaggggcug gccgaccucg cuaucaaaga cucucuaaau guucugacuu 600

gcuggaagga ucuagaugac uucaaccgga uuuucuggug uggucagagc aagcuggcug 660

agcgcgugcg ggacuccugg aaggaagaug ccuuauuugg guaccaguuu cuuaauggcg 720

ccaaccccgu ggugcugagg cgcucugcuc accuuccugc ucgccuagug uucccuccag 780

gcauggagga acugcaggcc cagcuggaga aggagcugga gggaggcaca cuguucgaag 840

cugacuucuc ccugcuggau gggaucaagg ccaacgucau ucucuguagc cagcagcacc 900

uggcugcccc ucuagucaug cugaaauugc agccugaugg gaaacucuug cccaugguca 960

uccagcucca gcugccccgc acaggauccc caccaccucc ccuuuucuug ccuacggauc 1020

ccccaauggc cuggcuucug gccaaaugcu gggugcgcag cucugacuuc cagcuccaug 1080

agcugcaguc ucaucuucug aggggacacu ugauggcuga ggucauuguu guggccacca 1140

ugaggugccu gccgucgaua cauccuaucu ucaagcuuau aauuccccac cugcgauaca 1200

ccuggaaau uaacguccgg gccaggacug ggcuggucuc ugacauggga auuuucgacc 1260

agauaaugag cacugguggg ggaggccacg ugcagcugcu caagcaagcu ggagccuucc 1320

uaaccuacag cuccuucugu cccccugaug acuuggccga ccgggggcuc cugggaguga 1380

agucuuccuu cuaugcccaa gaugcgcugc ggcucuggga aaucaucuau cgguaugugg 1440

1500

agaccuggug ucgagagauc acugaaaucg ggcugcaagg ggcccaggac cgaggguuuc 1560

cugucucuuu acaggcucgg gaccagguuu gccacuuugu caccaugugu aucuucaccu 1620

gcaccggcca acacgccucu gugcaccugg gccagcugga cugguacucu ugggugccua 1680

augcacccug cacgaugcgg cugcccccgc caaccaccaa ggaugcaacg cuggagacag 1740

ugaggcgac acugcccaac uuccaccagg cuucucucca gauguccauc acuuggcagc 1800

ugggcagacg ccagcccguu agguggcug ugggccagca ugaggaggag uauuuuucgg 1860

gccugagcc uaaggcugug cugaagaagu ucagggagga gcuggcugcc cuggauaagg 1920

1980

uggaaaacag uguggccauc uaagcgucgc cacccuuugg uuauuucagc ccccaucacc 2040

caagccacaa gcugaccccu ucgugguuau agcccugccc ucccaagucc cacccucuuc 2100

ccauguccca cccucccuag aggggcaccu uuucaugguc ucugcaccca gugaacacau 2160

uuuacucuag aggcaucacc ugggaccuua cuccucuuuc cuuccuuccu ccuuuccuau 2220

cuuccuuccu cucucucuuc cucuuucuuc auucagaucu auauggcaaa uagccacaau 2280

uauauaaauc auuucaagac uagaauaggg ggauauaaua cauauuacuc cacaccuuuu 2340

2400

uggagugcag uggugccauc accacggcuc acugcagccu cagcguccug ggcucaaaug 2460

auccuccac cucagccucc ugaguagcug ggacuacagg cucaugccau caugcccagc 2520

uaauauuuuu uuauuuucgu ggagacgggg ccucacuaug uugccuaggc uggaaauagg 2580

2640

agaacuagga cugaacuauu uuaaauaaaa uauuggcaaa agaaaaaaaa aaaaaaaaaa 2700

aaaaaaa 2707

<210> 4

<211> 2707

<212> DNA

<213> homo sapiens

<400> 4

caucuuugag caagaugggu cucuaccgca uccgcguguc cacuggggcc ucgcucuaug 60

ccgguuccaa caaccaggug cagcuguggc uggucggcca gcacggggag gcggcgcucg 120

ggaagcgacu guggcccgca cggggcaagg agacagaacu caagguggaa guaccgggagu 180

aucuggggcc gcugcuguuu gugaaacugc gcaaacggca ccuccuuaag gacgacgccu 240

gguucugcaa cuggaucucu gugcagggcc ccggagccgg ggacgagguc agguucccuu 300

guuaccgcug gguggagggc aacggcgucc ugagccugcc ugaaggcacc ggccgcacug 360

ugggcgagga cccucagggc cuguuccaga aacaccggga agaagagcug gaagagagaa 420

ggaaguugua ccggugggga aacuggaagg acggguuaau ucugaauaug gcuggggcca 480

aacuauauga ccucccugug gaugagcgau uucuggaaga caagagaguu gacuuugagg 540

uuucgcuggc caaggggcug gccgaccucg cuaucaaaga cucucuaaau guucugacuu 600

gcuggaagga ucuagaugac uucaaccgga uuuucuggug uggucagagc aagcuggcug 660

agcgcgugcg ggacuccugg aaggaagaug ccuuauuugg guaccaguuu cuuaauggcg 720

ccaaccccgu ggugcugagg cgcucugcuc accuuccugc ucgccuagug uucccuccag 780

gcauggagga acugcaggcc cagcuggaga aggagcugga gggaggcaca cuguucgaag 840

cugacuucuc ccugcuggau gggaucaagg ccaacgucau ucucuguagc cagcagcacc 900

uggcugcccc ucuagucaug cugaaauugc agccugaugg gaaacucuug cccaugguca 960

uccagcucca gcugccccgc acaggauccc caccaccucc ccuuuucuug ccuacggauc 1020

ccccaauggc cuggcuucug gccaaaugcu gggugcgcag cucugacuuc cagcuccaug 1080

agcugcaguc ucaucuucug aggggacacu ugauggcuga ggucauuguu guggccacca 1140

ugaggugccu gccgucgaua cauccuaucu ucaagcuuau aauuccccac cugcgauaca 1200

ccuggaaau uaacguccgg gccaggacug ggcuggucuc ugacauggga auuuucgacc 1260

agauaaugag cacugguggg ggaggccacg ugcagcugcu caagcaagcu ggagccuucc 1320

uaaccuacag cuccuucugu cccccugaug acuuggccga ccgggggcuc cugggaguga 1380

agucuuccuu cuaugcccaa gaugcgcugc ggcucuggga aaucaucuau cgguaugugg 1440

1500

agaccuggug ucgagagauc acugaaaucg ggcugcaagg ggcccaggac cgaggguuuc 1560

cugucucuuu acaggcucgg gaccagguuu gccacuuugu caccaugugu aucuucaccu 1620

gcaccggcca acacgccucu gugcaccugg gccagcugga cugguacucu ugggugccua 1680

augcacccug caugaugcgg cugcccccgc caaccaccaa ggaugcaacg cuggagacag 1740

ugaggcgac acugcccaac uuccaccagg cuucucucca gauguccauc acuuggcagc 1800

ugggcagacg ccagcccguu agguggcug ugggccagca ugaggaggag uauuuuucgg 1860

gccugagcc uaaggcugug cugaagaagu ucagggagga gcuggcugcc cuggauaagg 1920

1980

uggaaaacag uguggccauc uaagcgucgc cacccuuugg uuauuucagc ccccaucacc 2040

caagccacaa gcugaccccu ucgugguuau agcccugccc ucccaagucc cacccucuuc 2100

ccauguccca cccucccuag aggggcaccu uuucaugguc ucugcaccca gugaacacau 2160

uuuacucuag aggcaucacc ugggaccuua cuccucuuuc cuuccuuccu ccuuuccuau 2220

cuuccuuccu cucucucuuc cucuuucuuc auucagaucu auauggcaaa uagccacaau 2280

uauauaaauc auuucaagac uagaauaggg ggauauaaua cauauuacuc cacaccuuuu 2340

2400

uggagugcag uggugccauc accacggcuc acugcagccu cagcguccug ggcucaaaug 2460

auccuccac cucagccucc ugaguagcug ggacuacagg cucaugccau caugcccagc 2520

uaauauuuuu uuauuuucgu ggagacgggg ccucacuaug uugccuaggc uggaaauagg 2580

2640

agaacuagga cugaacuauu uuaaauaaaa uauuggcaaa agaaaaaaaa aaaaaaaaaa 2700

aaaaaaa 2707

<210> 5

<211> 2707

<212> DNA

<213> homo sapiens

<400> 5

catctttgag caagatgggt ctctaccgca tccgcgtgtc cactggggcc tcgctctatg 60

ccggttccaa caaccaggtg cagctgtggc tggtcggcca gcacggggag gcggcgctcg 120

ggaagcgact gtggcccgca cggggcaagg agacagaact caaggtggaa gtaccggagt 180

atctggggcc gctgctgttt gtgaaactgc gcaaacggca cctccttaag gacgacgcct 240

ggttctgcaa ctggatctct gtgcagggcc ccggagccgg ggacgaggtc aggttccctt 300

gttaccgctg ggtggagggc aacggcgtcc tgagcctgcc tgaaggcacc ggccgcactg 360

tgggcgagga ccctcagggc ctgttccaga aacaccggga agaagagctg gaagagagaa 420

ggaagttgta ccggtggggga aactggaagg acgggttaat tctgaatatg gctggggcca 480

aactatatga cctccctgtg gatgagcgat ttctggaaga caagagagtt gactttgagg 540

