KR101114033B1 - Polynucleotides comprising single nucleotide polymorphism, microarrays and diagnostic kits comprising the same, and analytic methods using the same - Google Patents

Polynucleotides comprising single nucleotide polymorphism, microarrays and diagnostic kits comprising the same, and analytic methods using the same Download PDF

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KR101114033B1
KR101114033B1 KR1020090031112A KR20090031112A KR101114033B1 KR 101114033 B1 KR101114033 B1 KR 101114033B1 KR 1020090031112 A KR1020090031112 A KR 1020090031112A KR 20090031112 A KR20090031112 A KR 20090031112A KR 101114033 B1 KR101114033 B1 KR 101114033B1
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김승현
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Abstract

본 발명은 CTNNA3 (catenin alpha 3, alpha-T catenin) 유전자 등의 다양한 유전자로부터 유래된 단일염기다형(Single-Nucleotide Polymorphism; SNP)을 포함하는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 제공하며, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드는 한국인에 있어서 톨루엔 디이소시아네이트 유발성 천식(toluene diisocyanate (TDI) - induced asthma)의 임상적 진단의 표지 인자로서 유용하게 사용될 수 있다. The present invention provides a polynucleotide or a complementary polynucleotide thereof including Single-Nucleotide Polymorphism (SNP) derived from various genes such as CTNNA3 (catenin alpha 3, alpha-T catenin) gene. Nucleotides or their complementary polynucleotides can be usefully used as markers in the clinical diagnosis of toluene diisocyanate (TDI) -induced asthma in Koreans.

톨루엔 디이소시아네이트 유발성 천식 Toluene Diisocyanate-Induced Asthma

Description

단일염기다형을 포함하는 폴리뉴클레오티드, 이를 포함하는 마이크로어레이 및 진단키트, 및 이를 이용한 분석방법{Polynucleotides comprising single nucleotide polymorphism, microarrays and diagnostic kits comprising the same, and analytic methods using the same}Polynucleotides comprising single nucleotide polymorphism, microarrays and diagnostic kits comprising the same, and analytic methods using the same

본 발명은 CTNNA3 (catenin alpha 3, alpha-T catenin) 유전자 등의 다양한 유전자로부터 유래된 단일염기다형을 포함하는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드; 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진 톨루엔 디이소시아네이트 유발성 천식(toluene diisocyanate (TDI) - induced asthma) 진단을 위한 증폭용 프라이머 또는 TDI-유발성 천식 진단용 프로브; 상기 프로브를 포함하는 마이크로어레이; 및 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 이용한 TDI-유발성 천식 진단에 필요한 정보를 제공하기 위한 검출 방법에 관한 것이다.The present invention is a polynucleotide or a complementary polynucleotide comprising a monobasic polymorphism derived from various genes such as CTNNA3 (catenin alpha 3, alpha-T catenin) gene; Amplification primers or TDI-induced asthma diagnostic probes for diagnosing toluene diisocyanate (TDI) -induced asthma consisting of the polynucleotide or its complementary polynucleotides; A microarray comprising the probe; And a detection method for providing information necessary for diagnosing TDI-induced asthma using the polynucleotide or its complementary polynucleotide.

인간유전체 전체 염기서열의 공개와 염기서열 분석기술의 발달로 인간 유전체(human genome) 염기 서열을 바탕으로 한 유방암과 심장혈관계 질환, 우울증, 천식과 같은 다양한 질병의 감수성(susceptibility)에 영향을 미치는 유전적 요인을 규명하고자 하는 연구가 활발히 진행되고 있다. 천식은 다양한 요인에 의하여 발생하며 가족력, 알레르기, 환경, 영양, 사회경제적 상태, 심리, 직업 등이 위험 요인으로 알려져 있다. 직업성 천식은 작업장에서 노출되는 물질에 의해 호흡곤란, 발작성 기침 및 천명 등의 증세를 보이는 질환으로서 산업화된 국가에서 직업과 관련된 호흡기 질환 중에서 가장 흔한 질환으로 보고되고 있다. 직업성 천식 (occupational asthma)은 작업 환경 중의 분진, 가스, 증기 및 흄 등에 의해 유발 되는 가역적 기도 협착으로 정의되며, 작업관련성 천식은 전형적 직업성 천식뿐만 아니라 직업적 노출에 의해 악화되는 기존의 천식도 포함한다. 특정 직업성 천식 유발물질에 노출 되거나 직종에 종사하는 근로자를 대상으로 유병률에 관한 연구에 의하면 유발 물질로는 톨루엔-디이소시아네이트(toluene-diisocyanate; TDI) 0.58-21.6%, 곡물분진 14%, 무수프탈산 6.7%, 반응성염료 5.9% 등이 있다. 이들 중 이소시아네이트와 같은 매우 반응성이 큰 작은 분자, 기도 반응에 변화를 주는 자극제, 특이 IgE의 생산을 자극하는 동, 식물성 생물학적 부산물 등이 속한다. 분자량에 따라 고분자 물질은 일반적인 알레르겐과 같은 기전으로 천식을 유발하는데 반해, 저 분자량 물질은 체내 단백질과 결합하여 면역 반응을 일으키는 것으로 추정되며, 정확한 기전은 아직 밝혀지지 않았지만 특이 IgE 와 IgG 매개반응뿐 아니라 세포 면역기전 등이 다양하게 작용하는 것으로 생각된다. 또한 원인 물질에 따라 면역학적 기전 외에도 다양한 비 면역학적 기전이 천식 발생에 관여한다. 대개 노출된 후 수 개월에서 수 년의 잠복기를 가지며 강력한 알레르기성을 지닌 물질은 낮은 농도에 노출되어도 쉽게 감작과 천식을 유발할 수 있는데, 여기에는 이소시아네이트나 백금염, 약제 등이 있다.Development of nucleotide sequence analysis and development of sequencing technology to influence the susceptibility of various diseases such as breast cancer, cardiovascular disease, depression and asthma based on human genome sequence There is an active research to identify the factors. Asthma is caused by various factors, and family history, allergies, environment, nutrition, socioeconomic status, psychology, and occupation are known risk factors. Occupational asthma is a disorder of respiratory distress, paroxysmal cough, and wheezing caused by substances exposed in the workplace. It is reported as the most common disease among occupational respiratory diseases in industrialized countries. Occupational asthma is defined as reversible airway narrowing caused by dust, gases, vapors and fumes in the working environment. Work-related asthma includes not only typical occupational asthma but also existing asthma exacerbated by occupational exposure. do. The prevalence of workers exposed to occupational asthma-causing agents or occupational occupational studies showed that the causative agents were toluene-diisocyanate (TDI) 0.58-21.6%, grain dust 14%, and phthalic anhydride. 6.7%, reactive dyes 5.9%. Among them are highly reactive small molecules such as isocyanates, stimulants that change airway responses, copper that stimulates the production of specific IgE, and plant biological by-products. Depending on the molecular weight, high molecular weight substances cause asthma by the same mechanisms as allergens, while low molecular weight substances are believed to bind to proteins in the body and cause an immune response.The exact mechanisms are not yet known, but specific IgE and IgG mediated reactions It is thought that cellular immune mechanisms and the like act in various ways. In addition, depending on the causative agent, various non-immunological mechanisms in addition to immunological mechanisms are involved in asthma development. In general, a substance with an incubation period of months to years after exposure and a strong allergic substance can easily cause sensitization and asthma even when exposed to low concentrations, such as isocyanates, platinum salts, and drugs.

직업성 천식은 주로 성인에서 발생하며, 이러한 나이의 성인 천식의 10명중 1명은 직업성 감작물질이 원인일 것으로 추정된다. 이소시아네이트에 의한 천식의 유병률은 국외 연구의 경우 약 5%, 국내 연구의 경우 2.1%-13%로 다양하게 보고되었다. 이들 환자의 50% 이상에서는 회피요법을 시행한 뒤에도 지속적인 천식 증상을 호소하였고, 혈청 특이 IgE와 IgG 항체도 상당기간 높게 남아 있었다. TDI는 국내에서 직업성 천식원인 중 가장 흔한 물질로 한국에서 노출 환경 근로자의 3-13%의 발병률을 보이는 직업성 천식의 가장 중요한 원인이다. 이소시아네이트에 의해 발생하는 직업성 천식은 TDI에 노출된 후에 천식 반응이 진행된 환자의 말초혈액 내에서 CD8+ 세포와 호산구(eosinophil) 증가가 관찰되었다. TDI-유발성 천식의 병인기전은 비 직업성 천식에 비해 더 복잡하며 많은 연구를 필요로 하고 있다. Occupational asthma occurs mainly in adults, and it is estimated that one in ten adults of this age are caused by occupational sensitizers. The prevalence of asthma by isocyanates has been reported to vary from about 5% in foreign studies and 2.1% to 13% in domestic studies. More than 50% of these patients complained of persistent asthma symptoms after avoidance therapy, and serum specific IgE and IgG antibodies remained high for some time. TDI is the most common cause of occupational asthma in Korea and is the most important cause of occupational asthma in Korea, with an incidence of 3-13% of exposed environmental workers. Occupational asthma caused by isocyanates was observed to increase CD8 + cells and eosinophils in the peripheral blood of patients undergoing asthma after exposure to TDI. The pathogenesis of TDI-induced asthma is more complicated than non-occupational asthma and requires much research.

한편, 단일염기 다형성(single nucleotide polymorphism: SNP)은 인간 유전체상에 가장 많이 존재하는 형태의 유전적 다형성으로 유전체 상의 특정 염기서열 하나의 변화를 말한다. 인간 유전체 상의 다형성의 90% 이상을 차지하는 SNP와 같은 인구집단 내에서 약 0.1%의 개인 간의 차이(즉, 약 1000염기 마다 한 개의 SNP)를 나타내고 있다. 현재 최대로 약 1000만개 이상 존재할 것으로 예측되는 SNP중 약 300만 개 이상이 밝혀졌으며 이들 중 약 1%정도는 유전자의 암호화(Coding) 부위에 존재한다. 유전자의 코딩 부위에 존재하는 SNP은 단백질의 구조를 변화시켜서 단백질의 기능의 변화를 초래할 수 있으므로 많은 연구의 대상이 되고 있다. On the other hand, single nucleotide polymorphism (SNP) is the most common form of genetic polymorphism in the human genome and refers to a change in one specific sequence on the genome. It represents a difference between about 0.1% of individuals (ie, one SNP per 1000 bases) within a population such as SNP, which accounts for more than 90% of polymorphisms on the human genome. Currently, about 3 million of the SNPs are expected to be present at a maximum of about 10 million, and about 1% of them are present in the coding region of the gene. SNPs present in the coding region of genes have been the subject of many studies because they can alter the structure of the protein and cause changes in the function of the protein.

