WO2001004302A1 - Gene d'atopie - Google Patents

Gene d'atopie Download PDF

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Publication number
WO2001004302A1
WO2001004302A1 PCT/JP2000/004599 JP0004599W WO0104302A1 WO 2001004302 A1 WO2001004302 A1 WO 2001004302A1 JP 0004599 W JP0004599 W JP 0004599W WO 0104302 A1 WO0104302 A1 WO 0104302A1
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Prior art keywords
dna
gene
present
sequence
base
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PCT/JP2000/004599
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English (en)
Japanese (ja)
Inventor
Chaker Nadim Adra
Taro Shirakawa
Julian Meurglyn Hopkin
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Mitsubishi Chemical Corporation
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Priority to AU58520/00A priority Critical patent/AU5852000A/en
Publication of WO2001004302A1 publication Critical patent/WO2001004302A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to a novel gene and its use. More specifically, the present invention relates to a therapeutic and diagnostic agent for diseases such as allergic disease, asthma, and atopic dermatitis, and a detection method using the gene of the present invention.
  • a therapeutic and diagnostic agent for diseases such as allergic disease, asthma, and atopic dermatitis
  • Allergic diseases include bronchial asthma, allergic rhinitis, atopic dermatitis, etc., and show immediate and delayed reactions to specific antigens called allergens. Allergic diseases are considered to be closely related to genetic factors due to clinically strong familial accumulation. For example, van Arsdel and Motulsky conducted a family survey of allergic diseases in about 6,000 students, with 58% of children having an allergic disease in their parents and 38% of allergies in only one parent having 38% of allergies. In children who had sexually transmitted diseases, but neither parent had allergic diseases, the rate was reported to drop to 13% (van Asdel, PP and Motulsky, AG, Acta. Genet. Med., 9, 104 (1959)).
  • atopy Today, the highly hereditary immunological constitution involved in the development of these allergic diseases is called atopy, and the genes that determine atopy are called atopy genes. Since many patients with allergies have a predisposition to atopy, if the atopy gene can be detected and identified before the onset of an allergic disease, the development of allergic diseases can be significantly improved by improving the living environment and dietary habits. It is believed that it can be reduced (Arshad, SH, et al., Lancet, 339, 1493 (1992)). In addition, if the atopic gene can be detected and identified after the onset of an allergic disease, it will be possible to construct a rational treatment strategy based on the cause of the disease and provide efficient and highly effective medical treatment Is expected.
  • Diagnosis of allergic diseases is mainly based on the presence or absence of clinical symptoms characteristic of each disease, and the existence of atopic predisposition itself depends on family history, serum total IgE levels, It can be indirectly inferred by the presence of allergen-specific IgE in serum (RAST positive) or immediate skin reaction (skin test) positive.
  • RAST positive serum total IgE levels
  • skin test immediate skin reaction
  • the present invention relates to the identification of an atopic gene that is a genetic cause of an allergic disease.
  • the present invention provides a method for detecting whether an atopic predisposition exists before the onset of an allergic disease, or for detecting an atopy gene that has caused the onset of an allergic disease after the onset of the allergic disease.
  • the present invention also provides a recombinant vector containing the gene, and a host containing the recombinant vector. By using these, it becomes possible to develop a novel antiallergic agent that regulates the expression of the gene.
  • the present inventors have conducted intensive studies based on the above-mentioned problems and found that human chromosome 11
  • the gene present in the ql3.1 region was cloned, and the nucleotide sequence of the gene was determined, thereby completing the present invention.
  • the gist of the present invention resides in a DNA having a base sequence having homology to any of the following base sequences (a) to (c) or a DNA having at least a part thereof.
  • the DNA is preferably derived from humans.
  • the present invention also relates to a DNA having the base sequence of SEQ ID NO: 1 or at least a part thereof, a DNA having the base sequence of SEQ ID NO: 2 or at least a part thereof, and a base sequence of SEQ ID NO: 3 or at least a part thereof. DNA having a portion is provided.
  • the present invention further provides a recombinant DNA comprising any one of the above DNAs.