tttcgctggc caaggggctg gccgacctcg ctatcaaaga ctctctaaat gttctgactt 600

gctggaagga tctagatgac ttcaaccggga ttttctggtg tggtcagagc aagctggctg 660

agcgcgtgcg ggactcctgg aaggaagatg ccttatttgg gtaccagttt cttaatggcg 720

ccaaccccgt ggtgctgagg cgctctgctc accttcctgc tcgcctagtg ttccctccag 780

gcatggagga actgcaggcc cagctggaga aggagctgga gggaggcaca ctgttcgaag 840

ctgacttctc cctgctggat gggatcaagg ccaacgtcat tctctgtagc cagcagcacc 900

tggctgcccc tctagtcatg ctgaaattgc agcctgatgg gaaactcttg cccatggtca 960

tccagctcca gctgccccgc acaggatccc caccacctcc ccttttcttg cctacggatc 1020

ccccaatggc ctggcttctg gccaaatgct gggtgcgcag ctctgacttc cagctccatg 1080

agctgcagtc tcatcttctg aggggacact tgatggctga ggtcattgtt gtggccacca 1140

tgaggtgcct gccgtcgata catcctatct tcaagcttat aattccccac ctgcgataca 1200

ccctggaaat taacgtccgg gccaggactg ggctggtctc tgacatggga attttcgacc 1260

agataatgag cactggtggg ggaggccacg tgcagctgct caagcaagct ggagccttcc 1320

taacctacag ctccttctgt ccccctgatg acttggccga ccggggggctc ctgggagtga 1380

agtcttcctt ctatgcccaa gatgcgctgc ggctctggga aatcatctat cggtatgtgg 1440

aaggaatcgt gagtctccac tataagacag acgtggctgt gaaagacgac ccagagctgc 1500

agacctggtg tcgagagatc actgaaatcg ggctgcaagg ggcccaggac cgagggtttc 1560

ctgtctcttt acaggctcgg gaccaggttt gccactttgt caccatgtgt atcttcacct 1620

gcaccggcca acacgcctct gtgcacctgg gccagctgga ctggtactct tgggtgccta 1680

atgcaccctg cacgatgcgg ctgcccccgc caaccaccaa ggatgcaacg ctggagacag 1740

tgatggcgac actgcccaac ttccaccagg cttctctcca gatgtccatc acttggcagc 1800

tgggcagacg ccagcccgtt atggtggctg tgggccagca tgaggaggag tatttttcgg 1860

gccctgagcc taaggctgtg ctgaagaagt tcagggagga gctggctgcc ctggataagg 1920

1980

tggaaaacag tgtggccatc taagcgtcgc caccctttgg ttatttcagc ccccatcacc 2040

caagccacaa gctgacccct tcgtggttat agccctgccc tcccaagtcc caccctcttc 2100

ccatgtccca ccctccctag aggggcacct tttcatggtc tctgcaccca gtgaacacat 2160

tttactctag aggcatcacc tgggacctta ctcctctttc cttccttcct ccttttcctat 2220

cttccttcct ctctctcttc ctctttcttc attcagatct atatggcaaa tagccacaat 2280

tatataaatc atttcaagac tagaataggg ggatataata catattactc cacacctttt 2340

atgaatcaaa tatgattttt ttgttgttgt taagacagag tctcactttg acacccaggc 2400

tggagtgcag tggtgccatc accacggctc actgcagcct cagcgtcctg ggctcaaatg 2460

atcctcccac ctcagcctcc tgagtagctg ggactacagg ctcatgccat catgcccagc 2520

taatattttt ttatttttcgt ggagacgggg cctcactatg ttgcctaggc tggaaatagg 2580

attttgaacc caaattgagt ttaacaataa taaaaagttg ttttacgcta aagatggaaa 2640

agaactagga ctgaactatt ttaaataaaa tattggcaaa agaaaaaaaa aaaaaaaaaa 2700

aaaaaaa 2707

<210> 6

<211> 2707

<212> DNA

<213> homo sapiens

<400> 6

catctttgag caagatgggt ctctaccgca tccgcgtgtc cactggggcc tcgctctatg 60

ccggttccaa caaccaggtg cagctgtggc tggtcggcca gcacggggag gcggcgctcg 120

ggaagcgact gtggcccgca cggggcaagg agacagaact caaggtggaa gtaccggagt 180

atctggggcc gctgctgttt gtgaaactgc gcaaacggca cctccttaag gacgacgcct 240

ggttctgcaa ctggatctct gtgcagggcc ccggagccgg ggacgaggtc aggttccctt 300

gttaccgctg ggtggagggc aacggcgtcc tgagcctgcc tgaaggcacc ggccgcactg 360

tgggcgagga ccctcagggc ctgttccaga aacaccggga agaagagctg gaagagagaa 420

ggaagttgta ccggtggggga aactggaagg acgggttaat tctgaatatg gctggggcca 480

aactatatga cctccctgtg gatgagcgat ttctggaaga caagagagtt gactttgagg 540

tttcgctggc caaggggctg gccgacctcg ctatcaaaga ctctctaaat gttctgactt 600

gctggaagga tctagatgac ttcaaccggga ttttctggtg tggtcagagc aagctggctg 660

agcgcgtgcg ggactcctgg aaggaagatg ccttatttgg gtaccagttt cttaatggcg 720

ccaaccccgt ggtgctgagg cgctctgctc accttcctgc tcgcctagtg ttccctccag 780

gcatggagga actgcaggcc cagctggaga aggagctgga gggaggcaca ctgttcgaag 840

ctgacttctc cctgctggat gggatcaagg ccaacgtcat tctctgtagc cagcagcacc 900

tggctgcccc tctagtcatg ctgaaattgc agcctgatgg gaaactcttg cccatggtca 960

tccagctcca gctgccccgc acaggatccc caccacctcc ccttttcttg cctacggatc 1020

ccccaatggc ctggcttctg gccaaatgct gggtgcgcag ctctgacttc cagctccatg 1080

agctgcagtc tcatcttctg aggggacact tgatggctga ggtcattgtt gtggccacca 1140

tgaggtgcct gccgtcgata catcctatct tcaagcttat aattccccac ctgcgataca 1200

ccctggaaat taacgtccgg gccaggactg ggctggtctc tgacatggga attttcgacc 1260

agataatgag cactggtggg ggaggccacg tgcagctgct caagcaagct ggagccttcc 1320

taacctacag ctccttctgt ccccctgatg acttggccga ccggggggctc ctgggagtga 1380

agtcttcctt ctatgcccaa gatgcgctgc ggctctggga aatcatctat cggtatgtgg 1440

aaggaatcgt gagtctccac tataagacag acgtggctgt gaaagacgac ccagagctgc 1500

agacctggtg tcgagagatc actgaaatcg ggctgcaagg ggcccaggac cgagggtttc 1560

ctgtctcttt acaggctcgg gaccaggttt gccactttgt caccatgtgt atcttcacct 1620

gcaccggcca acacgcctct gtgcacctgg gccagctgga ctggtactct tgggtgccta 1680

atgcaccctg catgatgcgg ctgcccccgc caaccaccaa ggatgcaacg ctggagacag 1740

tgatggcgac actgcccaac ttccaccagg cttctctcca gatgtccatc acttggcagc 1800

tgggcagacg ccagcccgtt atggtggctg tgggccagca tgaggaggag tatttttcgg 1860

gccctgagcc taaggctgtg ctgaagaagt tcagggagga gctggctgcc ctggataagg 1920

1980

tggaaaacag tgtggccatc taagcgtcgc caccctttgg ttatttcagc ccccatcacc 2040

caagccacaa gctgacccct tcgtggttat agccctgccc tcccaagtcc caccctcttc 2100

ccatgtccca ccctccctag aggggcacct tttcatggtc tctgcaccca gtgaacacat 2160

tttactctag aggcatcacc tgggacctta ctcctctttc cttccttcct ccttttcctat 2220

cttccttcct ctctctcttc ctctttcttc attcagatct atatggcaaa tagccacaat 2280

tatataaatc atttcaagac tagaataggg ggatataata catattactc cacacctttt 2340

atgaatcaaa tatgattttt ttgttgttgt taagacagag tctcactttg acacccaggc 2400

tggagtgcag tggtgccatc accacggctc actgcagcct cagcgtcctg ggctcaaatg 2460

atcctcccac ctcagcctcc tgagtagctg ggactacagg ctcatgccat catgcccagc 2520

taatattttt ttatttttcgt ggagacgggg cctcactatg ttgcctaggc tggaaatagg 2580

attttgaacc caaattgagt ttaacaataa taaaaagttg ttttacgcta aagatggaaa 2640

agaactagga ctgaactatt ttaaataaaa tattggcaaa agaaaaaaaa aaaaaaaaaa 2700

aaaaaaa 2707

<210> 7

<211> 662

<212> Protein

<213> homo sapiens

<400> 7

Met Gly Leu Tyr Arg Ile Arg Val Ser Thr Gly Ala Ser Leu Tyr Ala

1 5 10 15

Gly Ser Asn Asn Gln Val Gln Leu Trp Leu Val Gly Gln His Gly Glu

20 25 30

Ala Ala Leu Gly Lys Arg Leu Trp Pro Ala Arg Gly Lys Glu Thr Glu

35 40 45

Leu Lys Val Glu Val Pro Glu Tyr Leu Gly Pro Leu Leu Phe Val Lys