지금까지 TDI-유발성 천식의 병인기전과 연관된 것으로 보고된 유전자는 글 루타치온 S-트랜스퍼라아제(Mapp et al, J Allergy Clin Immunol 2002; 109:867-72), N-아세틸 트랜스퍼라아제(Wikman et al, Pharmacogenetics 2002; 12:227-33), Human leucocyte antigen (HLA) class II alleles (Mapp et al, Clin Exp Allergy 2000; 30:651-6; 및 Kim et al, Allergy 2006; 61:819-24), Neurokinin 2 receptor (Ye et al, Clin Exp Allergy 2006; 36: 1153-60) 등이 있다. GSTP1*Val allele은 TDI 천식과 기도 과민증에 대한 방어역할을 하는 것으로 보고되었으며, NK2R (Neurokinin 2 receptor) G231E(G>A)의 GG 유전자는 TDI 에 노출된 후 기도 염증의 결과에서 혈청 VEGF 레벨을 증가시키는 역할을 한다고 보고되었다 (Ye et al, Clin Exp Allergy 2006; 36: 1153-60). 그러나, 천식의 병인기전과 관련 있는 후보유전자(candidate gene)들의 유전자 다형성을 조사하는 접근방법은 직업성 천식의 복잡한 병인기전을 설명하는데 충분하지는 않다. 천식과 같은 복합질병의 유전적 병인기전은 소수의 효과를 가진 다양한 유전자의 상호작용으로부터 도출되기 때문이다. 천식에 관한 단일 후보 유전자에 대한 상관성 연구(candidate gene association study)는 비교적 간편한 연구 설계하에 진행될 수 있는 장점을 지니고 있지만, 대상군 선정에 의한 편기(bias)를 감소시키고 통계적으로 유의성 있는 결과를 얻기 위해서는 대규모의 집단을 대상으로 한 연구를 진행하는 것이 필요하다.Genes reported to be associated with the pathogenesis of TDI-induced asthma so far are glutathione S-transferase (Mapp et al, J Allergy Clin Immunol 2002; 109: 867-72), N-acetyl transferase ( Wikman et al, Pharmacogenetics 2002; 12: 227-33), Human leucocyte antigen (HLA) class II alleles (Mapp et al, Clin Exp Allergy 2000; 30: 651-6; and Kim et al, Allergy 2006; 61: 819 -24), Neurokinin 2 receptor (Ye et al, Clin Exp Allergy 2006; 36: 1153-60). GSTP1 * Val alleles have been reported to act as a defense against TDI asthma and airway hypersensitivity, and the GG gene of NK2R (Neurokinin 2 receptor) G231E (G> A) increased serum VEGF levels in airway inflammation following exposure to TDI. It has been reported to play an increasing role (Ye et al, Clin Exp Allergy 2006; 36: 1153-60). However, an approach to investigating gene polymorphisms in candidate genes associated with the pathogenesis of asthma is not sufficient to explain the complex pathogenesis of occupational asthma. The genetic pathogenesis of complex diseases such as asthma is derived from the interaction of various genes with few effects. Candidate gene association studies on asthma have the advantage of being able to proceed with a relatively simple study design, but in order to reduce bias and to obtain statistically significant results It is necessary to conduct research on large groups.

본 발명자들은 한국인에 있어서 톨루엔 디이소시아네이트 유발성 천식(toluene diisocyanate (TDI) - induced asthma)에 특이적으로 나타나는 단일염기다형을 찾아내고자, 50만개의 단일염기다형 칩 (SNP chip)을 이용하여 한국인 TDI-유발성 천식 환자와 대조군에서 전체 게놈 연관성 분석 연구(genome-wide association study)를 진행하였다. 그 결과, CTNNA3 (catenin alpha 3, alpha-T catenin) 유전자 등의 다양한 유전자로부터 TDI-유발성 천식 환자에 특이적으로 나타나는 단일염기다형을 발견하여 본 발명을 완성하게 되었다. The present inventors attempted to find a single base polymorphism that is specific to toluene diisocyanate (TDI) -induced asthma in Koreans. A genome-wide association study was conducted in patients with induced asthma and controls. As a result, the present invention has been completed by finding a single nucleotide polymorphism specific to TDI-induced asthma patients from various genes such as CTNNA3 (catenin alpha 3, alpha-T catenin) gene.

따라서, 본 발명은 TDI-유발성 천식과 관련된 단일염기다형을 포함하는 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 제공하는 것을 목적으로 한다.Accordingly, it is an object of the present invention to provide polynucleotides or their complementary polynucleotides comprising a monobasic polymorphism associated with TDI-induced asthma.

또한, 본 발명은 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진 TDI-유발성 천식 진단을 위한 증폭용 프라이머 또는 TDI-유발성 천식 진단용 프로브를 제공하는 것을 목적으로 한다.It is also an object of the present invention to provide an amplification primer or TDI-induced asthma diagnostic probe for diagnosing TDI-induced asthma consisting of the polynucleotide or its complementary polynucleotide.

또한, 본 발명은 상기 프로브를 포함하는 마이크로어레이를 제공하는 것을 목적으로 한다.Another object of the present invention is to provide a microarray including the probe.

또한, 본 발명은 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 이용한 TDI-유발성 천식 진단 방법을 제공하는 것을 목적으로 한다.It is also an object of the present invention to provide a TDI-induced asthma diagnostic method using the polynucleotide or its complementary polynucleotide.