  • the present invention further provides a medicine containing any one of the aforementioned DNAs.
  • the present invention further provides a transformant transformed with any of the above DNAs or the recombinant DNA.
  • the present invention also provides a method for detecting a predisposition to an allergic disease, comprising detecting a mutation in the base sequence of MA and detecting the presence or absence of a predisposition to an allergic disease based on the detection result.
  • the mutation include a mutation at base number 604 or 1723 of the base sequence shown in SEQ ID NO: 1.
  • BAC Bacteria Artificial Chromosome
  • SEQ ID NO: 1 Encodes a novel protein (hereinafter referred to as “A”) and encodes a 14-3-3 protein (Rommel, N. and Col, E. (1998) Curr. Op in. Genet. Dev. 8, 4 12-418), and a gene sequence having about 87% homology to the nucleotide sequence encoding FceRI-? Gene sequence.
  • SEQ ID NO: 2 Gene sequence encoding a novel protein (hereinafter, referred to as “B”).
  • SEQ ID NO: 3 Gene sequence encoding a novel protein (hereinafter referred to as “C”) and having 91% homology with the Germinal Center B cell gene in the human dbest database.
  • nucleotide sequences of the present invention shown in SEQ ID NOs: 1 to 3 are nucleotide sequences in the human chromosome 11 q13.1 region, each of which contains one kind of novel gene sequence.
  • nucleotide sequences represented by nucleotide numbers 612 to 1984 include two exon regions of a novel gene encoding a novel human protein “A”.
  • SEQ ID NO: 1 the base sequence represented by the following base number is FceRI-? (Kuster, H. et al., J. Biol. Chem., 267, 12782-12787 (1992); Shii-akawa , T. et al., Nature Genetics, 7, 125-130 (1994)).
  • the DNA of the present invention is provided based on the above findings, and has a base sequence having homology to any of the following base sequences (a) to (c).
  • homology means homology that includes a base sequence having a base difference between individuals that can occur in nature, and is usually calculated according to Smith-Waterman search method. It means that it has 50% or more, preferably 80% or more homology to any one of the nucleotide sequences (a) to (c). In addition, since there are unspecified bases in the base sequences (a) to (c), a plurality of base sequences are included in each base sequence. Of the sequences, the nucleotide sequence that gives the highest homology is adopted.
  • the DNA is preferably of human origin.
  • Human origin means having a nucleotide sequence that can naturally occur in humans.
  • DNA examples include a DNA having the nucleotide sequence shown in any one of SEQ ID NOs: 1 to 3.
  • the present invention also includes a DNA having at least a part of the above DNA.
  • the “part” is a DNA having the nucleotide sequence of each of the above novel genes encoding the protein of “A”, “B”, or “C”, and these genes and the FceR I-3 gene.
  • Means any part of the DNA having the nucleotide sequence of the intron sequence, and “having at least a portion” means that all or part of the DNA having the nucleotide sequence of these genes It means that it may be composed of a sequence in which any one or more bases are added to either or both of the 'terminal and the 3' terminal.
  • the added base may be, for example, a linker sequence, a base sequence encoding a signal peptide, a base sequence encoding another protein, or a DNA sequence.
  • a sequence or the like added for the purpose of increasing the detection sensitivity when producing a probe or the like may be mentioned.
  • a part thereof may be of a sufficient length as a probe for a hybridization method or a primer for a PCR method, specifically, a length of 20 to 50 bp. .
  • the DNA of the present invention may be a cDNA or a chromosomal DNA as long as it has at least a part of the above nucleotide sequence (preferably the nucleotide sequence shown in SEQ ID NOS: 1 to 3).
  • the DNA of the present invention preferably has a nucleotide sequence of a transcription regulatory region that regulates the expression of the novel gene and the transcription product of the FcRI- / 5 gene.
  • the physiological activity of this sequence can be determined, for example, by preparing a recombinant DNA molecule in which an appropriate repo-gene is connected downstream of a DNA having the nucleotide sequence of the above-mentioned transcription regulatory region, and using this to prepare an appropriate host cell.