50 55 60

Leu Arg Lys Arg His Leu Leu Lys Asp Asp Ala Trp Phe Cys Asn Trp

65 70 75 80

Ile Ser Val Gln Gly Pro Gly Ala Gly Asp Glu Val Arg Phe Pro Cys

85 90 95

Tyr Arg Trp Val Glu Gly Asn Gly Val Leu Ser Leu Pro Glu Gly Thr

100 105 110

Gly Arg Thr Val Gly Glu Asp Pro Gln Gly Leu Phe Gln Lys His Arg

115 120 125

Glu Glu Glu Leu Glu Glu Arg Arg Lys Leu Tyr Arg Trp Gly Asn Trp

130 135 140

Lys Asp Gly Leu Ile Leu Asn Met Ala Gly Ala Lys Leu Tyr Asp Leu

145 150 155 160

Pro Val Asp Glu Arg Phe Leu Glu Asp Lys Arg Val Asp Phe Glu Val

165 170 175

Ser Leu Ala Lys Gly Leu Ala Asp Leu Ala Ile Lys Asp Ser Leu Asn

180 185 190

Val Leu Thr Cys Trp Lys Asp Leu Asp Asp Phe Asn Arg Ile Phe Trp

195 200 205

Cys Gly Gln Ser Lys Leu Ala Glu Arg Val Arg Asp Ser Trp Lys Glu

210 215 220

Asp Ala Leu Phe Gly Tyr Gln Phe Leu Asn Gly Ala Asn Pro Val Val

225 230 235 240

Leu Arg Arg Ser Ala His Leu Pro Ala Arg Leu Val Phe Pro Pro Gly

245 250 255

Met Glu Glu Leu Gln Ala Gln Leu Glu Lys Glu Leu Glu Gly Gly Thr

260 265 270

Leu Phe Glu Ala Asp Phe Ser Leu Leu Asp Gly Ile Lys Ala Asn Val

275 280 285

Ile Leu Cys Ser Gln Gln His Leu Ala Ala Pro Leu Val Met Leu Lys

290 295 300

Leu Gln Pro Asp Gly Lys Leu Leu Pro Met Val Ile Gln Leu Gln Leu

305 310 315 320

Pro Arg Thr Gly Ser Pro Pro Pro Pro Leu Phe Leu Pro Thr Asp Pro

325 330 335

Pro Met Ala Trp Leu Leu Ala Lys Cys Trp Val Arg Ser Ser Asp Phe

340 345 350

Gln Leu His Glu Leu Gln Ser His Leu Leu Arg Gly His Leu Met Ala

355 360 365

Glu Val Ile Val Val Ala Thr Met Arg Cys Leu Pro Ser Ile His Pro

370 375 380

Ile Phe Lys Leu Ile Ile Pro His Leu Arg Tyr Thr Leu Glu Ile Asn

385 390 395 400

Val Arg Ala Arg Thr Gly Leu Val Ser Asp Met Gly Ile Phe Asp Gln

405 410 415

Ile Met Ser Thr Gly Gly Gly Gly His Val Gln Leu Leu Lys Gln Ala

420 425 430

Gly Ala Phe Leu Thr Tyr Ser Ser Phe Cys Pro Pro Asp Asp Leu Ala

435 440 445

Asp Arg Gly Leu Leu Gly Val Lys Ser Ser Phe Tyr Ala Gln Asp Ala

450 455 460

Leu Arg Leu Trp Glu Ile Ile Tyr Arg Tyr Val Glu Gly Ile Val Ser

465 470 475 480

Leu His Tyr Lys Thr Asp Val Ala Val Lys Asp Asp Pro Glu Leu Gln

485 490 495

Thr Trp Cys Arg Glu Ile Thr Glu Ile Gly Leu Gln Gly Ala Gln Asp

500 505 510

Arg Gly Phe Pro Val Ser Leu Gln Ala Arg Asp Gln Val Cys His Phe

515 520 525

Val Thr Met Cys Ile Phe Thr Cys Thr Gly Gln His Ala Ser Val His

530 535 540

Leu Gly Gln Leu Asp Trp Tyr Ser Trp Val Pro Asn Ala Pro Cys Thr

545 550 555 560

Met Arg Leu Pro Pro Pro Thr Thr Lys Asp Ala Thr Leu Glu Thr Val

565 570 575

Met Ala Thr Leu Pro Asn Phe His Gln Ala Ser Leu Gln Met Ser Ile

580 585 590

Thr Trp Gln Leu Gly Arg Arg Gln Pro Val Met Val Ala Val Gly Gln

595 600 605

His Glu Glu Glu Tyr Phe Ser Gly Pro Glu Pro Lys Ala Val Leu Lys

610 615 620

Lys Phe Arg Glu Glu Leu Ala Ala Leu Asp Lys Glu Ile Glu Ile Arg

625 630 635 640

Asn Ala Lys Leu Asp Met Pro Tyr Glu Tyr Leu Arg Pro Ser Val Val

645 650 655

Glu Asn Ser Val Ala Ile

660

<210> 8

<211> 662

<212> Protein

<213> homo sapiens

<400> 8

Met Gly Leu Tyr Arg Ile Arg Val Ser Thr Gly Ala Ser Leu Tyr Ala

1 5 10 15

Gly Ser Asn Asn Gln Val Gln Leu Trp Leu Val Gly Gln His Gly Glu

20 25 30

Ala Ala Leu Gly Lys Arg Leu Trp Pro Ala Arg Gly Lys Glu Thr Glu

35 40 45

Leu Lys Val Glu Val Pro Glu Tyr Leu Gly Pro Leu Leu Phe Val Lys

50 55 60

Leu Arg Lys Arg His Leu Leu Lys Asp Asp Ala Trp Phe Cys Asn Trp

65 70 75 80

Ile Ser Val Gln Gly Pro Gly Ala Gly Asp Glu Val Arg Phe Pro Cys

85 90 95

Tyr Arg Trp Val Glu Gly Asn Gly Val Leu Ser Leu Pro Glu Gly Thr

100 105 110

Gly Arg Thr Val Gly Glu Asp Pro Gln Gly Leu Phe Gln Lys His Arg

115 120 125

Glu Glu Glu Leu Glu Glu Arg Arg Lys Leu Tyr Arg Trp Gly Asn Trp

130 135 140

Lys Asp Gly Leu Ile Leu Asn Met Ala Gly Ala Lys Leu Tyr Asp Leu

145 150 155 160

Pro Val Asp Glu Arg Phe Leu Glu Asp Lys Arg Val Asp Phe Glu Val

165 170 175

Ser Leu Ala Lys Gly Leu Ala Asp Leu Ala Ile Lys Asp Ser Leu Asn

180 185 190

Val Leu Thr Cys Trp Lys Asp Leu Asp Asp Phe Asn Arg Ile Phe Trp

195 200 205

Cys Gly Gln Ser Lys Leu Ala Glu Arg Val Arg Asp Ser Trp Lys Glu

210 215 220

Asp Ala Leu Phe Gly Tyr Gln Phe Leu Asn Gly Ala Asn Pro Val Val

225 230 235 240

Leu Arg Arg Ser Ala His Leu Pro Ala Arg Leu Val Phe Pro Pro Gly

245 250 255

Met Glu Glu Leu Gln Ala Gln Leu Glu Lys Glu Leu Glu Gly Gly Thr

260 265 270

Leu Phe Glu Ala Asp Phe Ser Leu Leu Asp Gly Ile Lys Ala Asn Val

275 280 285

Ile Leu Cys Ser Gln Gln His Leu Ala Ala Pro Leu Val Met Leu Lys

290 295 300

Leu Gln Pro Asp Gly Lys Leu Leu Pro Met Val Ile Gln Leu Gln Leu

305 310 315 320

Pro Arg Thr Gly Ser Pro Pro Pro Pro Leu Phe Leu Pro Thr Asp Pro

325 330 335

Pro Met Ala Trp Leu Leu Ala Lys Cys Trp Val Arg Ser Ser Asp Phe

340 345 350

Gln Leu His Glu Leu Gln Ser His Leu Leu Arg Gly His Leu Met Ala

355 360 365

Glu Val Ile Val Val Ala Thr Met Arg Cys Leu Pro Ser Ile His Pro

370 375 380

Ile Phe Lys Leu Ile Ile Pro His Leu Arg Tyr Thr Leu Glu Ile Asn

385 390 395 400

Val Arg Ala Arg Thr Gly Leu Val Ser Asp Met Gly Ile Phe Asp Gln

405 410 415

Ile Met Ser Thr Gly Gly Gly Gly His Val Gln Leu Leu Lys Gln Ala

420 425 430

Gly Ala Phe Leu Thr Tyr Ser Ser Phe Cys Pro Pro Asp Asp Leu Ala

435 440 445

Asp Arg Gly Leu Leu Gly Val Lys Ser Ser Phe Tyr Ala Gln Asp Ala

450 455 460

Leu Arg Leu Trp Glu Ile Ile Tyr Arg Tyr Val Glu Gly Ile Val Ser

465 470 475 480

Leu His Tyr Lys Thr Asp Val Ala Val Lys Asp Asp Pro Glu Leu Gln

485 490 495

Thr Trp Cys Arg Glu Ile Thr Glu Ile Gly Leu Gln Gly Ala Gln Asp

500 505 510

Arg Gly Phe Pro Val Ser Leu Gln Ala Arg Asp Gln Val Cys His Phe

515 520 525

Val Thr Met Cys Ile Phe Thr Cys Thr Gly Gln His Ala Ser Val His

530 535 540

Leu Gly Gln Leu Asp Trp Tyr Ser Trp Val Pro Asn Ala Pro Cys Met

545 550 555 560

Met Arg Leu Pro Pro Pro Thr Thr Lys Asp Ala Thr Leu Glu Thr Val

565 570 575

Met Ala Thr Leu Pro Asn Phe His Gln Ala Ser Leu Gln Met Ser Ile

580 585 590

Thr Trp Gln Leu Gly Arg Arg Gln Pro Val Met Val Ala Val Gly Gln

595 600 605

His Glu Glu Glu Tyr Phe Ser Gly Pro Glu Pro Lys Ala Val Leu Lys