본 발명의 일 태양에 따라, 서열번호 1의 DNA 서열로 구성된 폴리뉴클레오티 드에서, 382번째 염기(다형성 부위)가 T이고, 상기 382번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-1; 서열번호 2의 DNA 서열로 구성된 폴리뉴클레오티드에서, 233번째 염기(다형성 부위)가 G이고, 상기 233번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-2; 서열번호 3의 DNA 서열로 구성된 폴리뉴클레오티드에서, 101번째 염기(다형성 부위)가 G이고, 상기 101번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-3; 서열번호 4의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 G이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-4; 서열번호 5의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 A이고, 상기 251번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-5; 서열번호 6의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 G이고, 상기 251번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-6; 서열번호 7의 DNA 서열로 구성된 폴리뉴클레오티드에서, 1217번째 염기(다형성 부위)가 G이고, 상기 1217번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-7; 서열번호 8의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 T이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-8; 서열번호 9의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 C이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구 성되는 폴리뉴클레오티드-9; 서열번호 10의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 A이고, 상기 401번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-10; 서열번호 11의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-11; 서열번호 12의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-12; 서열번호 13의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 G이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-13; 서열번호 14의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-14; 서열번호 15의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-15; 서열번호 16의 DNA 서열로 구성된 폴리뉴클레오티드에서, 345번째 염기(다형성 부위)가 A이고, 상기 345번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-16; 서열번호 17의 DNA 서열로 구성된 폴리뉴클레오티드에서, 753번째 염기(다형성 부위)가 C이고, 상기 753번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-17; 서열번호 18의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염 기(다형성 부위)가 A이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-18; 서열번호 19의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-19; 서열번호 20의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 T이고, 상기 251번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-20; 서열번호 21의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 T이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-21; 서열번호 22의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 A이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-22; 서열번호 23의 DNA 서열로 구성된 폴리뉴클레오티드에서, 399번째 염기(다형성 부위)가 C이고, 상기 399번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-23; 서열번호 24의 DNA 서열로 구성된 폴리뉴클레오티드에서, 1298번째 염기(다형성 부위)가 G이고, 상기 1298번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-24; 서열번호 25의 DNA 서열로 구성된 폴리뉴클레오티드에서, 858번째 염기(다형성 부위)가 G이고, 상기 858번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-25; 서열번호 26의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구 성되는 폴리뉴클레오티드-26; 서열번호 27의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-27; 서열번호 28의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 T이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-28; 서열번호 29의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 T이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-29; 서열번호 30의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 T이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-30; 서열번호 31의 DNA 서열로 구성된 폴리뉴클레오티드에서, 294번째 염기(다형성 부위)가 T이고, 상기 294번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-31; 서열번호 32의 DNA 서열로 구성된 폴리뉴클레오티드에서, 492번째 염기(다형성 부위)가 C이고, 상기 492번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-32; 서열번호 33의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 C이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-33; 서열번호 34의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-34; 서열번호 35의 DNA 서열로 구성된 폴리뉴클레오티드에서, 1572번째 염기(다형성 부위)가 A이고, 상기 1572번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-35; 서열번호 36의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 T이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-36; 서열번호 37의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 A이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-37; 서열번호 38의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 C이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-38; 서열번호 39의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 A이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-39; 서열번호 40의 DNA 서열로 구성된 폴리뉴클레오티드에서, 1281번째 염기(다형성 부위)가 C이고, 상기 1281번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-40; 서열번호 41의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 T이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-41; 서열번호 42의 DNA 서열로 구성된 폴리뉴클레오티드에서, 483번째 염기(다형성 부위)가 G이고, 상기 483번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-42; 서열번호 43의 DNA 서열로 구성된 폴리뉴클레오티드에서, 222번째 염기(다형성 부위)가 A이고, 상기 222번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구 성되는 폴리뉴클레오티드-43; 서열번호 44의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 A이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-44; 서열번호 45의 DNA 서열로 구성된 폴리뉴클레오티드에서, 287번째 염기(다형성 부위)가 G이고, 상기 287번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-45; 서열번호 46의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-46; 서열번호 47의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 T이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-47; 서열번호 48의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-48; 서열번호 49의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 G이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-49; 서열번호 50의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 G이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-50; 서열번호 51의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 G이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-51; 서열번호 52의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염 기(다형성 부위)가 C이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-52; 서열번호 53의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-53; 서열번호 54의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 C이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-54; 서열번호 55의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 C이고, 상기 251번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-55; 서열번호 56의 DNA 서열로 구성된 폴리뉴클레오티드에서, 254번째 염기(다형성 부위)가 A이고, 상기 254번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-56; 서열번호 57의 DNA 서열로 구성된 폴리뉴클레오티드에서, 747번째 염기(다형성 부위)가 G이고, 상기 747번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-57; 및 서열번호 58의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-58 로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드가 제공된다.According to one aspect of the invention, in the polynucleotide consisting of the DNA sequence of SEQ ID NO: 1, the 382 th base (polymorphic site) is T and consists of 10 to 100 contiguous DNA sequences comprising the 382 th base Polynucleotide-1; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 2, wherein the 233th base (polymorphic site) is G and polynucleotide-2 consisting of 10 to 100 consecutive DNA sequences comprising the 233th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 3, wherein the 101 st base (polymorphic site) is G, and the polynucleotide-3 consists of 10 to 100 contiguous DNA sequences comprising the 101 st base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 4, wherein the 201 base (polymorphic site) is G and a polynucleotide-4 consisting of 10 to 100 contiguous DNA sequences comprising said 201 base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 5, Polynucleotide-5 consisting of 10 to 100 consecutive DNA sequences comprising the 251 st base (polymorphic site) is A, the 251 st base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 6, wherein the 251 st base (polymorphic site) is G and the polynucleotide-6 consists of 10 to 100 contiguous DNA sequences comprising the 251 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 7, a polynucleotide-7 consisting of 10 to 100 contiguous DNA sequences comprising a 1217th base (polymorphic site) G and comprising the 1217th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 8, Polynucleotide-8 consisting of 10 to 100 contiguous DNA sequences comprising the 301th base (polymorphic site) is T; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 9, the polynucleotide-9 consisting of 10 to 100 consecutive DNA sequences comprising the 301th base (polymorphic site) is C, the 301th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 10, Polynucleotide-10 consisting of 10 to 100 contiguous DNA sequences comprising the 401 th base (A polymorphic site) is A, and the 401 th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 11, Polynucleotide-11 consisting of 10 to 100 consecutive DNA sequences comprising the 301th base (polymorphic site) is G, the 301th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 12, a polynucleotide-12 consisting of 10 to 100 contiguous DNA sequences comprising a 301 th base (polymorphic site) G and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 13, a polynucleotide-13 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base (G polymorphic site) G and comprising the 201 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 14, a polynucleotide-14 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base (polymorphic site) A and comprising the 201 base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 15, Polynucleotide-15 consisting of 10 to 100 contiguous DNA sequences comprising the 301th base (polymorphic site) is G and the 301th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 16, Polynucleotide-16 consisting of 10 to 100 consecutive DNA sequence comprising the 345th base (polymorphic site) is A, the 345th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 17, a polynucleotide-17 consisting of 10 to 100 contiguous DNA sequences comprising the 753th base (polymorphic site) as C and comprising the 753th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 18, Polynucleotide-18 consisting of 10 to 100 consecutive DNA sequence containing the 301th base (polymorphic site) is A, the 301th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 19, a polynucleotide-19 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base of A and a 201 base (polymorphic site); In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 20, Polynucleotide-20 consisting of 10 to 100 contiguous DNA sequences comprising the 251 th base (T polymorphic site) is T; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 21, a polynucleotide-21 consisting of 10 to 100 contiguous DNA sequences comprising a 501st base (polymorphic site) T and comprising the 501th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 22, a polynucleotide-22 consisting of 10 to 100 contiguous DNA sequences comprising a 501st base (polymorphic site) A and comprising the 501th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 23, wherein the 399th base (polymorphic site) is C and polynucleotide-23 consisting of 10 to 100 consecutive DNA sequences comprising said 399th base; In a polynucleotide consisting of a DNA sequence of SEQ ID NO: 24, a polynucleotide-24 consisting of 10 to 100 consecutive DNA sequences comprising a 1298th base (polymorphic site) G and comprising the 1298th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 25, the polynucleotide-25 consisting of 10 to 100 contiguous DNA sequences comprising the 858th base (polymorphic site) G and comprising the 858th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 26, the nucleotide 301 (polymorphic site) is G, and the polynucleotide-26 is composed of 10 to 100 consecutive DNA sequences comprising the 301 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 27, a polynucleotide-27 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base (polymorphic site) A and comprising the 201 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 28, the polynucleotide-28 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) is T and the 301 th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 29, the polynucleotide-29 consisting of 10 to 100 consecutive DNA sequences each including the 301th base (polymorphic site) is T and the 301th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 30, Polynucleotide-30 consisting of 10 to 100 consecutive DNA sequences comprising the 501th base (T polymorphic site) is T, the 501th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 31, the polynucleotide-31 consisting of 10 to 100 consecutive DNA sequences comprising the 294 th base having a T94th (polymorphic site); In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 32, the polynucleotide-32 consisting of 10 to 100 contiguous DNA sequences comprising the 492th base of the 492th base (polymorphic site) and C; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 33, polynucleotide-33 consisting of 10 to 100 consecutive DNA sequences comprising the 501th base (polymorphic site) C and comprising the 501th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 34, polynucleotide-34 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) G and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 35, polynucleotide-35 consisting of 10 to 100 consecutive DNA sequences comprising the 1572th base of A and wherein the 1572th base (polymorphic site) is A; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 36, wherein the 201 base (polymorphic site) is T and polynucleotide-36 consisting of 10 to 100 contiguous DNA sequences comprising said 201 base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 37, the polynucleotide-37 consisting of 10 to 100 contiguous DNA sequences including the 301th base (polymorphic site) is A and the 301th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 38, the polynucleotide-38 consisting of 10 to 100 consecutive DNA sequences comprising the 301th base (polymorphic site) C and comprising the 301th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 39, wherein the 501th base (polymorphic site) is A and polynucleotide-39 consisting of 10 to 100 contiguous DNA sequences comprising the 501th base; In a polynucleotide consisting of a DNA sequence of SEQ ID NO: 40, a polynucleotide-40 consisting of 10 to 100 contiguous DNA sequences comprising a 1281th base (polymorphic site) C and comprising the 1281th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 41, a polynucleotide-41 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base of T and a 201 base (polymorphic site); A polynucleotide consisting of the DNA sequence of SEQ ID NO: 42, a polynucleotide-42 consisting of 10 to 100 contiguous DNA sequences including a 483th base (polymorphic site) G and comprising the 483th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 43, polynucleotide-43 consisting of 10 to 100 contiguous DNA sequences including the 222nd base of A and the 222nd base (polymorphic site); In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 44, a polynucleotide-44 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) is A and the 301 th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 45, wherein the 287th base (polymorphic site) is G and polynucleotide-45 consisting of 10 to 100 contiguous DNA sequences comprising said 287th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 46, a polynucleotide-46 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base (polymorphic site) A and comprising the 201 base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 47, the polynucleotide-47 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) is T and the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 48, a polynucleotide-48 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) G and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 49, a polynucleotide-49 consisting of 10 to 100 contiguous DNA sequences including the 201 base of G and a 201 base (polymorphic site); In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 50, Polynucleotide-50 consisting of 10 to 100 consecutive DNA sequences comprising the 501th base (polymorphic site) is G, the 501th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 51, a polynucleotide-51 consisting of 10 to 100 contiguous DNA sequences comprising a 501st base (polymorphic site) G and comprising the 501th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 52, polynucleotide-52 consisting of 10 to 100 consecutive DNA sequences comprising the 501th base (polymorphic site) C and comprising the 501th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 53, polynucleotide-53 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) G and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 54, polynucleotide-54 consisting of 10 to 100 consecutive DNA sequences comprising the 301th base (polymorphic site) C and comprising the 301th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 55, polynucleotide-55 consisting of 10 to 100 contiguous DNA sequences comprising the 251 st base (polymorphic site) C and comprising the 251 st base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 56, wherein the 254th base (polymorphic site) is A and is composed of 10 to 100 contiguous DNA sequences comprising the 254th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 57, polynucleotide-57 consisting of 10 to 100 contiguous DNA sequences comprising the 747 base (G) and G comprising the 747 base; And in a polynucleotide consisting of the DNA sequence of SEQ ID NO: 58, one from the group consisting of polynucleotide-58 consisting of 10 to 100 consecutive DNA sequences comprising the 301th base (polymorphic site) G and comprising the 301th base; Polynucleotides selected above or complementary polynucleotides thereof are provided.

또한, 본 발명의 다른 태양에 따라, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진, TDI-유발성 천식 진단을 위한 증폭용 프라이머가 제공된다.In addition, according to another aspect of the present invention, there is provided a primer for amplification for TDI-induced asthma diagnosis, consisting of the polynucleotide or its complementary polynucleotide.

또한, 본 발명의 다른 태양에 따라, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진, TDI-유발성 천식 진단용 프로브 및 이를 포함한 마이크로어레이가 제공된다.In addition, according to another aspect of the present invention, there is provided a TDI-induced asthma diagnostic probe and a microarray comprising the polynucleotide or a complementary polynucleotide thereof.

또한, 본 발명의 다른 태양에 따라, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 포함하는 TDI-유발성 천식 진단용 키트가 제공된다.According to another aspect of the present invention, there is also provided a TDI-induced asthma diagnostic kit comprising the polynucleotide or its complementary polynucleotide.

또한, 본 발명의 다른 태양에 따라, TDI-유발성 천식 진단에 필요한 정보를 제공하기 위하여, (i) 검체로부터 핵산 시료를 얻는 단계; 및 (ii) 상기 핵산 시료로부터, 서열번호 1 내지 58의 폴리뉴클레오티드로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드의 다형성 부위의 염기 서열을 분석하는 단계 (단, 상기 다형성 부위는 상기에서 정의한 바와 같다)를 포함하는, 검체 중의 단일염기다형을 검출하는 방법이 제공된다.In addition, according to another aspect of the present invention, to provide information necessary for diagnosing TDI-induced asthma, (i) obtaining a nucleic acid sample from a sample; And (ii) analyzing the nucleotide sequence of the polymorphic site of at least one polynucleotide selected from polynucleotides of SEQ ID NOs: 1 to 58 or complementary polynucleotides thereof from the nucleic acid sample, wherein the polymorphic site is as defined above A method for detecting a monobasic polymorph in a sample is provided.