  • a reporter gene assay for detecting and quantifying a reporter gene product produced by the transformant obtained by the transformation, or a known gel shift assay using a labeled DNA having the nucleotide sequence of the transcription regulatory region. Etc. can be evaluated.
  • such an Atsey method can be used to screen for a molecule that inhibits or activates the activity of the gene transcript.
  • the DNA of the present invention may be DNA obtained by any method. That is, it may be chemically synthesized with reference to the nucleotide sequence in the sequence listing, or may be cloned from an appropriate DNA library.
  • the following method can be used to chemically synthesize the DNA of the present invention. That is, first, DNA having the nucleotide sequence in the sequence listing is divided into fragments of about 20 bases and synthesized using a DNA chemical synthesizer, and then, if necessary, phosphorylation of the 5 ′ end is performed. Fragments are ligated and ligated to obtain the desired DNA.
  • the DNA of the present invention is obtained by labeling a DNA having the above base sequence or a partial sequence thereof with 3 P or the like to obtain a probe, and screening a known genomic DNA library or cDNA library (Molecular Cloning, a). Laboratory Manual., 1982, Cold Spring Harbor Laboratory, New York, Maniatis T.).
  • the DNA of the present invention can also be obtained by PCR (Polymerase Chain Reaction) using a genomic DNA library or a cDNA library as type III. PCR creates sense primers and antisense primers based on the base sequence in the sequence listing,
  • the DNA of the present invention can be obtained by applying a known method (PCR Protocols, A Guide to Molecular and Applications, Academic Press, Michael AI 1990) and the like to the DNA library of (1).
  • the nucleotide sequence of the primer can be designed based on the nucleotide sequence of the DNA of the present invention.
  • the DNA of the present invention when the DNA of the present invention is prepared from a cDNA library, it often does not contain an intron sequence, but even if the DNA does not contain such an intron sequence, it is included in the MA of the present invention. It is.
  • the nucleotide sequence of a novel human gene has been elucidated, and the complementary DNA sequence and RNA sequence can be unambiguously determined. DNA having a specific sequence is also provided.
  • novel DNA of the present invention may be single-stranded or double-stranded by binding to DNA or RNA having a sequence complementary thereto.
  • the DNA of the present invention is labeled with an enzyme such as horseradish peroxidase (HRP), a radioisotope, a fluorescent substance, a chemiluminescent substance, or the like, and the “A” or “A” It can be used to check the expression status of “B” or “C” protein.
  • HRP horseradish peroxidase
  • the DNA of the present invention can be introduced into cells in a living body and used, for example, for gene therapy of allergic diseases and the like.
  • antisense drugs can be developed based on the nucleotide sequence of the DNA of the present invention. That is, a part of the DNA of the present invention or a derivative thereof is synthesized by a known method, and the expression of the “A”, “B”, or “C” protein is adjusted using the synthesized DNA or the derivative of the DNA of the present invention. Oligonucleotides or derivatives thereof containing a sequence complementary to the above can be used to regulate the expression of the “A” or “B” or “C” protein.
  • the DNA of the present invention can be used as a means for diagnosing an allergic disease, in a method for detecting a genetic mutation or a gene polymorphism in a gene strongly correlated with atopic predisposition.
  • a method for detecting a genetic mutation or a gene polymorphism in a gene strongly correlated with atopic predisposition examples include a hybridization method using the DNA of the present invention using a probe labeled with an enzyme such as horseradish peroxidase (HRP), a radioisotope, a fluorescent substance, or a chemiluminescent substance.
  • HRP horseradish peroxidase
  • a radioisotope a fluorescent substance
  • chemiluminescent substance e.g., a PCR method using a primer designed from the DNA sequence may be used.
  • the recombinant DNA of the present invention includes the DNA of the present invention.
  • the recombinant DNA of the present invention may be in any form, such as circular or linear. Further, the recombinant DNA of the present invention may be used for any purpose. For example, it may be used to amplify and obtain a large amount of the DNA of the present invention.
  • the recombinant DNA of the present invention can be obtained by ligating the DNA of the present invention to another DNA fragment having an arbitrary nucleotide sequence, or inserting the DNA of the present invention into an arbitrary vector.