610 615 620

Lys Phe Arg Glu Glu Leu Ala Ala Leu Asp Lys Glu Ile Glu Ile Arg

625 630 635 640

Asn Ala Lys Leu Asp Met Pro Tyr Glu Tyr Leu Arg Pro Ser Val Val

645 650 655

Glu Asn Ser Val Ala Ile

660

<210> 9

<211> 59

<212> DNA

<213> artificial sequence

<220>

<223> shRNA ALOX15

<400> 9

ccgggaaact ggaaggacgg gttaactcga gttaacccgt ccttccagtt tcttttttg 59

<210> 10

<211> 58

<212> DNA

<213> artificial sequence

<220>

<223> shRNA ALOX15

<400> 10

ccggggctatc aaagactctc taaatctcga gatttagaga gtctttgata gctttttg 58

<210> 11

<211> 58

<212> DNA

<213> artificial sequence

<220>

<223> shRNA ALOX15

<400> 11

ccggtgggaa atcatctatc ggtatctcga gataccgata gatgatttcc catttttg 58

<210> 12

<211> 58

<212> DNA

<213> artificial sequence

<220>

<223> shRNA ALOX15

<400> 12

ccggcctgga aggaagatgc cttatctcga gataaggcat cttccttcca ggtttttg 58

<210> 13

<211> 58

<212> DNA

<213> artificial sequence

<220>

<223> shRNA ALOX15

<400> 13

ccggccagtt tcttaatggc gccaactcga gttggcgcca ttaagaaact ggtttttg 58

<210> 14

<211> 58

<212> DNA

<213> artificial sequence

<220>

<223> shRNA ALOX15

<400> 14

ccgggccgtc gatacatcct atcttctcga gaagatagga tgtatcgacg gctttttg 58

<210> 15

<211> 59

<212> DNA

<213> artificial sequence

<220>

<223> shRNA ALOX15

<400> 15

ccggtagatg acttcaaccg gatttctcga gaaatccggt tgaagtcatc tattttttg 59

<210> 16

<211> 59

<212> DNA

<213> artificial sequence

<220>

<223> shRNA ALOX15

<400> 16

ccggtggtac tcttgggtgc ctaatctcga gattaggcac ccaagagtac cattttttg 59

<210> 17

<211> 170

<212> Protein

<213> artificial sequence

<220>

<223> PP1 inhibitory peptide

<400> 17

Met Glu Pro Asp Asn Ser Pro Arg Lys Ile Gln Phe Thr Val Pro Leu

1 5 10 15

Leu Glu Pro His Leu Asp Pro Glu Ala Ala Glu Gln Ile Arg Arg Arg

20 25 30

Arg Pro Thr Pro Ala Thr Leu Val Leu Thr Ser Asp Gln Ser Ser Pro

35 40 45

Glu Ile Asp Glu Asp Arg Ile Pro Asn Ser Leu Leu Lys Ser Thr Leu

50 55 60

Ser Met Ser Pro Arg Gln Arg Lys Lys Met Thr Arg Thr Thr Pro Thr

65 70 75 80

Met Lys Glu Leu Gln Thr Met Val His His Leu Gly Gln Gln Lys Gln

85 90 95

Gly Glu Glu Pro Glu Gly Ala Thr Glu Ser Thr Gly Asn Gln Glu Ser

100 105 110

Cys Pro Pro Gly Ile Pro Asp Thr Gly Ser Ala Ser Arg Pro Asp Thr

115 120 125

Pro Gly Thr Ala Gln Lys Ser Ala Glu Ser Asn Pro Lys Thr Gln Glu

130 135 140

Gln Cys Gly Val Glu Pro Arg Thr Glu Asp Ser Ser Ala His Met Leu

145 150 155 160

Pro Leu Asp Ser Gln Gly Ala Ser Leu Val

165 170

<210> 18

<211> 205

<212> Protein

<213> artificial sequence

<220>

<223> PP1 inhibitory peptide

<400> 18

Met Ala Ala Ser Thr Ala Ser His Arg Pro Ile Lys Gly Ile Leu Lys

1 5 10 15

Asn Lys Thr Ser Ser Thr Ser Ser Arg Val Ala Ser Ala Glu Gln Pro

20 25 30

Arg Gly Ser Val Asp Glu Glu Leu Ser Lys Lys Ser Gln Lys Trp Asp

35 40 45

Glu Met Asn Ile Leu Ala Thr Tyr His Pro Ala Asp Lys Asp Tyr Gly

50 55 60

Leu Met Lys Ile Asp Glu Pro Ser Thr Pro Tyr His Ser Met Ile Gly

65 70 75 80

Asp Asp Asp Asp Ala Tyr Ser Asp Thr Glu Thr Thr Glu Ala Met Thr

85 90 95

Pro Asp Thr Leu Ala Lys Lys Leu Ala Ala Ala Glu Gly Ser Glu Pro

100 105 110

Lys Tyr Arg Ile Arg Glu Gln Glu Ser Ser Gly Glu Glu Asp Ser Asp

115 120 125

Leu Ser Pro Glu Glu Arg Glu Lys Lys Arg Gln Phe Glu Met Lys Arg

130 135 140

Lys Leu His Tyr Asn Glu Gly Leu Asn Ile Lys Leu Ala Arg Gln Leu

145 150 155 160

Ile Ser Lys Asp Leu His Asp Asp Glu Glu Asp Glu Glu Met Ser Glu

165 170 175

Thr Ala Asp Gly Glu Ser Met Asn Thr Glu Glu Ser Asn Gln Gly Ser

180 185 190

Thr Pro Ser Asp Gln Arg Gln Asn Lys Ser Gln Ser Ser

195 200 205

<210> 19

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 19

taccaagcac gcgagccccg tgg 23

<210> 20

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 20

gaccacgggg ctcgcgtgct tgg 23

<210> 21

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 21

acggggctcg cgtgcttggt agg 23

<210> 22

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 22

gcatccttgg tggttggcgg ggg 23

<210> 23

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 23

cgggggcagc cgcatcgtgc agg 23

<210> 24

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 24

ttagctggac tggtactctt ggg 23

<210> 25

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 25

gggggcagcc gcatcgtgca ggg 23

<210> 26

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 26

cttagctgga ctggtactct tgg 23

<210> 27

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 27

tgcatccttg gtggttggcg ggg 23

<210> 28

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 28

caagagtacc agtccagcta agg 23

<210> 29

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 29

gatgtccatc acttggcagc tgg 23

<210> 30

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 30

gtaccagtcc agctaaggaa ggg 23

<210> 31

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 31

ttgcatcctt ggtggttggc ggg 23

<210> 32

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 32

ctgtgtgcag gtggaccacg ggg 23

<210> 33

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 33

tctgtgtgca ggtggaccac ggg 23

<210> 34

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 34

tgcttggtag gcactgactc tgg 23

<210> 35

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 35

agtaccagtc cagctaagga agg 23

<210> 36

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 36

ctgcccttcc ttagctggac tgg 23

<210> 37

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 37

gacactgccc aacttccacc agg 23

<210> 38

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 38

agagaagcct ggtggaagtt ggg 23

<210> 39

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 39

gatccctgcc cttccttagc tgg 23

<210> 40

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 40

gtctgtgtgc aggtggacca cgg 23

<210> 41

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 41

cagtccagct aaggaagggc agg 23

<210> 42

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 42

gctgccaagt gatggacatc tgg 23

<210> 43

<211> 23

<212> DNA

<213> artificial sequence

<220>

<223> ALOX15 gRNA recognition sequence

<400> 43

tctgcccagc tgccaagtga tgg 23

<---

Claims (169)