본 발명에 따른 폴리뉴클레오티드-1 내지 58로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드는 톨루엔 디이소시아네이트 유발성 천식(toluene diisocyanate (TDI) - induced asthma)의 진단에 유용하게 사용될 수 있다. 또한, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진 프라이머 또는 프로브, 및 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드 키트는 TDI-유발성 천식의 예측진단에 유용하게 사용될 수 있다. 또한 본 발명의 검출방법은 TDI-유발성 천식 진단에 필요한 정보를 제공하는데 유용하게 사용될 수 있다.One or more polynucleotides selected from the group consisting of polynucleotides 1 to 58 according to the present invention or complementary polynucleotides thereof may be usefully used for the diagnosis of toluene diisocyanate (TDI) -induced asthma. . In addition, a primer or probe consisting of the polynucleotide or its complementary polynucleotide, and the polynucleotide or the complementary polynucleotide kit thereof may be usefully used for predictive diagnosis of TDI-induced asthma. In addition, the detection method of the present invention can be usefully used to provide information necessary for diagnosing TDI-induced asthma.

본 발명은 톨루엔 디이소시아네이트 유발성 천식(즉, TDI-유발성 천식)과 관련된 것으로 새롭게 밝혀진 서열번호 1 내지 58의 서열로부터 유래하는 폴리뉴클레오티드-1 내지 58로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 제공한다. 즉, 본 발명은 서열번호 1의 DNA 서열로 구성된 폴리뉴클레오티드에서, 382번째 염기(다형성 부위)가 T이고, 상기 382번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-1; 서열번호 2의 DNA 서열로 구성된 폴리뉴클레오티드에서, 233번째 염기(다형성 부위)가 G이고, 상기 233번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-2; 서열번호 3의 DNA 서열로 구성된 폴리뉴클레오티드에서, 101번째 염기(다형성 부위)가 G이고, 상기 101번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-3; 서열번호 4의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 G이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-4; 서열번호 5의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 A이고, 상기 251번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-5; 서열번호 6의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 G이고, 상기 251번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-6; 서열번호 7의 DNA 서열로 구성된 폴리뉴클레오티드에서, 1217번째 염기(다형성 부위)가 G이고, 상기 1217번 째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-7; 서열번호 8의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 T이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-8; 서열번호 9의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 C이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-9; 서열번호 10의 DNA 서열로 구성된 폴리뉴클레오티드에서, 401번째 염기(다형성 부위)가 A이고, 상기 401번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-10; 서열번호 11의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-11; 서열번호 12의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-12; 서열번호 13의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 G이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-13; 서열번호 14의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-14; 서열번호 15의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-15; 서열번호 16의 DNA 서 열로 구성된 폴리뉴클레오티드에서, 345번째 염기(다형성 부위)가 A이고, 상기 345번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-16; 서열번호 17의 DNA 서열로 구성된 폴리뉴클레오티드에서, 753번째 염기(다형성 부위)가 C이고, 상기 753번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-17; 서열번호 18의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 A이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-18; 서열번호 19의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-19; 서열번호 20의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 T이고, 상기 251번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-20; 서열번호 21의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 T이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-21; 서열번호 22의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 A이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-22; 서열번호 23의 DNA 서열로 구성된 폴리뉴클레오티드에서, 399번째 염기(다형성 부위)가 C이고, 상기 399번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-23; 서열번호 24의 DNA 서열로 구성된 폴리뉴클레오티드에서, 1298번째 염기(다형성 부위)가 G이고, 상기 1298번째 염기 를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-24; 서열번호 25의 DNA 서열로 구성된 폴리뉴클레오티드에서, 858번째 염기(다형성 부위)가 G이고, 상기 858번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-25; 서열번호 26의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-26; 서열번호 27의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-27; 서열번호 28의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 T이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-28; 서열번호 29의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 T이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-29; 서열번호 30의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 T이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-30; 서열번호 31의 DNA 서열로 구성된 폴리뉴클레오티드에서, 294번째 염기(다형성 부위)가 T이고, 상기 294번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-31; 서열번호 32의 DNA 서열로 구성된 폴리뉴클레오티드에서, 492번째 염기(다형성 부위)가 C이고, 상기 492번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-32; 서열번호 33의 DNA 서 열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 C이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-33; 서열번호 34의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-34; 서열번호 35의 DNA 서열로 구성된 폴리뉴클레오티드에서, 1572번째 염기(다형성 부위)가 A이고, 상기 1572번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-35; 서열번호 36의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 T이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-36; 서열번호 37의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 A이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-37; 서열번호 38의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 C이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-38; 서열번호 39의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 A이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-39; 서열번호 40의 DNA 서열로 구성된 폴리뉴클레오티드에서, 1281번째 염기(다형성 부위)가 C이고, 상기 1281번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-40; 서열번호 41의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 T이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-41; 서열번호 42의 DNA 서열로 구성된 폴리뉴클레오티드에서, 483번째 염기(다형성 부위)가 G이고, 상기 483번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-42; 서열번호 43의 DNA 서열로 구성된 폴리뉴클레오티드에서, 222번째 염기(다형성 부위)가 A이고, 상기 222번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-43; 서열번호 44의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 A이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-44; 서열번호 45의 DNA 서열로 구성된 폴리뉴클레오티드에서, 287번째 염기(다형성 부위)가 G이고, 상기 287번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-45; 서열번호 46의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 A이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-46; 서열번호 47의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 T이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-47; 서열번호 48의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-48; 서열번호 49의 DNA 서열로 구성된 폴리뉴클레오티드에서, 201번째 염기(다형성 부위)가 G이고, 상기 201번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-49; 서열번호 50의 DNA 서 열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 G이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-50; 서열번호 51의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 G이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-51; 서열번호 52의 DNA 서열로 구성된 폴리뉴클레오티드에서, 501번째 염기(다형성 부위)가 C이고, 상기 501번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-52; 서열번호 53의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-53; 서열번호 54의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 C이고, 상기 301번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-54; 서열번호 55의 DNA 서열로 구성된 폴리뉴클레오티드에서, 251번째 염기(다형성 부위)가 C이고, 상기 251번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-55; 서열번호 56의 DNA 서열로 구성된 폴리뉴클레오티드에서, 254번째 염기(다형성 부위)가 A이고, 상기 254번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-56; 서열번호 57의 DNA 서열로 구성된 폴리뉴클레오티드에서, 747번째 염기(다형성 부위)가 G이고, 상기 747번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-57; 및 서열번호 58의 DNA 서열로 구성된 폴리뉴클레오티드에서, 301번째 염기(다형성 부위)가 G이고, 상기 301번째 염 기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성되는 폴리뉴클레오티드-58 로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 제공한다.The present invention relates to a polynucleotide selected from the group consisting of polynucleotides 1 to 58 derived from the sequences of SEQ ID NOs 1 to 58 newly found to be related to toluene diisocyanate-induced asthma (ie, TDI-induced asthma) or Complementary polynucleotides are provided. That is, the present invention provides a polynucleotide composed of the DNA sequence of SEQ ID NO: 1, wherein the 382th base (polymorphic site) is T, and the polynucleotide-1 comprises 10 to 100 consecutive DNA sequences comprising the 382th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 2, wherein the 233th base (polymorphic site) is G and polynucleotide-2 consisting of 10 to 100 consecutive DNA sequences comprising the 233th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 3, wherein the 101 st base (polymorphic site) is G, and the polynucleotide-3 consists of 10 to 100 contiguous DNA sequences comprising the 101 st base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 4, wherein the 201 base (polymorphic site) is G and a polynucleotide-4 consisting of 10 to 100 contiguous DNA sequences comprising said 201 base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 5, Polynucleotide-5 consisting of 10 to 100 consecutive DNA sequences comprising the 251 st base (polymorphic site) is A, the 251 st base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 6, wherein the 251 st base (polymorphic site) is G and the polynucleotide-6 consists of 10 to 100 contiguous DNA sequences comprising the 251 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 7, a polynucleotide-7 consisting of 10 to 100 consecutive DNA sequences comprising a 1217th base (polymorphic site) G and comprising the 1217th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 8, Polynucleotide-8 consisting of 10 to 100 contiguous DNA sequences comprising the 301th base (polymorphic site) is T; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 9, a polynucleotide-9 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) is C and the 301 th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 10, Polynucleotide-10 consisting of 10 to 100 contiguous DNA sequences comprising the 401 th base (A polymorphic site) is A, and the 401 th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 11, Polynucleotide-11 consisting of 10 to 100 consecutive DNA sequences comprising the 301th base (polymorphic site) is G, the 301th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 12, a polynucleotide-12 consisting of 10 to 100 contiguous DNA sequences comprising a 301 th base (polymorphic site) G and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 13, a polynucleotide-13 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base (G polymorphic site) G and comprising the 201 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 14, a polynucleotide-14 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base (polymorphic site) A and comprising the 201 base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 15, Polynucleotide-15 consisting of 10 to 100 contiguous DNA sequences comprising the 301th base (polymorphic site) is G and the 301th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 16, Polynucleotide-16 consisting of 10 to 100 consecutive DNA sequence containing the 345th base (polymorphic site) is A, the 345th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 17, a polynucleotide-17 consisting of 10 to 100 contiguous DNA sequences comprising the 753th base (polymorphic site) as C and comprising the 753th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 18, Polynucleotide-18 consisting of 10 to 100 consecutive DNA sequences comprising the 301th base (polymorphic site) is A, the 301th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 19, a polynucleotide-19 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base of A and a 201 base (polymorphic site); In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 20, Polynucleotide-20 consisting of 10 to 100 contiguous DNA sequences comprising the 251 th base (T polymorphic site) is T; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 21, a polynucleotide-21 consisting of 10 to 100 contiguous DNA sequences comprising a 501st base (polymorphic site) T and comprising the 501th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 22, a polynucleotide-22 consisting of 10 to 100 contiguous DNA sequences comprising a 501st base (polymorphic site) A and comprising the 501th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 23, wherein the 399th base (polymorphic site) is C and polynucleotide-23 consisting of 10 to 100 consecutive DNA sequences comprising said 399th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 24, a polynucleotide-24 consisting of 10 to 100 consecutive DNA sequences comprising a 1298th base (polymorphic site) G and comprising the 1298th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 25, the polynucleotide-25 consisting of 10 to 100 contiguous DNA sequences comprising the 858th base (polymorphic site) G and comprising the 858th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 26, the polynucleotide-26 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) G and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 27, a polynucleotide-27 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base (polymorphic site) A and comprising the 201 base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 28, the polynucleotide-28 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) is T and the 301 th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 29, the polynucleotide-29 consisting of 10 to 100 consecutive DNA sequences each including the 301th base (polymorphic site) is T and the 301th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 30, Polynucleotide-30 consisting of 10 to 100 consecutive DNA sequences comprising the 501th base (T polymorphic site) is T, the 501th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 31, the polynucleotide-31 consisting of 10 to 100 consecutive DNA sequences comprising the 294 th base having a T94th (polymorphic site); In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 32, the polynucleotide-32 consisting of 10 to 100 contiguous DNA sequences comprising the 492th base of the 492th base (polymorphic site) and C; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 33, polynucleotide-33 consisting of 10 to 100 contiguous DNA sequences comprising the 501st base (C polymorphic site) and C; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 34, polynucleotide-34 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) G and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 35, polynucleotide-35 consisting of 10 to 100 consecutive DNA sequences comprising the 1572th base of A and wherein the 1572th base (polymorphic site) is A; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 36, wherein the 201 base (polymorphic site) is T and polynucleotide-36 consisting of 10 to 100 contiguous DNA sequences comprising said 201 base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 37, the polynucleotide-37 consisting of 10 to 100 contiguous DNA sequences including the 301th base (polymorphic site) is A and the 301th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 38, the polynucleotide-38 consisting of 10 to 100 consecutive DNA sequences comprising the 301th base (polymorphic site) C and comprising the 301th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 39, wherein the 501th base (polymorphic site) is A and polynucleotide-39 consisting of 10 to 100 contiguous DNA sequences comprising the 501th base; In a polynucleotide consisting of a DNA sequence of SEQ ID NO: 40, a polynucleotide-40 consisting of 10 to 100 contiguous DNA sequences comprising a 1281th base (polymorphic site) C and comprising the 1281th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 41, a polynucleotide-41 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base of T and a 201 base (polymorphic site); A polynucleotide consisting of the DNA sequence of SEQ ID NO: 42, a polynucleotide-42 consisting of 10 to 100 contiguous DNA sequences including a 483th base (polymorphic site) G and comprising the 483th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 43, polynucleotide-43 consisting of 10 to 100 contiguous DNA sequences comprising the 222nd base of the 222nd base (polymorphic site) A; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 44, a polynucleotide-44 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) is A and the 301 th base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 45, wherein the 287th base (polymorphic site) is G and polynucleotide-45 consisting of 10 to 100 contiguous DNA sequences comprising said 287th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 46, a polynucleotide-46 consisting of 10 to 100 contiguous DNA sequences comprising a 201 base (polymorphic site) A and comprising the 201 base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 47, the polynucleotide-47 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) is T and the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 48, a polynucleotide-48 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) G and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 49, a polynucleotide-49 consisting of 10 to 100 contiguous DNA sequences including the 201 base of G and a 201 base (polymorphic site); In the polynucleotide consisting of a DNA sequence of SEQ ID NO: 50, the 501th base (polymorphic site) is G, Polynucleotide-50 consisting of 10 to 100 consecutive DNA sequences comprising the 501th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 51, a polynucleotide-51 consisting of 10 to 100 contiguous DNA sequences comprising a 501st base (polymorphic site) G and comprising the 501th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 52, polynucleotide-52 consisting of 10 to 100 consecutive DNA sequences comprising the 501th base (polymorphic site) C and comprising the 501th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 53, polynucleotide-53 consisting of 10 to 100 contiguous DNA sequences comprising the 301 th base (polymorphic site) G and comprising the 301 th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 54, polynucleotide-54 consisting of 10 to 100 consecutive DNA sequences comprising the 301th base (polymorphic site) C and comprising the 301th base; In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 55, polynucleotide-55 consisting of 10 to 100 contiguous DNA sequences comprising the 251 st base (polymorphic site) C and comprising the 251 st base; A polynucleotide consisting of the DNA sequence of SEQ ID NO: 56, wherein the 254th base (polymorphic site) is A and is composed of 10 to 100 contiguous DNA sequences comprising the 254th base; In a polynucleotide consisting of the DNA sequence of SEQ ID NO: 57, polynucleotide-57 consisting of 10 to 100 contiguous DNA sequences comprising the 747 base (G) and G comprising the 747 base; And a polynucleotide consisting of the DNA sequence of SEQ ID NO: 58, one from the group consisting of polynucleotide-58 consisting of 10 to 100 contiguous DNA sequences comprising the 301th base (polymorphic site) G and comprising the 301th base Provided above is a polynucleotide selected or complementary polynucleotides thereof.