  • a method for inserting DNA into a vector is known (see Molecular Cloning, a Laboratory Manual, 2nd ed., 1989, Cold @ pnng ribor Laboratory, New York). That is, the DNA and vector of the present invention may be digested with appropriate restriction enzymes, and the resulting fragments may be ligated using DNA ligase.
  • the vector may be any vector such as a plasmid vector, a phage vector, and a virus vector, and a suitable vector can be selected depending on the host into which the recombinant DNA of the present invention is introduced.
  • the recombinant DNA of the present invention may have another base sequence, if necessary, in addition to the DNA of the present invention.
  • Other nucleotide sequences include, for example, a sequence of an enhancer, a sequence of a promoter, a ribosome binding site, a sequence used to amplify the copy number, a nucleotide sequence encoding a signal peptide, and a sequence encoding another polypeptide.
  • the recombinant DNA of the present invention has at least a replication origin and a marker gene in addition to the DNA of the present invention.
  • a marker gene include an ampicillin resistance gene, a kanamycin resistance gene, a neomycin resistance gene, a thymidine kinase gene, and the like.
  • a suitable marker gene can be selected according to the host.
  • the recombinant DNA of the present invention is preferably capable of transforming Escherichia coli so that at least the DNA of the present invention is transcribed. That is, it is preferable to have at least a promoter sequence that functions in Escherichia coli in addition to a replication origin and a marker gene that function in Escherichia coli.
  • the promoter sequence corresponds to the coding region of the DNA of the present invention. Connected upstream.
  • the recombinant DNA of the present invention may be one that can transform a eukaryotic cell such as a yeast, an insect cell, or an animal cell so that at least the DNA of the present invention is transcribed.
  • a recombinant DNA preferably has at least a polyA addition sequence in addition to the marker gene.
  • at least an alcohol oxidase (AOX) l promoter that functions in yeast at least an alcohol oxidase (AOX) l promoter that functions in yeast, a polyhydrin promoter that functions in insect cells, or SV40, CMV, SR, and FE1 promoters that function in animal cells. It is preferable to have a promoter sequence such as
  • the medicament of the present invention contains the DNA of the present invention.
  • the DNA of the present invention is associated with atopic predisposition. Therefore, the DNA of the present invention or the recombinant DNA containing the same can be used as a drug (for example, an antiallergic agent) for regulating the expression of a gene strongly correlated with atopic predisposition.
  • the antisense strand of the DNA of the present invention can be used as an antisense drug that suppresses the expression of the gene.
  • the recombinant DNA designed to express the sense strand or antisense strand of the DNA of the present invention can be used for human gene therapy.
  • the medicament of the present invention may contain a pharmaceutically acceptable carrier and the like in addition to the DNA of the present invention.
  • Formulation can be performed according to a known method.
  • Administration can be performed according to known gene therapy techniques.
  • the transformant of the present invention is a transformant transformed with the DNA of the present invention or the recombinant DNA of the present invention.
  • This provides a model system for diseases associated with or caused by the function of the genes and gene products of the present invention. Examples of such a model system are cultured cells into which the gene or the mutant gene has been artificially introduced, transgenic animals, and gene-deficient animals. These models can be used to screen for drugs used to treat allergic diseases or to evaluate their efficacy.
  • the transformant of the present invention can be obtained by transforming an appropriate host with the DNA of the present invention or the recombinant DNA of the present invention by a known method. ⁇ 5> Detection method of the present invention
  • the detection method of the present invention includes detecting a mutation in the base sequence of the DNA, and detecting the presence or absence of a predisposition to an allergic disease based on the detection result.
  • the mutation in the above nucleotide sequence is not particularly limited as long as it causes a predisposition to an allergic disease.
  • the mutation is not limited to one within the coding region, but may be one within the regulatory sequence, such as promoter all over. Examples of such a mutation include a mutation at base number 604 or 1723 of the base sequence shown in SEQ ID NO: 1.
  • the method for detecting the mutation is not particularly limited as long as the above mutation can be determined.