1. A method of treating a patient having a respiratory disorder selected from nasal polyp, allergic rhinitis, asthma, or aspirin-induced respiratory disease (AIRD), comprising the steps of: detection of the presence or absence of a variant nucleic acid molecule with a predictive loss of function ALOX15 encoding a human ALOX15 polypeptide in a biological sample from a patient, where the ALOX15 polypeptide is Thr560Met, Tyr139Cys, Leu651fs, Pro565Leu, Asn658Lys, Gly283Arg, Val474Ala, Gly422Arg, or Leu106f s; And, if the patient lacks a variant nucleic acid with predicted loss of function ALOX15, or the patient is heterozygous for a variant nucleic acid with predicted loss of function ALOX15, administering to the patient an inhibitor of arachidonate 15-lipoxygenase (ALOX15). 2. The method of claim 1, wherein the ALOX15 inhibitor comprises an antisense nucleic acid molecule, small interfering RNA (siRNA) or short hairpin RNA (shRNA) that hybridizes to ALOX15 mRNA. 3. The method according to claim 2, characterized in that shRNA includes: a) CCGGGAAACTGGAAGGACGGGTTAACTCGAGTTAACCCGTCCTTCCAGTTTCTTTTTG (SEQ ID NO: 9); b) CCGGGCTATCAAAGACTCTCTAAATCTCGAGATTTAGAGAGTCTTTGATAGCTTTTTG (SEQ ID NO: 10); c) CCGGTGGGAAATCATCTATCGGTATCTCGAGATACCGATAGATGATTTCCCATTTTTG (SEQ ID NO: 11); d) CCGGCCTGGAAGGAAGATGCCTTATCTCGAGATAAGGCATCTTCCTTCAGGTTTTTG (SEQ ID NO: 12); e) CCGGCCAGTTTCTTAATGGCGCCAACTCGAGTTGGCGCCATTAAGAAACTGGTTTTTG (SEQ ID NO: 13); f) CCGGGCCGTCGATACATCCTATCTTCTCGAGAAGATAGGATGTATCGACGGCTTTTTG (SEQ ID NO: 14); g) CCGGTAGATGACTTCAACCGGATTTCTCGAGAAATCCGGTTGAAGTCATCTATTTTTTG (SEQ ID NO: 15) or h) CCGGTGGTACTCTTGGGTGCCTAATCTCGAGATTAGGCACCCAAGAGTACCATTTTTTG (SEQ ID NO: 16). 4. The method according to any one of paragraphs. 1-3, characterized in that the ALOX15 inhibitor includes the Cas protein and guide RNA (gRNA), which hybridizes with the gRNA recognition sequence in the ALOX15 genomic nucleic acid molecule. 5. The method according to claim 4, wherein the Cas protein is Cas9 or Cpf1. 6. The method according to claim 4 or 5, characterized in that the gRNA recognition sequence contains or is located near the position corresponding to position 9917 in accordance with SEQ ID NO: 1. 7. The method according to claim 4 or 5, characterized in that the gRNA recognition sequence is located at a distance of about 1000, about 500, about 400, about 300, about 200, about 100, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10, or about 5 nucleotides from the position corresponding to position 9917 according to SEQ ID NO: 1. 8. The method of claim 4 or 5, wherein the protospacer adjacent motif (PAM) sequence is located about 2 to about 6 nucleotides downstream (in the 3′ direction) of the gRNA recognition sequence. 9. The method according to any one of paragraphs. 4-8, characterized in that the gRNA contains from about 17 to about 23 nucleotides. 10. The method according to any one of paragraphs. 4-8, characterized in that the gRNA recognition sequence contains a nucleotide sequence according to any one of SEQ ID NOs: 19-43. 11. The method according to any one of paragraphs. 1-10, characterized in that when the patient is a reference for ALOX15, the patient is also administered a therapeutic agent that treats or inhibits a respiratory disorder, in the amount of a standard dose. 12. The method according to any one of paragraphs. 1-10, characterized in that when the patient is heterozygous for the predicted loss of ALOX15 function variant, the patient is also administered a therapeutic agent that treats or inhibits a respiratory disorder in an amount equal to or less than the standard dose amount. 13. The method of claim 1, wherein the variant nucleic acid molecule with predicted loss of function ALOX15 is a nucleic acid molecule encoding ALOX15 Thr560Met. 14. The method according to claim 11 or 12, wherein the variant nucleic acid molecule with predicted loss of ALOX15 function is: a genomic nucleic acid molecule having a nucleotide sequence containing thymine at a position corresponding to position 9917 in accordance with SEQ ID NO: 2; an mRNA molecule having a nucleotide sequence containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4, or a cDNA molecule derived from an mRNA molecule, wherein the cDNA molecule has a nucleotide sequence containing thymine at position corresponding to position 1693 in according to SEQ ID NO: 6. 15. The method according to any one of paragraphs. 1-14, characterized in that the detection step is performed in vitro . 16. The method according to any one of paragraphs. 1-15, characterized in that the detection step includes sequencing at least a part of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule in a biological sample, while the sequenced part contains a position corresponding to position 9917 in accordance with SEQ ID NO: 2 or its complementary nucleotide sequence ; wherein when the sequenced portion of the ALOX15 genomic nucleic acid molecule in the biological sample contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2, then the ALOX15 genomic nucleic acid molecule in the biological sample is a variant genomic nucleic acid molecule with predicted loss of function ALOX15. 17. The method according to any one of paragraphs. 1-15, characterized in that the stage of detection includes sequencing at least part of the nucleotide sequence of the ALOX15 mRNA molecule in a biological sample, while the sequenced part contains the position corresponding to position 1693 in accordance with SEQ ID NO: 4 or its complementary nucleotide sequence; wherein when the sequenced portion of the ALOX15 mRNA molecule in the biological sample contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4, then the ALOX15 mRNA molecule in the biological sample is a variant mRNA molecule with predicted loss of ALOX15 function. 18. The method according to any one of paragraphs. 1-15, characterized in that the detection step includes sequencing at least part of the nucleotide sequence of the ALOX15 cDNA molecule obtained from the mRNA molecule in the biological sample, while the sequenced part contains the position corresponding to position 1693 in accordance with SEQ ID NO: 6 or complementary her nucleotide sequence; wherein when the sequenced portion of the ALOX15 cDNA molecule in the biological sample contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6, then the ALOX15 cDNA molecule in the biological sample is a variant cDNA molecule with a predicted loss of ALOX15 function. 19. The method according to any one of paragraphs. 1-15, characterized in that the detection step includes: a) bringing the biological sample into contact with a primer that hybridizes with a part of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule located near the position corresponding to position 9917 in accordance with SEQ ID NO: 2; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule corresponding to position 9917 in accordance with SEQ ID NO: 2; and c) determining if the primer extension product contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2. 20. The method according to any one of paragraphs. 1-15, characterized in that the detection step includes: a) bringing the biological sample into contact with a primer that hybridizes with a part of the nucleotide sequence of the ALOX15 mRNA molecule located near the position corresponding to position 1693 in accordance with SEQ ID NO: 4; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 mRNA molecule corresponding to position 1693 in accordance with SEQ ID NO: 4; and c) determining if the primer extension product contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4. 21. The method according to any one of paragraphs. 1-15, characterized in that the detection step includes: a) bringing the biological sample into contact with a primer that hybridizes with a part of the nucleotide sequence of the ALOX15 cDNA molecule located near the position corresponding to position 1693 in accordance with SEQ ID NO: 6; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 cDNA molecule corresponding to position 1693 in accordance with SEQ ID NO: 6; and c) determining if the primer extension product contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6. 22. The method according to any one of paragraphs. 16-21, characterized in that the discovery step includes sequencing the entire nucleic acid molecule. 23. The method according to any one of paragraphs. 1-15, characterized in that the stage of detection includes: a) amplification of at least part of the nucleic acid molecule that encodes the human ALOX15 polypeptide, while the part contains thymine in the position corresponding to position 9917 in accordance with SEQ ID NO: 2 or complementary her nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing the substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; and d) detecting a detectable label. 24. The method according to any one of paragraphs. 1-15, characterized in that the stage of detection includes: a) amplification of at least part of the nucleic acid molecule that encodes the human ALOX15 polypeptide, while the part contains uracil in the position corresponding to position 1693 in accordance with SEQ ID NO: 4 or complementary her nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing a substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and d) detecting a detectable label. 25. The method according to any one of paragraphs. 1-15, characterized in that the stage of detection includes: a) amplification of at least part of the nucleic acid molecule that encodes the human ALOX15 polypeptide, while the part contains thymine in the position corresponding to position 1693 in accordance with SEQ ID NO: 6 or complementary her nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing the substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and d) detecting a detectable label. 26. The method according to claim 25, characterized in that the nucleic acid molecule in the sample is mRNA, and reverse transcription of the mRNA into cDNA is carried out before the amplification step. 27. The method according to any one of paragraphs. 1-15, characterized in that the detection stage includes: bringing a nucleic acid molecule in a biological sample into contact with a replacement-specific probe containing a detectable label, while the replacement-specific probe contains a nucleotide sequence that, under harsh conditions, hybridizes with the nucleotide sequence of the amplified nucleic acid molecule, containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; and detecting a detectable label. 28. The method according to any one of paragraphs. 1-15, characterized in that the detection stage includes: bringing a nucleic acid molecule in a biological sample into contact with a replacement-specific probe containing a detectable label, while the replacement-specific probe contains a nucleotide sequence that, under harsh conditions, hybridizes with the nucleotide sequence of the amplified nucleic acid molecule, containing uracil in the position corresponding to position 1693 in accordance with SEQ ID NO: 4 or its complementary nucleotide sequence; and detecting a detectable label. 29. The method according to any one of paragraphs. 1-15, characterized in that the detection stage includes: bringing a nucleic acid molecule in a biological sample into contact with a replacement-specific probe containing a detectable label, while the replacement-specific probe contains a nucleotide sequence that, under harsh conditions, hybridizes with the nucleotide sequence of the amplified nucleic acid molecule, containing thymine at the position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and detecting a detectable label. 