상기 서열번호 1 내지 58의 DNA 서열은 TDI-유발성 천식 환자군과 정상인군에서 통계학적으로 유의성 있는 차이(유의수준 p value < 0.0001)를 보이는 단일염기다형이다. 본 발명자들은 한국인 TDI-유발성 천식 환자 84명과 정상인 263명을 대상으로 유전자형 분석 및 통계학적 분석을 수행하였으며, 놀랍게도 수많은 단일염기다형 중 약 54개의 단일염기다형이 TDI-유발성 천식 환자군과 정상인군에서 통계적으로 유의성 있는 차이를 나타낸다는 것을 발견하였으며, 또한 fine mapping 과 연관성 분석읕 통하여 4종의 단일염기다형이 TDI-유발성 천식 환자군과 정상인군에서 통계적으로 유의성 있는 차이를 나타낸다는 것을 발견하였다.The DNA sequences of SEQ ID NOs: 1 to 58 are monobasic polymorphisms showing statistically significant difference (significance level p value <0.0001) in the TDI-induced asthma patient group and the normal group. We performed genotyping and statistical analysis on 84 Korean TDI-induced asthma patients and 263 normal patients. We found statistically significant differences in, and also found that four single nucleotide polymorphisms showed statistically significant differences in TDI-induced asthma and normal subjects.

본 발명은 상기 폴리뉴클레오티드-1 내지 58로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드와 혼성화하는 폴리뉴클레오티드를 포함하며, 상기 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드의 길이는 10 내지 100 뉴클레오티드, 바람직하게는 20 내지 60 뉴클레오티드, 더욱 바람직하게는 40 내지 60 뉴클레오티드이다. The present invention includes a polynucleotide hybridizing with at least one polynucleotide selected from the group consisting of the polynucleotides 1 to 58 or complementary polynucleotides thereof, and the length of the polynucleotide or the complementary polynucleotides thereof is 10 to 100 nucleotides. , Preferably 20 to 60 nucleotides, more preferably 40 to 60 nucleotides.

본 발명에 따른 상기 폴리뉴클레오티드-1 내지 58로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드는 다형성 서열이다. 다형성 서열 (polymorphic sequence)이란 뉴클레오티드 서열 중에 단일염기다형을 나타내는 다형성 부위 (polymorphic site)를 포함하는 서열을 말한다. 다형성 부위 (polymorphic site)란 다형성 서열 중 단일염기다형이 일어나는 부위를 말한다. 상기 폴리뉴클레오티드는 DNA 또는 RNA가 될 수 있다.At least one polynucleotide selected from the group consisting of the polynucleotides 1 to 58 according to the present invention is a polymorphic sequence. A polymorphic sequence refers to a sequence comprising a polymorphic site representing a monobasic polymorphism in a nucleotide sequence. A polymorphic site refers to a site where a monobasic polymorphism occurs in the polymorphic sequence. The polynucleotide can be DNA or RNA.

본 발명은 또한, 상기 폴리뉴클레오티드-1 내지 58로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진, TDI-유발성 천식 진단을 위한 증폭용 대립형질 특이적 프라이머를 포함한다. 여기서 "프라이머(primer)"란 적절한 버퍼 중의 적절한 조건 (예를 들면, 4개의 다른 뉴클레오시드 트리포스페이트(ATP,GTP,CTP,TTP) 및 DNA 폴리머라제) 및 적당한 온도 하에서 주형-지시 DNA 합성의 시작점으로서 작용할 수 있는 단일가닥 올리고뉴클레오티드를 말한다. 상기 프라이머의 적절한 길이는 사용 목적에 따라 달라질 수 있으나, 통상 10 내지 100, 바람직하게는 10 내지 80 뉴클레오티드이다. 짧은 프라이머 분자는 일반적으로 주형과 안정한 혼성체를 형성하기 위해서는 더 낮은 온도를 필요로 한다. 프라이머 서열은 주형과 완전하게 상보적일 필요는 없으나, 주형과 혼성화 할 정도로 충분히 상보적이어야 한다. 상기 프라이머는 3'-말단이 서열번호 1 내지 58의 단일염기다형과 정렬하는 것이 바람직하다. 상기 프라이머는 다형성 부위를 포함하는 표적 DNA에 혼성화하고, 상기 프라이머가 완전한 상동성을 보이는 대립형질 형태의 DNA에서 증폭을 개시한다. 이 프라이머는 반대편에 혼성화하는 제2 프라이머와 쌍을 이루어 사용된다. 증폭에 의하여 두 개의 프라이머로부터 산물이 증폭되고, 증폭된 산물만을 특이적으로 염색하여 시각화한다. 이는 특정 대립형질 형태가 존재한다는 것을 의미한다. 여기서 사용되는 대립형질 특이적 폴 리뉴클레오티드들이 다른 변성화 과정을 거치게 되면, InfiniumTM Assay I 뿐만 아니라 다른 방법들에 의해서도 사용될 수 있다. The invention also includes an allele specific primer for amplification for TDI-induced asthma diagnosis, consisting of at least one polynucleotide selected from the group consisting of polynucleotides 1 to 58 or complementary polynucleotides thereof. “Primer” herein refers to the synthesis of template-directed DNA synthesis under appropriate conditions (eg, four different nucleoside triphosphates (ATP, GTP, CTP, TTP) and DNA polymerase) in a suitable buffer and at a suitable temperature. It refers to a single stranded oligonucleotide that can act as a starting point. The appropriate length of the primer may vary depending on the purpose of use, but is usually 10 to 100, preferably 10 to 80 nucleotides. Short primer molecules generally require lower temperatures to form stable hybrids with the template. The primer sequence need not be completely complementary to the template, but should be sufficiently complementary to hybridize with the template. The primer is preferably 3'-terminal alignment with the monobasic polymorphism of SEQ ID NO: 1 to 58. The primer hybridizes to the target DNA comprising the polymorphic site and initiates amplification in allelic form of DNA where the primer exhibits complete homology. This primer is used in pairs with a second primer that hybridizes to the other side. The product is amplified from two primers by amplification, and only the amplified product is specifically stained and visualized. This means that certain allelic forms exist. If the allele-specific polynucleotides used herein undergo different denaturation processes, they may be used by other methods as well as Infinium ™ Assay I.