  • DNA extracted by extracting MA from a sample such as blood collected from a subject, or extracting mRNA and preparing cDNA by reverse transcription is used as type II, containing the desired mutation It can be performed by performing PCR using primers set to amplify the portion and analyzing the base sequence of the obtained PCR product.
  • primers set to amplify the portion and analyzing the base sequence of the obtained PCR product In the analysis of the nucleotide sequence of the PCR product, it is not always necessary to determine the complete nucleotide sequence, and it may be analyzed as a restriction fragment length polymorphism.
  • Known methods using such a PCR method include the PCR-RFLP method, the PCR-SSCP method, and the PCR-CFLP method.
  • the detection of the presence or absence of a predisposition to allergic disease based on the detection result is based on the fact that the genotype determined by detecting the mutation is predisposed to allergic disease by examining in advance whether or not there is association with an allergic disease (eg, asthma) Can be determined based on whether the genotype is the same as the identified genotype.
  • an allergic disease eg, asthma
  • the genotypes of 604A and 1723C indicate the predisposition to allergic disease.
  • atopy gene To identify the atopy gene, we performed positional cloning near the HTm4 gene, which is known to be located in the ql3.1 region of human chromosome 11, which has been reported to be strongly correlated with atopy predisposition. BAC from Mick DNA Library A clone was obtained.
  • a human genomic livestock (Genome System Inc., St. Louis, Missouri, USA) in which a human genomic fragment was introduced into BAC (Bacteria Artificial Chromosome) was type II, and ⁇ ⁇ 4 specific Screening was performed by the polymerase chain reaction (pCR) method using a set of primers, and a BAC clone that was amplified in any of the primer sets was isolated, and human genomic DNA containing the HTm4 gene region was isolated. A fragment was obtained.
  • BAC Bacte Chain reaction
  • this BAC DNA is digested with EcoRI or EcoRI and Hindill or BamHI DNA restriction enzymes, and then subcloned into pBluescript KSII + (Strataene, San Diego, CA, USA), and E. coli DH10B (GIBC0 -Purchased from BRL) (Sambrook J., Fiitsch E. and Maniatis T. Molecular Cloning: A Laboratory Manual, CSHL press, Plain view, NY).
  • Genomic MA inserts were sequenced directly with BAC DNA using BigDye Terminator Cycle Sequencing Kit and ABI prism 377 DNA sequencer (PE Applied Biosystems, Foster City, CA), and at the same time, the sequence of the obtained subclones. And the gene sequence was determined.
  • nucleotide sequences determined by the sequence were linked based on the overlapping sequences by the analysis of the DNA sequencer by the combination analysis.
  • sequences of the three genes, which are the DNAs of the present invention were identified.
  • the nucleotide sequences of the identified genes are shown in SEQ ID NOs: 1 to 3.
  • "n" indicates a, g, c or t or unknown.
  • SEQ ID NO: 1 The nucleotide sequence represented by base numbers 612 to 1984 is a region containing two exons of a novel gene encoding a novel human protein “A”. This area is 14-3-3 zeta / delta and 87 ° /. (Two unique 5 untranslated regions mRNAs encoding human 14-3-3 zeta: differential expression in hematopoietic cells. Biochim Biophys Acta 1998 Feb 11; 1395: 281-7).
  • SEQ ID NO: 2; 0RF of the gene encoding the novel human protein “B” starts at base number 1551 and ends at base number 5644.
  • the nucleotide sequence of this 0RF shows 80% or more homology with the human PAC clone DJ0093 I03 obtained from the q23 region of the X chromosome and the PAC clone of the ql2.2 region of the human chromosome 11 from the analysis of the human dbest database. did.
  • SEQ ID NO: 3; base numbers 3635 to 3841 are 0RF encoding human protein “C”.
  • the nucleotide sequence of this 0RF showed the homology of 91 with 435 bp cDNA AA262547 isolated from human tonsil CD20 +, IgD-germinal center B cell by analysis of human dbest database.
  • a PCR reaction was performed under cycle conditions to obtain a DNA fragment containing the entire coding region of the gene.