30. A method of treating a patient with a therapeutic agent that treats or inhibits a respiratory disorder selected from nasal polyp, allergic rhinitis, asthma, or aspirin-induced respiratory disease (AIRD), wherein the patient is suffering from a respiratory disorder, comprising the steps of: determining whether a patient has an ALOX15 predictive loss-of-function variant nucleic acid molecule encoding a human ALOX15 polypeptide, wherein the ALOX15 polypeptide is Thr560Met, Tyr139Cys, Leu651fs, Pro565Leu, Asn658Lys, Gly283Arg, Val474Ala, Gly422Arg, or Leu106fs, by: obtaining or having received a biological sample from a patient; And performing or performing genotyping of a biological sample to determine if the patient has a genotype containing a variant nucleic acid molecule with predicted loss of ALOX15 function; And when the patient is ALOX15 reference, then by administering or continuing to administer to the patient a therapeutic agent that treats or inhibits a respiratory disorder in a unit dose amount, and administering an ALOX15 inhibitor to the patient; And when the patient is heterozygous for the predicted loss of ALOX15 function variant, then by administering or continuing to administer to the patient a therapeutic agent that treats or inhibits the respiratory disorder in an amount equal to or less than the standard dose amount and administering to the patient an ALOX15 inhibitor; wherein the presence of a genotype having a variant ALOX15 loss-of-function nucleic acid molecule encoding a human ALOX15 polypeptide indicates that the patient has a reduced risk of developing a respiratory disorder. 31. The method of claim 30, wherein the patient is ALOX15 reference and the patient is or continues to be administered a therapeutic agent that treats or inhibits a respiratory disorder in a unit dose amount and an ALOX15 inhibitor is administered. 32. The method of claim 30, wherein the patient is heterozygous for the predicted loss of ALOX15 function variant and the patient is administered or continues to be administered a therapeutic agent that treats or inhibits a respiratory disorder in an amount equal to or less than the standard dose amount, and administering an ALOX15 inhibitor. 33. The method according to any one of paragraphs. 30-32, characterized in that the variant nucleic acid molecule with predicted loss of ALOX15 function is a nucleic acid molecule encoding ALOX15 Thr560Met. 34. The method according to any one of paragraphs. 30-32, characterized in that the variant nucleic acid molecule with predicted loss of ALOX15 function is: a genomic nucleic acid molecule having a nucleotide sequence containing thymine at a position corresponding to position 9917 in accordance with SEQ ID NO: 2; an mRNA molecule having a nucleotide sequence containing uracil at the position corresponding to position 1693 according to SEQ ID NO: 4; or a cDNA molecule derived from an mRNA molecule, wherein the cDNA molecule has a nucleotide sequence containing thymine at a position corresponding to position 1693 according to SEQ ID NO: 6. 35. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes sequencing at least part of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule in a biological sample, wherein the sequenced part contains a position corresponding to position 9917 in accordance with SEQ ID NO: 2 or its complementary nucleotide sequence; wherein when the sequenced portion of the ALOX15 genomic nucleic acid molecule in the biological sample contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2, then the ALOX15 genomic nucleic acid molecule in the biological sample is a variant genomic nucleic acid molecule with predicted loss of function ALOX15. 36. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes sequencing at least part of the nucleotide sequence of the ALOX15 mRNA molecule in a biological sample, while the sequenced part contains the position corresponding to position 1693 in accordance with SEQ ID NO: 4 or its complementary nucleotide sequence; wherein when the sequenced portion of the ALOX15 mRNA molecule in the biological sample contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4, then the ALOX15 mRNA molecule in the biological sample is a variant mRNA molecule with predicted loss of ALOX15 function. 37. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes sequencing at least a part of the nucleotide sequence of the ALOX15 cDNA molecule obtained from an mRNA molecule in a biological sample, while the sequenced part contains a position corresponding to position 1693 in accordance with SEQ ID NO: 6 or complementary to it nucleotide sequence; wherein when the sequenced portion of the ALOX15 cDNA molecule in the biological sample contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6, then the ALOX15 cDNA molecule in the biological sample is a variant cDNA molecule with a predicted loss of ALOX15 function. 38. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes: a) bringing the biological sample into contact with a primer that hybridizes with a part of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule located near the position corresponding to position 9917 in accordance with SEQ ID NO: 2; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule corresponding to position 9917 in accordance with SEQ ID NO: 2; and c) determining if the primer extension product contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2. 39. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes a) bringing the biological sample into contact with a primer that hybridizes with a part of the nucleotide sequence of the ALOX15 mRNA molecule located near the position corresponding to position 1693 in accordance with SEQ ID NO: 4; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 mRNA molecule corresponding to position 1693 in accordance with SEQ ID NO: 4; and c) determining if the primer extension product contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4. 40. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes: a) bringing the biological sample into contact with a primer that hybridizes with a part of the nucleotide sequence of the ALOX15 cDNA molecule located near the position corresponding to position 1693 in accordance with SEQ ID NO: 6; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 cDNA molecule corresponding to position 1693 in accordance with SEQ ID NO: 6; and c) determining if the primer extension product contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6. 41. The method according to any one of paragraphs. 35-40, characterized in that genotyping includes sequencing of the entire nucleic acid molecule. 42. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes: a) amplification of at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the portion contains thymine at a position corresponding to position 9917 in accordance with SEQ ID NO: 2 or complementary to it nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing the substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; and d) detecting a detectable label. 43. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes: a) amplification of at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the portion contains uracil at a position corresponding to position 1693 in accordance with SEQ ID NO: 4 or complementary to it nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing a substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and d) detecting a detectable label. 44. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes: a) amplification of at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the portion contains thymine at a position corresponding to position 1693 in accordance with SEQ ID NO: 6 or complementary to it nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing the substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and d) detecting a detectable label. 45. The method according to claim 44, characterized in that the nucleic acid molecule in the sample is mRNA, and reverse transcription of the mRNA into cDNA is carried out before the amplification step. 46. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes: bringing a nucleic acid molecule in a biological sample into contact with a replacement-specific probe containing a detectable label, while the replacement-specific probe contains a nucleotide sequence that, under harsh conditions, hybridizes with the nucleotide sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; and detecting a detectable label. 47. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes: bringing a nucleic acid molecule in a biological sample into contact with a replacement-specific probe containing a detectable label, while the replacement-specific probe contains a nucleotide sequence that, under harsh conditions, hybridizes with the nucleotide sequence of the amplified nucleic acid molecule containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and detecting a detectable label. 48. The method according to any one of paragraphs. 30-34, characterized in that genotyping includes: bringing a nucleic acid molecule in a biological sample into contact with a replacement-specific probe containing a detectable label, while the replacement-specific probe contains a nucleotide sequence that, under harsh conditions, hybridizes with the nucleotide sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and detecting a detectable label. 49. The method according to any one of paragraphs. 30-48, characterized in that the nucleic acid molecule is present in a cell obtained from a human subject. 50. The method according to any one of paragraphs. 30-49, characterized in that the ALOX15 inhibitor includes an antisense nucleic acid molecule, small interfering RNA (siRNA) or short hairpin RNA (shRNA) that hybridizes with ALOX15 mRNA. 51. The method of claim 50, wherein the shRNA comprises: a) CCGGGAAACTGGAAGGACGGGTTAACTCGAGTTAACCCGTCCTTCCAGTTTCTTTTTG (SEQ ID NO: 9); b) CCGGGCTATCAAAGACTCTCTAAATCTCGAGATTTAGAGAGTCTTTGATAGCTTTTTG (SEQ ID NO: 10); c) CCGGTGGGAAATCATCTATCGGTATCTCGAGATACCGATAGATGATTTCCCATTTTG (SEQ ID NO: 11); d) CCGGCCTGGAAGGAAGATGCCTTATCTCGAGATAAGGCATCTTCCTTCAGGTTTTTG (SEQ ID NO: 12); e) CCGGCCAGTTTCTTAATGGCGCCAACTCGAGTTGGCGCCATTAAGAAACTGGTTTTTG (SEQ ID NO: 13); f) CCGGGCCGTCGATACATCCTATCTTCTCGAGAAGATAGGATGTATCGACGGCTTTTTG (SEQ ID NO: 14); g) CCGGTAGATGACTTCAACCGGATTTCTCGAGAAATCCGGTTGAAGTCATCTATTTTTTG (SEQ ID NO: 15) or h) CCGGTGGTACTCTTGGGTGCCTAATCTCGAGATTAGGCACCCAAGAGTACCATTTTTTG (SEQ ID NO: 16). 52. The method according to any one of paragraphs. 30-49, characterized in that the ALOX15 inhibitor includes the Cas protein and guide RNA (gRNA), which hybridizes with the gRNA recognition sequence in the ALOX15 genomic nucleic acid molecule. 53. The method of claim 52, wherein the Cas protein is Cas9 or Cpf1. 54. The method according to claim 52 or 53, characterized in that the gRNA recognition sequence contains or is located near the position corresponding to position 9917 in accordance with SEQ ID NO: 1. 55. The method according to claim 52 or 53, characterized in that the gRNA recognition sequence is located at a distance of about 1000, about 500, about 400, about 300, about 200, about 100, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10, or about 5 nucleotides from the position corresponding to position 9917 according to SEQ ID NO: 1. 56. The method of claim 52 or 53, wherein the protospacer adjacent motif (PAM) sequence is located about 2 to 6 nucleotides downstream (in the 3' direction) of the gRNA recognition sequence. 57. The method according to any one of paragraphs. 52-56, characterized in that the gRNA contains from about 17 to about 23 nucleotides. 58. The method according to any one of paragraphs. 52-57, characterized in that the gRNA recognition sequence contains a nucleotide sequence according to any of SEQ ID NOs: 19-43. 59. A method for identifying a human subject at increased risk of developing a respiratory disorder selected from nasal polyp, allergic rhinitis, asthma, or aspirin-induced respiratory disease (AIRD), the method comprising: determining the presence or absence of an ALOX15 predictive loss-of-function variant nucleic acid molecule encoding a human ALOX15 polypeptide, wherein the ALOX15 polypeptide is Thr560Met, Tyr139Cys, Leu651fs, Pro565Leu, Asn658Lys, Gly283Arg, Val474Ala, Gly422Arg, or Leu106fs, in a biological sample, received from the subject; wherein: when the human subject is ALOX15 reference, then the human subject is at increased risk of developing a respiratory disorder; And when the human subject is heterozygous for the ALOX15 predictive loss of function variant or homozygous for the ALOX15 predictive loss of function variant, then the human subject has a reduced risk of developing a respiratory disorder. 