본 발명은 폴리뉴클레오티드-1 내지 58로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드로 이루어진, TDI-유발성 천식 진단용 프로브 및 이를 포함하는 TDI-유발성 천식 진단용 마이크로어레이를 포함한다. 또한, 본 발명은 폴리뉴클레오티드-1 내지 58로 이루어진 군으로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 포함하는, TDI-유발성 천식 진단용 키트를 포함한다.The present invention includes a TDI-induced asthma diagnostic probe and a TDI-induced asthma diagnostic microarray comprising the polynucleotide-1 to 58 or one or more complementary polynucleotides thereof. The present invention also includes a kit for diagnosing TDI-induced asthma comprising at least one polynucleotide selected from the group consisting of polynucleotides 1 to 58 or complementary polynucleotides thereof.

본 발명은 TDI-유발성 천식 진단에 필요한 정보를 제공하기 위하여, (i) 검체로부터 핵산 시료를 얻는 단계; 및 (ii) 상기 핵산 시료로부터, 서열번호 1 내지 58의 폴리뉴클레오티드로부터 하나 이상 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드의 다형성 부위의 염기 서열을 분석하는 단계 (단, 상기 다형성 부위는 상기에서 정의한 바와 같다)를 포함하는, 검체 중의 단일염기다형을 검출하는 방법을 포함한다.The present invention provides a method for diagnosing TDI-induced asthma, comprising the steps of: (i) obtaining a nucleic acid sample from a sample; And (ii) analyzing the nucleotide sequence of the polymorphic site of at least one polynucleotide selected from polynucleotides of SEQ ID NOs: 1 to 58 or complementary polynucleotides thereof from the nucleic acid sample, wherein the polymorphic site is as defined above Method for detecting a monobasic polymorph in a sample.

상기 검체는 혈액, 조직, 세포 등을 포함하며, 핵산 시료는 통상의 방법에 따라 얻을 수 있다. 예를 들어 혈액에 경우 다음과 같이 핵산 시료를 얻을 수 있다. 혈액을 원심분리 시험관으로 옮기고 낮은 농도의 염 성분 완충용액(low-salt buffer solution(10mM Tris-HCl [pH 7.6], 10mM KCl, 10mM MgCl2, 및 2mM EDTA))을 첨가한다. 그리고 Nonidet P-40을 첨가한 다음, 얻어진 용액을 잘 섞어준 후, 상온 에서 10분간 약 2,200 rpm으로 원심분리한다. 이때 얻어진 덩어리는 고농도의 염 성분 완충용액(high-salt buffer solution(10mM Tris-HCl [pH 7.6], 10mM KCl, 10mM MgCl2, 0.4M NaCl, 및 2mM EDTA))으로 재현탁한다. 게놈 DNA는 50ul의 10% SDS와 섞은 후, 약 55℃에서 밤새 반응시킨다. 반응 후에, 각 게놈 DNA들은 1.5ml 용량의 원심분리 시험관으로 옮겨, 6M NaCl을 0.3ml 첨가한다. 게놈 DNA들을 잘 섞어준 후, 약 12,000rpm에서 10분간 원심분리한다. 원심분리 후, 게놈 DNA가 들어있는 상층을 모아서 새로운 시험관으로 옮기고, 상온에서 동량의 100% 에탄올을 첨가한다. 게놈 DNA들이 침전될 때까지 잘 섞어 주고, 침전이 되면 70% 에탄올로 게놈 DNA들을 세척한다. 이 과정이 끝나면 시험관 뚜껑을 열어, 용액성분이 마르도록 놓아둔다. 그리고 TE 완충용액(pH 8.0)을 넣어 게놈 DNA를 재현탁함으로써, 핵산 시료를 얻을 수 있다.The sample includes blood, tissue, cells, and the like, and a nucleic acid sample can be obtained according to a conventional method. For example, in the case of blood, a nucleic acid sample can be obtained as follows. Transfer blood to a centrifuge tube and add low concentrations of salt component buffer (10 mM Tris-HCl [pH 7.6], 10 mM KCl, 10 mM MgCl 2 , and 2 mM EDTA). After adding Nonidet P-40, the resulting solution was mixed well and centrifuged at about 2,200 rpm for 10 minutes at room temperature. The resulting mass is resuspended in a high concentration of salt component buffer (10 mM Tris-HCl [pH 7.6], 10 mM KCl, 10 mM MgCl 2 , 0.4M NaCl, and 2 mM EDTA). Genomic DNA is mixed with 50ul of 10% SDS and reacted at about 55 ° C overnight. After the reaction, each genomic DNA is transferred to a 1.5 ml centrifuge tube and 0.3 ml of 6 M NaCl is added. After mixing the genomic DNA well, centrifuge for 10 minutes at about 12,000rpm. After centrifugation, the upper layer containing genomic DNA is collected, transferred to a new test tube, and the same amount of 100% ethanol is added at room temperature. Mix the genomic DNA well until it is settled, and wash the genomic DNA with 70% ethanol when settling. At the end of this procedure, open the test tube lid and allow the solution to dry. The nucleic acid sample can be obtained by resuspending genomic DNA by adding TE buffer solution (pH 8.0).

여기에서, 상기 다형성 부위의 염기 서열을 분석하는 단계는 서열번호 1 내지 58의 폴리뉴클레오티드로 이루어진 군으로부터 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드 서열로서 다형성 부위를 포함하는 서열(단, 상기 다형성 부위는 상기에서 정의한 바와 같다)을 주형으로 하는 프라이머 또는 프로브를 이용하여 수행될 수 있다. 상기 프라이머 또는 프로브는 상기에서 설명한 바와 같다. Here, the step of analyzing the nucleotide sequence of the polymorphic site is a sequence comprising a polymorphic site as a polynucleotide or a complementary polynucleotide sequence thereof selected from the group consisting of polynucleotides of SEQ ID NOs: 1 to 58, wherein the polymorphic site is It can be carried out using a primer or a probe (as defined above) as a template. The primer or probe is as described above.

또한, 상기 다형성 부위의 염기 서열을 분석하는 단계는 폴리뉴클레오티드-1 내지 58로 이루어진 군으로부터 선택된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴 클레오티드가 고정된 마이크로어레이에 상기 핵산 시료를 혼성화시키는 단계 (단, 상기 폴리뉴클레오티드-1 내지 58은 상기에서 정의한 바와 같다); 및 얻어진 혼성화 결과를 분석하는 단계를 포함하여 수행될 수 있으며, 상기 마이크로어레이에 고정되는 폴리뉴클레오티드 또는 그의 상보적 뉴클레오티드의 DNA 서열의 길이는 각각 10 내지 100 뉴클레오티드일 수 있다.In addition, analyzing the nucleotide sequence of the polymorphic site comprises hybridizing the nucleic acid sample in a microarray to which a polynucleotide selected from the group consisting of polynucleotides 1 to 58 or a complementary polynucleotide thereof is immobilized, provided that Polynucleotide-1 to 58 are as defined above); And analyzing the obtained hybridization results, wherein the lengths of the DNA sequences of the polynucleotides or complementary nucleotides immobilized on the microarrays may be 10 to 100 nucleotides, respectively.

본 발명의 검체 중의 단일염기다형을 검출하는 방법에 따라 얻어진 결과는 TDI-유발성 천식 진단에 필요한 정보를 제공할 수 있으며 예를 들어, 서열번호 1 내지 58의 다형성 부위의 염기가 위험 대립인자(표 2a, 2b, 및 4 참조)인 것이 하나 이상 존재하는 경우, TDI-유발성 천식에 걸릴 확률이 높은 위험군에 속하는 것으로 판정할 수 있다. 상기 위험 대립 인자를 갖는 핵산 서열이 하나의 검체에서 많이 검출되면 될수록 위험군에서 속하는 확률은 더 높은 것으로 판단할 수 있다. The results obtained according to the method for detecting a monobasic polymorphism in a sample of the present invention may provide information necessary for diagnosing TDI-induced asthma, for example, the base of the polymorphic site of SEQ ID NOs: 1 to 58 may be a risk allele ( If one or more of those present in Tables 2a, 2b, and 4 are present, it may be determined that they belong to a high risk group of TDI-induced asthma. The more the nucleic acid sequence having the risk allele is detected in one sample, the higher the probability of belonging to the risk group can be determined.

또한, 상기 다형성 부위의 염기 서열을 분석하는 단계는 서열번호 1 내지 58의 DNA 서열로 이루어진 군으로부터 선택된 DNA 서열의 다형성 부위의 유전자형(genotype) 분석을 포함할 수 있다. 예를 들어, 서열번호 2의 다형성 부위의 유전자형이 G/G, 서열번호 6의 다형성 부위의 유전자형이 G/G, 서열번호 10의 다형성 부위의 유전자형이 T/T인 경우, TDI-유발성 천식에 걸릴 위험도가 높은 것으로 판단할 수 있다. 상기 위험 유전자형을 갖는 핵산 서열이 하나의 검체에서 많이 검출되면 될수록 위험군에서 속하는 확률은 더 높은 것으로 판단할 수 있다.In addition, analyzing the base sequence of the polymorphic site may include genotype analysis of the polymorphic site of the DNA sequence selected from the group consisting of DNA sequences of SEQ ID NOs: 1 to 58. For example, if the genotype of the polymorphic site of SEQ ID NO: 2 is G / G, the genotype of the polymorphic site of SEQ ID NO: 6 is G / G, and the genotype of the polymorphic site of SEQ ID NO: 10 is T / T, TDI-induced asthma The risk of getting sick can be judged to be high. The more the nucleic acid sequence having the risk genotype is detected in one sample, the higher the probability of belonging to the risk group can be determined.