  • the primers used were set based on the nucleotide sequence determined in Example 1, such as those having the nucleotide sequences shown in SEQ ID NOS: 8 and 9, respectively.
  • the nucleotide sequence of the obtained DNA fragment was analyzed using an automatic sequencer (Perkin Elmer Prism 310).
  • Example 2 To determine whether the single nucleotide substitution detected in Example 2 is associated with an allergic reaction, an association analysis method for gene linkage (Mao X. -Q., Et al., Lancet, 348, 581-583 (1996); Gao, P.-S., et al., Hum. Genet., 103, 57-59 (1998)).
  • atopic patients among the analysis subjects shown in Example 2, patients exhibiting hyper-IgE bloodemia or having a positive specific antibody titer against allergen were defined as atopic patients.
  • Hyper-IgE was defined as a total blood IgE level of 400 kU / L or higher.
  • DNA samples were extracted using a commercial kit (IsoQuick, Microprobe). In the PCR reaction, denaturation was performed at 95 ° C for 10 minutes, and then 45 cycles of 94 ° C for 30 seconds, 5 ° C for 30 seconds, and 72 ° C for 30 seconds were performed using AmpliTaq Gold (PerkinElmer-Citas). Was performed under the following conditions.
  • the primers used each had the base sequence shown in SEQ ID NOS: 10 and 11.
  • the resulting PCR product was digested overnight with Tsp5091, and the fragment size was measured by electrophoresis. In this method, the 1723A gene produces a 570 bp fragment and the 1723C gene produces 441 and 129 bp fragments.
  • Figures in parentheses indicate 95% confidence limits.
  • the 1723A / C mutation was significantly more frequently detected in the British atopic patients, and the 604G / A mutation was higher in the British atopic patients. A trend was observed.
  • Example 3 it was determined whether the single nucleotide substitution detected in Example 2 was associated with asthma by an association analysis method for gene linkage (Mao X.-Q., et al., Lancet, 348, 581-583). (1996); Gao, P.-S., et al., Hum. Genet., 103, 57-59 (1998)).
  • asthma patients includes: (1) recurrent apnea and chest tightness requiring treatment, (2) wheezing, and (3) unstable ventilation disorder with peak flow fluctuating over 30 or more. All were defined as physician recognized patients.
  • Figures in parentheses indicate 95% confidence limits.
  • the 1723A / C mutation was significantly more frequently detected in the group of British asthmatics, and also tended to be higher in the group of Japanese asthmatics Was done.
  • the 604G / A mutation tended to be higher in the British asthma patient group.
  • the gene of the present invention is located at the chromosome 11 ql3.1 locus linked to atopic disease and is considered to play some role in the onset and maintenance of atopic disease. Therefore, the present invention is considered to be useful for treatment and diagnosis of atopic diseases.

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Abstract

L'invention concerne un gène HTm4 contenant un domaine et existant dans le domaine q13.1 du 11ème chromosome. Ce gène, qui serait étroitement lié à des maladies atopiques, est amplifié par PCR à partir d'une banque génomique humaine construite par transfert de fragments de génome humain dans un chromosome artificiel bactérien. A partir de ce fragment ainsi amplifié, on a identifié et isolé un gène d'atopie provoquant de manière génétique des maladies allergiques. On peut utiliser ce gène, par exemple, dans la détection de l'atopie.
PCT/JP2000/004599 1999-07-09 2000-07-10 Gene d'atopie WO2001004302A1 (fr)

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AU58520/00A AU5852000A (en) 1999-07-09 2000-07-10 Atopy gene

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JP11/196517 1999-07-09
JP19651799A JP2003180356A (ja) 1999-07-09 1999-07-09 アトピー遺伝子

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004016783A1 (fr) * 2002-08-06 2004-02-26 Genox Research, Inc. Procede permettant d'examiner une dermatite atopique
WO2010051288A1 (fr) 2008-10-27 2010-05-06 Revivicor, Inc. Ongulés immunodéprimés
EP2527456A1 (fr) 2004-10-22 2012-11-28 Revivicor Inc. Porcs transgéniques déficients en chaîne légère d'immunoglobuline endogène

Citations (2)

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