60. The method of claim 59, wherein the variant nucleic acid molecule with predicted loss of function ALOX15 is a nucleic acid molecule encoding ALOX15 Thr560Met. 61. The method according to any one of paragraphs. 59-60, characterized in that the variant nucleic acid molecule with predicted loss of ALOX15 function is: a genomic nucleic acid molecule having a nucleotide sequence containing thymine at a position corresponding to position 9917 in accordance with SEQ ID NO: 2, an mRNA molecule having a nucleotide sequence containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4, or a cDNA molecule derived from an mRNA molecule, wherein the cDNA molecule has a nucleotide sequence containing thymine at position corresponding to position 1693 according to SEQ ID NO:6. 62. The method according to any one of paragraphs. 59-61, characterized in that the determination step is performed in vitro . 63. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes sequencing at least a part of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule in a biological sample, while the sequenced part contains the position corresponding to position 9917 in accordance with SEQ ID NO: 2 or its complementary nucleotide sequence ; wherein when the sequenced portion of the ALOX15 genomic nucleic acid molecule in the biological sample contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2, then the ALOX15 genomic nucleic acid molecule in the biological sample is a variant genomic nucleic acid molecule with predicted loss of function ALOX15. 64. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes sequencing at least part of the nucleotide sequence of the ALOX15 mRNA molecule in a biological sample, while the sequenced part contains the position corresponding to position 1693 in accordance with SEQ ID NO: 4 or its complementary nucleotide sequence; wherein when the sequenced portion of the ALOX15 mRNA molecule in the biological sample contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4, then the ALOX15 mRNA molecule in the biological sample is a variant mRNA molecule with predicted loss of ALOX15 function. 65. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes sequencing at least a part of the nucleotide sequence of the ALOX15 cDNA molecule in a biological sample, while the sequenced part contains the position corresponding to position 1693 in accordance with SEQ ID NO: 6 or its complementary nucleotide sequence; wherein when the sequenced portion of the ALOX15 cDNA molecule in the biological sample contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6, then the ALOX15 cDNA molecule in the biological sample is a variant cDNA molecule with a predicted loss of ALOX15 function. 66. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes: a) bringing the biological sample into contact with a primer that hybridizes with a part of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule located near the position corresponding to position 9917 in accordance with SEQ ID NO: 2; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 genomic nucleic acid molecule corresponding to position 9917 in accordance with SEQ ID NO: 2; and c) determining if the primer extension product contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2. 67. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes: a) bringing the biological sample into contact with a primer that hybridizes with a part of the nucleotide sequence of the ALOX15 mRNA molecule located near the position corresponding to position 1693 in accordance with SEQ ID NO: 4; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 mRNA molecule corresponding to position 1693 in accordance with SEQ ID NO: 4; and c) determining if the primer extension product contains uracil at position corresponding to position 1693 according to SEQ ID NO: 4. 68. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes: a) bringing the biological sample into contact with a primer that hybridizes with a part of the nucleotide sequence of the ALOX15 cDNA molecule located near the position corresponding to position 1693 in accordance with SEQ ID NO: 6; b) extending the primer at least inclusive to the position of the nucleotide sequence of the ALOX15 cDNA molecule corresponding to position 1693 in accordance with SEQ ID NO: 6; and c) determining if the primer extension product contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6. 69. The method according to any one of paragraphs. 63-68, characterized in that the determination step includes sequencing the entire nucleic acid molecule. 70. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes: a) amplification of at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the portion contains thymine at a position corresponding to position 9917 in accordance with SEQ ID NO: 2 or complementary her nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing the substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; and d) detecting a detectable label. 71. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes: a) amplification of at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the portion contains uracil at a position corresponding to position 1693 in accordance with SEQ ID NO:4 or complementary her nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing a substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing uracil at position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; and d) detecting a detectable label. 72. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes: a) amplification of at least a portion of a nucleic acid molecule that encodes a human ALOX15 polypeptide, wherein the portion contains thymine at a position corresponding to position 1693 in accordance with SEQ ID NO: 6 or complementary her nucleotide sequence; b) labeling the amplified nucleic acid molecule with a detectable label; c) bringing the labeled nucleic acid molecule into contact with a support containing the substitution-specific probe, wherein the substitution-specific probe contains a nucleotide sequence that hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule containing thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and d) detecting a detectable label. 73. The method according to p. 72, characterized in that the nucleic acid molecule in the sample is mRNA, and reverse transcription of the mRNA into cDNA is carried out before the amplification stage. 74. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes: bringing a nucleic acid molecule in a biological sample into contact with a replacement-specific probe containing a detectable label, while the replacement-specific probe contains a nucleotide sequence that hybridizes under harsh conditions with the nucleotide sequence of the amplified nucleic acid molecule, containing thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; and detecting a detectable label. 75. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes: bringing a nucleic acid molecule in a biological sample into contact with a replacement-specific probe containing a detectable label, while the replacement-specific probe contains a nucleotide sequence that hybridizes under harsh conditions with the nucleotide sequence of the amplified nucleic acid molecule, containing uracil in the position corresponding to position 1693 in accordance with SEQ ID NO: 4 or its complementary nucleotide sequence; and detecting a detectable label. 76. The method according to any one of paragraphs. 59-62, characterized in that the determination step includes: bringing a nucleic acid molecule in a biological sample into contact with a replacement-specific probe containing a detectable label, while the replacement-specific probe contains a nucleotide sequence that hybridizes under harsh conditions with the nucleotide sequence of the amplified nucleic acid molecule, containing thymine at the position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; and detecting a detectable label. 77. The method according to any one of paragraphs. 59-76, characterized in that the human subject is a reference for ALOX15 and the therapeutic agent that treats or inhibits a respiratory disorder is administered to the human subject in the amount of a standard dose, and an ALOX15 inhibitor is administered. 78. The method according to any one of paragraphs. 59-76, characterized in that the human subject is heterozygous for the predicted loss of ALOX15 function variant, and the human subject is administered a therapeutic agent that treats or inhibits a respiratory disorder in an amount equal to or lower than the standard dose amount, and an inhibitor is administered ALOX15. 79. A method for detecting an ALOX15 variant nucleic acid molecule in a human subject, comprising analyzing a sample obtained from a human subject to determine whether the nucleic acid molecule in the sample is: a genomic nucleic acid molecule containing a nucleotide sequence containing thymine at the position, corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; an mRNA molecule containing a nucleotide sequence containing uracil at the position corresponding to position 1693 according to SEQ ID NO: 4 or its complementary nucleotide sequence; or a cDNA molecule containing a nucleotide sequence containing thymine at the position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence 80. A method for detecting the presence of a variant human ALOX15 Thr560Met polypeptide, comprising analyzing a biological sample obtained from a human subject to determine whether the ALOX15 protein in the biological sample contains methionine at a position corresponding to position 560 in accordance with SEQ ID NO: 8. 81. The use of a therapeutic agent for the treatment or inhibition of a respiratory disorder in a human subject heterozygous for: i) a genomic nucleic acid molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein the nucleotide sequence contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; ii) an mRNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein the nucleotide sequence contains uracil at position corresponding to position 1693 according to SEQ ID NO:4 or its complementary nucleotide sequence; or iii) a cDNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein the nucleotide sequence contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; or where the human subject is ALOX15 reference, where the therapeutic agent contains: i) a leukotriene modifier containing montelukast, pranlukast and/or zafirlukast; ii) a 5-lipoxygenase inhibitor containing azelastine, diethylcarbamazine, nordihydroguaiaretic acid and/or zileuton; iii) dupilumab; iv) a non-steroidal anti-inflammatory agent, comprising: a) cromolyn; b) an aminoarylcarboxylic acid derivative containing enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate and/or tolfenamic acid; c) an arylacetic acid derivative containing acemethacin, alklofenac, amfenac, bufexamac, cinmethacin, clopirac, diclofenac, etodolac, felbinac, fenclofenac, fenclorac, fenclosic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, isoxepak, lonazol ak, methiazinic acid, oxamethacin , proglumethacin, sulindac, thiaramide, tolmetin and/or zomepirak; d) an arylbutyric acid derivative containing bumadison, butibufen, fenbufen and/or xenbucin; e) an arylcarboxylic acid containing clidanac, ketorolac and/or tinoridin; f) an arylpropionic acid derivative containing alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miroprofen, naproxen, oxaprozin, piketoprofen, pyrprofen, pranoprofen, protizic acid, supprofen and/ or thiaprofenic acid; g) pyrazole containing difenamisole and/or epirizole; h) pyrazolone containing apazone, benzpiperilone, feprazone, mofebutazone, morazone, oxyphenbutazone, phenibutazone, pipebusone, propyphenazone, ramiphenazone, suxibuzon and/or thiazolinobutazone; i) salicylic acid and its derivative containing acetaminosalol, aspirin, benylate, bromosaligenin, calcium acetylsalicylate, diflunisal, estersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl salicylate lat, olsalazin, parsalmid , phenylacetylsalicylate, phenyl salicylate, salacetamide, salicylamine o-acetic acid, sulfosalicylic acid, salsalate and/or sulfasalazine; j) thiazinecarboxamide containing droxicam, isoxicam, piroxicam and/or tenoxicam; and/or