본 발명은 또한, TDI-유발성 천식 진단에 필요한 정보를 제공하기 위하여, (i) 검체로부터 핵산 시료를 얻는 단계; 및 (ii) 상기 핵산 시료로부터 반수체 형(haplotype)을 분석하는 단계를 포함하는, 검체 중의 단일염기다형을 검출하는 방법을 포함한다. 예를 들어, 상기 반수체형 분석은 상기 핵산 시료로부터, 서열번호 2 및 6의 DNA 서열의 다형성 부위로부터 결정되는 반수체형을 분석함으로써 수행될 수 있다. 즉, 서열번호 2 및 6의 DNA 서열의 다형성 부위로부터 결정된 반수체형 분석결과, 서열번호 2 및 6의 DNA 서열이 연관 비평형 블록을 형성하였으며, 서열번호 2 및 6의 DNA 서열이 GG (ht2) 반수체형을 가지는 경우, 그렇지 않은 사람보다 TDI-유발성 천식에 걸릴 위험이 높은 것으로 판정할 수 있으며, CA (ht1)로 나타내는 경우 TDI-유발성 천식에 저항성을 갖는 것으로 판정할 수 있다 (표 3, 도 1 참조).The present invention also provides a method for the diagnosis of TDI-induced asthma, comprising the steps of: (i) obtaining a nucleic acid sample from a sample; And (ii) analyzing haplotypes from the nucleic acid sample. For example, the haplotype analysis may be performed by analyzing the haplotype determined from the polymorphic site of the DNA sequence of SEQ ID NOs: 2 and 6 from the nucleic acid sample. That is, the haplotype analysis determined from the polymorphic sites of the DNA sequences of SEQ ID NOs: 2 and 6 showed that the DNA sequences of SEQ ID NOs: 2 and 6 formed an associative non-equilibrium block, and that the DNA sequences of SEQ ID NOs: 2 and 6 were GG (ht2). If you have haplotypes, you can determine that you have a higher risk of developing TDI-induced asthma than those who do not, and if you represent CA (ht1), you can determine that you are resistant to TDI-induced asthma (Table 3). , See FIG. 1).

이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

실시예 Example

1. 시험 방법1. Test Method

(1) 피검자 선정(1) Selection of subjects

본 연구에서는 TDI에 쉽게 노출되는 직업인 가구나 악기 만드는 회사에서 스프레이 페인팅을 하거나 윤을 내는 부서에 종사하여 TDI-유발성 천식이 유발된 환자를 연구 대상으로 하였다. TDI에 의한 직업성 천식 환자는 이전에 보고된 방법대로 (Park HS et al, J Allergy Clin Immunol 1999; 104:847-51) 뚜렷한 직업력과 노출에 따른 천식 증상 악화 등의 전형적인 병력과 함께 메타콜린 및 TDI를 이용한 기관지유발시험을 통하여 확진하였다. TDI-유발성 천식 환자 83명과 일반 대조군 263명에 대한 샘플은 아주대, 순천향대, 인하대, 연세대 병원에서 상호협력에 의해 모은 것을 대상으로 하였다. TDI-유발성 천식 환자는 모두 각 병원에서 실시한 TDI 기관지유발시험에서 양성 반응을 보였다. 본 연구에 참가한 사람들은 모두 설문지와 엑스선 촬영, 피부반응 검사, 메타콜린 기관지 유발검사, 원인 항원 유발 검사, 혈청 총 IgE, 특이 IgE 및 IgG , CK에 대한 항체 검사, 폐기능 검사를 실시하였다. In this study, a study was conducted on patients with TDI-induced asthma who worked in a spray painting or polishing department at a furniture or musical instrument making company that is easily exposed to TDI. Occupational asthma patients with TDI follow the previously reported method (Park HS et al, J Allergy Clin Immunol 1999; 104: 847-51), with a typical history of asthma symptoms associated with a marked occupational history and exposure. Confirmed by bronchial induction test using TDI. Samples of 83 TDI-induced asthma patients and 263 general control subjects were collected from the cooperative work at Ajou University, Soonchunhyang University, Inha University, and Yonsei University Hospital. All TDI-induced asthma patients were positive in the TDI bronchial challenge test at each hospital. All participants in this study were questionnaire, X-ray, skin test, methacholine bronchial challenge test, causative antigen challenge test, serum total IgE, specific IgE and IgG, CK antibody test, lung function test.

(2) TDI와 메타콜린 기관지유발시험(2) TDI and methacholine bronchial challenge test

TDI-유발성 천식 환자는 이전에 발표된 논문의 프로토콜에 따라 시행한 메타콜린 기관지유발시험과 TDI 기관지유발시험에서 양성 반응을 확인하였다 (Park HS et al, J Allergy Clin Immunol 1999; 104:847-51 및 Ye et al, Clin Exp Allergy 2006; 36: 1153-60). 메타콜린 기관지유발시험은 Chai등이 기술한 방법을 변형하여 시행하였다 (Chai et al, J Allergy Clin Immunol 1975; 56: 323-327). 메타콜린을 생리식염수로 희석하여 0.075, 0.15, 0.31, 0.62, 1.25, 2.5, 5, 10, 25, 50 mg/ml 농도로 준비하였다. 흡입방법은 Dosimeter (De Vilbiss, USA)를 이용하여 각 농도를 5회 흡입하고 3분을 관찰한 후 폐기능을 측정하였다. 검사 중 FEV1 20% 이상 감소하며 중단하고, 기관지확장제를 투여하여 가역성 여부를 판단하였다. PC20치가 25mg/ml 이하인 경우를 메타콜린 시험 양성으로 판정하였다.Patients with TDI-induced asthma were positive in the methacholine bronchial challenge test and TDI bronchial challenge test in accordance with the protocol of a previously published paper (Park HS et al, J Allergy Clin Immunol 1999; 104: 847-). 51 and Ye et al, Clin Exp Allergy 2006; 36: 1153-60. Methacholine bronchial challenge was performed by a modification of the method described by Chai et al. (Chai et al, J Allergy Clin Immunol 1975; 56: 323-327). Methacholine was diluted with physiological saline to prepare a concentration of 0.075, 0.15, 0.31, 0.62, 1.25, 2.5, 5, 10, 25, 50 mg / ml. Inhalation was performed by Dosimeter (De Vilbiss, USA), and each lung was inhaled 5 times, and 3 minutes were observed for pulmonary function. FEV 1 was stopped by more than 20% during the test, and bronchodilator was administered to determine reversibility. When the PC 20 value was 25 mg / ml or less, it was judged as methacholine test positive.

TDI 기관지 유발 시험은 복용했던 약물을 24시간 이상 중단한 후 시행하였 다. Devilbiss 646 nebulizer로 생리식염수를 상시 호흡량으로 10회 흡입하고 폐기능 검사를 시행하여 FEV1을 측정하여 이를 기저치로 하였다. TDI 기관지 유발시험은 작은 밀폐된 방에서 TDI(80:20 =2,4 form:2, 4-form:2, 6-form, Sigma-Aldrich,St. Louis,MO,USA)를 5분에서 15분까지, 천식증상이 나타날 때까지 흡입하도록 하였으며, 이때 유독가스 측정기인 TLD-1(MDA Scientific, USA)로 측정한 TDI의 농도는 20ppb 이하이었다. 흡입 후 첫 1시간 동안은 10분마다 3회, 30분마다 1회 폐 기능 검사를 시행하였으며, 후기 반응을 관찰하기 이해 7시간까지 매시간 폐 기능검사를 시행하여 FEV1이 기저치 보다 20%이상 감소하는 경우를 양성반응으로 간주하였다. The TDI bronchial challenge test was performed after stopping the drug for more than 24 hours. Devilbiss 646 nebulizer was used to inhale 10 times of normal saline with normal respiratory volume and pulmonary function test to measure FEV1 as baseline. TDI bronchial challenge tests were performed in small, closed rooms with TDI (80:20 = 2,4 form: 2, 4-form: 2, 6-form, Sigma-Aldrich, St. Louis, MO, USA) from 5 minutes to 15 minutes. Inhalation was performed until asthma symptoms appeared, and the concentration of TDI measured by TLD-1 (MDA Scientific, USA), a toxic gas detector, was 20 ppb or less. After the intake for the first time is three times, one time lung function decreased by more than 20% FEV 1 than baseline to conduct every time pulmonary function tests to test was performed, to observe the late phase response understanding 7 hours every 30 minutes, every 10 minutes Was considered a positive reaction.

(3) 사이토케라틴(Cytokeratin)에 대한 특이 항체측정(3) Specific antibody measurement against cytokeratin

CK18 과 CK19에 대한 혈청 특이 IgG 항체는 이전에 나온 논문을 토대로 ELISA (enzyme-linked immunosorbent assay)방법을 통해 측정하였다 (Park et al, Clin Exp Allergy 2002; 32:198-204; 및 Ye et al, Clin Exp Allergy 2006; 36: 1153-60). 환자의 혈청이나 음성대조군 혈청을 1:200으로 희석시킨 50 ul를 PBS에 녹아있는 CK8, CK18, CK19 100 ng/well 로 부착된 ELISA 플레이트의 모든 well에 추가 하여 블록킹 완충액(10% 소태아혈청(FBS)이 포함된 PBS) 200 ul으로 차단하였다. 실온에서 1시간 정도 인큐베이션한 후에 플레이트를 PBS-T로 세번 세척하였다. 10% FBS-PBS에 1:10000으로 희석한 Alkaline phosphatase-conjugated antihuman IgG (100 ul; Sigma-Aldrich)를 37℃에서 한 시간 동안 반응시킨 후 PBS-T로 세척 한 후 기질용액으로 p-nitro-phenyl phosphate (Sigma-Aldrich)를 추가하였다. 그 후 1 N NaOH를 더하여 반응을 정지시켰다. 용액의 OD(optical density)는 405 nm에서 측정하였다. 최종 흡광도는 음성 blank의 흡광도로 보정하여 계산하였다. 흡광도는 standard curve 판독 범위 내에서 측정하였다.Serum specific IgG antibodies against CK18 and CK19 were measured by an enzyme-linked immunosorbent assay (ELISA) based on the previous paper (Park et al, Clin Exp Allergy 2002; 32: 198-204; and Ye et al, Clin Exp Allergy 2006; 36: 1153-60. 50 ul diluted 1: 200 of the patient's serum or negative control serum was added to all wells of the ELISA plate attached with CK8, CK18, CK19 100 ng / well dissolved in PBS and added to the blocking buffer (10% fetal bovine serum) FBS) was blocked with 200 ul of PBS). After incubation for about 1 hour at room temperature the plates were washed three times with PBS-T. Alkaline phosphatase-conjugated antihuman IgG (100 ul; Sigma-Aldrich) diluted 1: 10000 in 10% FBS-PBS was reacted for 1 hour at 37 ° C, washed with PBS-T, and then p-nitro- with substrate solution. phenyl phosphate (Sigma-Aldrich) was added. Then 1 N NaOH was added to stop the reaction. Optical density (OD) of the solution was measured at 405 nm. The final absorbance was calculated by calibrating the absorbance of the negative blank. Absorbance was measured within the standard curve reading range.