k) ε-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrin, bendazac, benzidamine, bucol, diphenpyramide, ditazol, emorphazone, guaiazulene, nabumetone, nimesulide, orgotheine, oxaceprol, paraniline, perisoxal, pifoxime, proquazone, proxazole and/or tenidap; v) an antihistamine containing: a) a first generation H1 antihistamine containing: I) ethylenediamine containing mepyramine (pyrilamine) and/or antazoline; II) ethanolamine containing diphenhydramine, carbinoxamine, doxylamine, clemastine and/or dimenhydrinate; III) an alkylamine containing pheniramine, curorenamine (chlorpheniramine), cycloalkylnaphthoylmethyl Na Min dextrose, brompheniramine and/or triprolidine; iV) piperazine containing cyclizine, hydroxyzine and/or meclizine; V) a tricyclic containing promethazine, alimemazine (trimeprazine), cyproheptadine and/or azatadine; and/or VI) piperoxam; b) a second generation antihistamine containing: I) a systemic drug containing acrivastine, astemizole, cetirizine, loratadine, mizolastine and terfenadine; and/or II) a local drug containing azelastine, levocabastine and/or olopatadine; c) a third generation antihistamine containing levocetirizine, desloratadine (desloratidine) and/or fexofenadine; vi) a muscle relaxant containing: a) an anticholinergic agent containing adifenin, alverin, ambutonomy, aminopentamide, amixetrin, amprotropine phosphate, anisotropine methyl bromide, apoatropine, atropine, atropine n-oxide, benactizine, benaprisine, benzethimide, benzylonia, benztropine mesylate, bevonium methyl sulfate, biperiden, butropium, n -butylscopolammonium bromide, busepid, camilofin, caramiphene, chlorobenzoxamine, chlorophenoxamine, cimetropium, clidinium, cyclodrin, cyclonium, cycrimin, deptropine, dexetimide, dibutolin sulfate, dicyclomine, diethazine, diphemerin, dihexiverine, diphemanyl methyl sulfate, n-(1,2-diphenylethyl ) nicotinamide, dipiverin, diponium, emepronium, endobenziline, etopropazine, ethbenztropine, ethylbenzhydramine, etomidoline, eucatropine, fenpiverinium, fentonium, flutropium, glycopyrrolate, heteronium, hexocyclium methyl sulfate, homatropine, hyoscyamine, ipratropium, isopropamide, levomepat, mek loxamine, mepenzolate, methcarafen, methantheline , methixene, metscopolamine, octylamine, oxybutynine, oxyphencyclimine, oxyphenonium, pentapiperide, pentienate, phencarbamide, fenglutarimide, pipenzolate, piperidolate, piperylate, halfdine methisulfate, pridinol, prifinium, procyclidine, propanteline, propenzolate, propiverine, propyromazine, scop olamine, scopolamine n-oxide , stramonium, sultroponium, tifenamil, thiemonium, timepidium, tikvizium, tridihexetyl iodide, trihexyphenidyl hydrochloride, trimebutine, tropacin, tropenzil, tropicamide, trospium, valetamate, vamicamide and/or xenitropium; b) a benzodiazepine containing clozapine and/or diazepam; c) alcuronium, atracurium, baclofen, botulinum toxin, 4-amino-3-(4-chlorophenyl)-butanoic acid, carbolonium, carisoprodol, chlorphenesin, chlorzoxazone, cyclobenzaprine, cyclandelate, dantrolene, decamethonium bromide, diazepam, hydralazine, fazadinium, gallamine , guaifenesin, hexafluorenium, isoxsuprine, meladrazine, mefenzine, metaxalone, methocarbamol, nilidrine, methocurine iodide, orphenadrine, pancuronium, papaverine, pridinol, styramate, suxamethonium, suxetonium, thiocolchicoside, tizanidine, suxamethonium, tolperisone and/or tuboc urarine; and/or d) a bronchodilator containing: I) an ephedrine derivative containing albuterol, bambuterol, bitolterol, carbuterol, clenbuterol, clorprenaline, dioxetedrine, ephedrine, epiniphrine, eprosinol, etafedrine, ethylnorepinephrine, fenoterol, hexoprenaline, isoetarine, isoproterenol, mabuterol, metaproterenol, n-methylephedrine , pirbuterol, prokaterol, protokilol, reproterol, rimiterol, salmeterol, soterenol, terbutaline and/or tulobuterol; ii) quaternary ammonium compounds containing bevonium methyl sulfate, clatropium bromide, ipratropium bromide and/or oxitropium bromide; III) a xanthine derivative containing acephyllin, acephyllin piperazine, ambuphyllin, aminophyllin, bamiphyllin, choline theophyllinate, doxophyllin, difillin, enprophyllin, etamifillin, etophyllin, guaityllin, proxyfillin, theobromine, 1-theobrominoacetic acid and/or theophylline; and/or IV) fenspiride, medibazine, monteculast, methoxyphenanim, tretoquinol and/or zafirkulast; V) a catecholamine analog containing formoterol; VI) an antispasmodic agent containing alibendol, ambucetamide, aminopromazine, apoatropine, bevonium methyl sulfate, bietamiverine, butaverine, butropium bromide, n-butylscopolammonium bromide, caroverine, cimetropium bromide, cinnamedrin, cleboprid, coniine hydrobromide, coniine hydrochloride, cyclo nia iodide, difemerin, diisopromine , dioxafetyl butyrate, diponium bromide, drophenin, emepronium bromide, etaverine, feclemin, fenalamide, fenoverine, fenpipran, fenpiverinium bromide, fentonium bromide, flavoxate, flopropion, gluconic acid, guaiactamine, hydramitrazine, hymecromone, leiopyrrole, mebeverine, moxaverine, nafiverine, octylamine , octaverine, oxybutynine chloride, pentapiperide, fenamacid hydrochloride, phloroglucinol, pinaverium bromide, piperylate, pipoxolane hydrochloride, pramiverine, prifinium bromide, properidin, propivane, propyromazine, prozapine, racefemin, rociverine, spasmolitol, stilonium iodide, sultropo nii, thiemonium iodide, tikwizia bromide , tiropramide, trepibutone, tricromyl, trifolium, trimebutine, n,n-1trimethyl-3,3-diphenylpropylamine, tropenzil, trospium chloride and/or xenitropium bromide; and/or VII) an anticholinergic agent containing adifenin, alverin, ambutonomy, aminopentamide, amixetrin, amprotropine phosphate, anisotropine methyl bromide, apoatropine, atropine, atropine n-oxide, benactizine, benaprisine, benzethimide, benzylonium, benztropine mesylate, bevonium methylsulfide at, biperiden, butropium, n -butylscopolammonium bromide, busepid, camilofin, caramiphene, chlorobenzoxamine, chlorophenoxamine, cimetropium, clidinium, cyclodrin, cyclonium, cycrimin, deptropine, dexetimide, dibutolin sulfate, dicyclomine, diethazine, diphemerin, dihexiverine, diphemanyl methyl sulfate, n-(1,2-diphenylethyl ) nicotinamide, dipiverin, diponium, emepronium, endobenziline, etopropazine, ethbenztropine, ethylbenzhydramine, etomidoline, eucatropine, fenpiverinium, fentonium, flutropium, glycopyrrolate, heteronium, hexocyclium methyl sulfate, homatropine, hyoscyamine, ipratropium, isopropamide, levomepat, mek loxamine, mepenzolate, methcarafen, methantheline , methixene, metscopolamine, octylamine, oxybutynine, oxyphencyclimine, oxyphenonium, pentapiperide, pentienate, phencarbamide, fenglutarimide, pipenzolate, piperidolate, piperylate, halfdine methisulfate, pridinol, prifinium, procyclidine, propanteline, propenzolate, propiverine, propyromazine, scop olamine, scopolamine n-oxide , stramonium, sultroponium, tifenamil, thiemonium, timepidium, tikvizium, tridihexetyl iodide, trihexyphenidyl hydrochloride, trimebutine, tropacin, tropenzil, tropicamide, trospium, valetamate, vamicamide and/or xenitropium; and/or vii) a steroidal anti-inflammatory agent, comprising: a) 21-acetoxypregnenolone, alklomethasone, algestone, amycinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, deoxymethasone, dexamethasone, diflorazone, diflucor tolon, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortine butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidone acetate, fluprednisolone, flurandrenolide, fluticasone, formocortal, halcinonide, halobetasol priopi onat, halomethasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate , mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisone sodium phosphate, prednisone, prednival, prednilidene, rimexolone, thixocortal, triamcinolone, triamcinolone acetonide, triamcinolone benetonide and triamcinolone hexacetonide, fluticasone propionate , budesonide, flunisolide, triamcinolone acetonide, rofleponide and/or ciclesonide; b) a beclomethasone ester containing a 17-propionate ester and/or a 17,21-dipropionate ester; and/or c) an ester of mometasone containing a furoate ester. 82. Use of an ALOX15 inhibitor for the treatment of a respiratory disorder in a human subject heterozygous for: i) a genomic nucleic acid molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein the nucleotide sequence contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; ii) an mRNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein the nucleotide sequence contains uracil at position corresponding to position 1693 according to SEQ ID NO:4 or its complementary nucleotide sequence; or iii) a cDNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein the nucleotide sequence contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; or where the human subject is ALOX15 reference, wherein the ALOX15 inhibitor comprises an antisense nucleic acid molecule, small interfering RNA (siRNA) or short hairpin RNA (shRNA) that hybridizes to ALOX15 mRNA. 83. Use according to claim 82, characterized in that shRNA includes: a) CCGGGAAACTGGAAGGACGGGTTAACTCGAGTTAACCCGTCCTTCCAGTTTCTTTTTG (SEQ ID NO: 9); b) CCGGGCTATCAAAGACTCTCTAAATCTCGAGATTTAGAGAGTCTTTGATAGCTTTTTG (SEQ ID NO: 10); c) CCGGTGGGAAATCATCTATCGGTATCTCGAGATACCGATAGATGATTTCCCATTTTTG (SEQ ID NO: 11); d) CCGGCCTGGAAGGAAGATGCCTTATCTCGAGATAAGGCATCTTCCTTCAGGTTTTTG (SEQ ID NO: 12); e) CCGGCCAGTTTCTTAATGGCGCCAACTCGAGTTGGCGCCATTAAGAAACTGGTTTTTG (SEQ ID NO: 13); f) CCGGGCCGTCGATACATCCTATCTTCTCGAGAAGATAGGATGTATCGACGGCTTTTTG (SEQ ID NO: 14); g) CCGGTAGATGACTTCAACCGGATTTCTCGAGAAATCCGGTTGAAGTCATCTATTTTTTG (SEQ ID NO:15) or h) CCGGTGGTACTCTTGGGTGCCTAATCTCGAGATTAGGCACCCAAGAGTACCATTTTTTG (SEQ ID NO: 16). 84. Use according to claim 82, characterized in that the ALOX15 inhibitor comprises the Cas protein and a guide RNA (gRNA) that hybridizes to the gRNA recognition sequence in the ALOX15 genomic nucleic acid molecule. 85. Use according to claim 84, characterized in that the Cas protein is Cas9 or Cpf1. 86. Use according to claim 84 or 85, characterized in that the gRNA recognition sequence contains or is located near the position corresponding to position 9917 in accordance with SEQ ID NO: 1. 87. Use according to claim 84 or 85, characterized in that the gRNA recognition sequence is located at a distance of about 1000, about 500, about 400, about 300, about 200, about 100, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10, or about 5 nucleotides from the position corresponding to position 9917 according to SEQ ID NO: 1. 88. The use of claim 84 or 87, wherein the protospacer adjacent motif (PAM) sequence is located about 2 to about 6 nucleotides downstream (in the 3′ direction) of the gRNA recognition sequence. 89. Application according to any one of paragraphs. 84-88, characterized in that the gRNA contains from about 17 to about 23 nucleotides. 90. Application according to any one of paragraphs. 84-88, characterized in that the gRNA recognition sequence contains a nucleotide sequence according to any one of SEQ ID NOs: 19-43. 91. The use of claim 81 wherein the therapeutic agent is dupilumab. 92. Use of an ALOX15 inhibitor for the treatment of a respiratory disorder in a human subject heterozygous for: i) a genomic nucleic acid molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein the nucleotide sequence contains thymine at position corresponding to position 9917 according to SEQ ID NO: 2 or its complementary nucleotide sequence; ii) an mRNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein the nucleotide sequence contains uracil at position corresponding to position 1693 according to SEQ ID NO:4 or its complementary nucleotide sequence; or iii) a cDNA molecule having a nucleotide sequence encoding a human ALOX15 polypeptide, wherein the nucleotide sequence contains thymine at position corresponding to position 1693 according to SEQ ID NO: 6 or its complementary nucleotide sequence; or where the human subject is ALOX15 reference, wherein the ALOX15 inhibitor contains 6,11-dihydro[1]benzothiopyrano[4,3-b]indole (PD146176), 2-bromophenol, 2,4-dibromophenol, 2-(1- thienyl)ethyl 3,4-dihydroxybenzylidenecyanoacetate (TEDC), 4,4'-(2,3-dimethyl-1,4-butandiyl)bis-1,2-benzenediol (nordihydroguaiaretic acid) or cinnamyl-3,4-dihydroxy -a-cyanocinnamate (CDC).

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