(4) Affymetrix SNP 칩을 이용한 단일 염기 다형성 분석(4) Single nucleotide polymorphism analysis using Affymetrix SNP chip

Affymetrix GeneChip Human Mapping 500K Array(Affymetrix,Santa Clara,CA,USA) 를 사용하여 347명의 샘플을 유전자형분석(genotyping)을 하였다. Mapping assay는 각각 대략 262,000의 SNP를 포함하는 Nsp I array와 238,000인 Sty I arrays로 구성되어 있다. 대략 250 ng의 게놈 DNA가 Affymetrix사의 프로토콜에 따라 Nsp I 와 Sty I 에 융합되어 있다. 게놈 DNA를 각각 Nsp I 또는 Sty I 제한효소로 자르고 여기에 linker DNA를 ligation하여 universal PCR이 가능하도록 하였다. 이들 시료를 PCR로 증폭하고 다시 fragmentation 한 후에 end-labeling 한다. 이후에 유전자칩(genechip)에 혼성화시켜 각 스팟에서 시그날을 분석하였다. BRLMM 알고리즘을 이용하여 유전자형을 불러오게 된다.347 samples were genotyped using an Affymetrix GeneChip Human Mapping 500K Array (Affymetrix, Santa Clara, CA, USA). The mapping assay consists of an Nsp I array containing approximately 262,000 SNPs and a Sty I array of 238,000. Approximately 250 ng of genomic DNA is fused to Nsp I and Sty I according to Affymetrix's protocol. Genomic DNA was cut with Nsp I or Sty I restriction enzyme, respectively, and ligation of linker DNA was performed to enable universal PCR. These samples are amplified by PCR and re-fragmented before end-labeling. Thereafter, hybridization was carried out on a genechip to analyze signals at each spot. Genotypes are retrieved using the BRLMM algorithm.

(5) SNP칩 데이터 필터링(5) SNP chip data filtering

SNP CHIP 데이터 50만개를 1차 품질관리(Quality control)를 이용하여 20만개의 SNP를 제외 시켰다. PLINK 프로그램(http://pngu.mgh.harvard.edu/~purcell/plink)을 이용하여 생 데이터(raw data)의 품질관리(Quality control)을 통해 필터링을 진행하였다. QQ plot을 이용하여 call rate가 95% 이상을 기준으로 잡았으며 X-염색체의 이형접합성 (Heterozygosity)은 각 샘플의 성별을 구별한다. SNP들 중 call rate가 95% 이하이거나 minor allele frequency가 5%미만, 정상인에서 Hardy-Weinberg equilibrium(H.W.E.) (p < 0.0001)인 177,316개의 SNP가 제외되었다. 또한 연관성 분석에서 p-value<0.0001 이하의 SNP들을 대상으로 TDI-유발성 천식과 정상인의 군집 품질 관리(Cluster quality control)를 진행하였다. 군집 품질 관리는 각각의 SNP가 3가지의 유전자형으로 독립적으로 읽혀졌는지를 파악할 수 있게 유전자형 종류별로 그룹을 이룬 이미지 파일로 분석하였다. 1차 품질관리를 통과하였더라도 유전자형의 분포가 군집을 명확하게 이루고 있지 않을 경우 제외시켰다.500,000 SNP CHIP data were excluded from 200,000 SNPs using primary quality control. Filtering was performed through quality control of raw data using the PLINK program (http://pngu.mgh.harvard.edu/~purcell/plink). The call rate was set to 95% or more using the QQ plot, and the heterozygosity of the X-chromosome distinguishes the sex of each sample. Among the SNPs, 177,316 SNPs with a Hardy-Weinberg equilibrium (HWE) ( p <0.0001) were excluded from normal subjects with a call rate of less than 95% or a minor allele frequency of less than 5%. In the correlation analysis, TDI-induced asthma and cluster quality control (Cluster quality control) of SNPs with p-value <0.0001 were performed. Cluster quality control was analyzed in image files grouped by genotype to determine whether each SNP was read independently of the three genotypes. Even if primary quality control passes, the distribution of genotypes is excluded unless the population is clearly defined.

(6) 통계적 분석(6) statistical analysis

표본집단 안에서 각 유전자의 Hardy-Weinberg Equilibrium (H.W.E.)을 분석하기 위해 순열 검정 테스트(permutation test)를 실시하였다. 모든 단일염기 다형성과 TDI-유발성 천식과의 연관성 분석을 위해 모수적 방법인 chi-square 테스트, 비모수적 방법인 Cochran-Armitage trend 테스트를 사용하였다. 또한 TDI-유발성 천식 환자와 정상인 간의 유전자형(genotype)과 반수체형(haplotype) 분석은 세 가지 유전적 모델 (dominant, recessive, codominant)을 성별과 나이로 보정한 로지스틱 회귀 (logistic regression) 분석을 이용하여 연관성 분석을 실시하였다. 오즈비 (Odds ratio)와 신뢰구간 (confidence interval)은 SAS (version9.1.3: SAS Institute Inc.,Cary,NC,USA)를 이용하여 chi-square 테스트로 구하였다. Haplotype은 Stephens 등 (PHASE version 2.1)에 의해 개발된 알고리즘으로 추론하였다. 유전자형(genotype)과 표현형 (phenotype)간의 분석은 T-테스트와 Mann- Whiteny 테스트를 이용하였다.Permutation tests were performed to analyze the Hardy-Weinberg Equilibrium (H.W.E.) of each gene in the population. The parametric chi-square test and the nonparametric Cochran-Armitage trend test were used to analyze the association between all monobasic polymorphisms and TDI-induced asthma. In addition, genotype and haplotype analysis between TDI-induced asthma patients and normal humans uses logistic regression analysis, in which three genetic models (dominant, recessive, and codominant) are corrected by gender and age. Correlation analysis was performed. Odds ratio and confidence interval were obtained by chi-square test using SAS (version 9.1.3: SAS Institute Inc., Cary, NC, USA). Haplotype was inferred from the algorithm developed by Stephens et al. (PHASE version 2.1). The analysis between genotype and phenotype was performed using T-test and Mann-Whiteny test.

2. 시험결과2. Test result

(1) TDI-유발성 천식 환자의 임상적 특성(1) Clinical characteristics of TDI-induced asthma patients

TDI-유발성 천식 환자의 평균나이는 41.21세(±9.56)이고 대조군은 48.4세(±9.86)이다(표 1 참조). 두 그룹에서 남성이 차지하는 비율이 더 높았지만 (TDI-유발성 천식 환자 67.9%, 대조군 63.87%), 성비는 차이가 없었다. 이전에 발표된 논문(Ye et al., Clin Exp Allergy 2006; 36: 1153-60)을 참고하면 정상인의 혈청 특이 IgG의 빈도가 보통 3.3% 인데 반해 TDI-유발성 천식 환자의 경우 CK18에 대한 혈청 특이 IgG의 빈도가 15.6%, CK19에 대한 특이 IgG의 빈도는 24.4%로 정상인에 비해 높은 수치를 보였다. The mean age of TDI-induced asthma patients was 41.21 years (± 9.56) and the control group was 48.4 years (± 9.86) (see Table 1). The proportion of men in both groups was higher (67.9% in TDI-induced asthma, 63.87% in the control group), but there was no difference in sex ratio. In a previously published paper (Ye et al., Clin Exp Allergy 2006; 36: 1153-60), the serum specific IgG levels in normal subjects were usually 3.3%, whereas serum for CK18 in TDI-induced asthma patients. The frequency of specific IgG was 15.6% and the frequency of specific IgG for CK19 was 24.4%, which was higher than that of normal people.

　 TDI-유발성 천식 환자TDI-Induced Asthma Patients 정상인Normal p-valuep-value 나이(년)Age (years) 41.21±9.56/8441.21 ± 9.56 / 84 48.4±9.86/26348.4 ± 9.86 / 263 <0.001<0.001 성 (남성)Sex (male) 57/84 (67.9%)57/84 (67.9%) 168/263(63.87%)168/263 (63.87%) NSNS Atopy (presence/total)Atopy (presence / total) 30/62 (48.4%)30/62 (48.4%) NANA NANA Exposure duration (year)Exposure duration (year) 6.86±4.85/426.86 ± 4.85 / 42 NANA NANA Baseline FEV1 (%)Baseline FEV1 (%) 87.64±20.84/6387.64 ± 20.84 / 63 NANA NANA PC20 methacholine (mg/mL)PC20 methacholine (mg / mL) 5.36±8.02/615.36 ± 8.02 / 61 NANA NANA 혈청 총 IgE (IU/mL)Serum Total IgE (IU / mL) 261.88±334.99/67261.88 ± 334.99 / 67 NANA NANA CK18에 대한 특이 IgG (%)Specific IgG for CK18 (%) 7/45 (15.6%)7/45 (15.6%) NANA NANA CK19에 대한 특이 IgG (%)Specific IgG for CK19 (%) 11/45 (24.4%)11/45 (24.4%) NANA NANA

* NS: 유의성 없음(not significant)* NS: not significant

* NA: 비적용(not applicable)NA: not applicable

(2) 유의성 있는 차이를 나타내는 단일염기다형의 분석(2) Analysis of monobasic polymorphisms showing significant differences

Affymetrix 500K 유전자칩 마이크로어레이를 이용하여 TDI-유발성 천식 환자 84명과 TDI에 노출되지 않은 건강한 대조군 263명을 대상으로 전체 게놈 연관성 분석 (genome-wide association study)를 진행하였다. 서로 관계가 없는 대조군과 비교군 샘플의 초기 분석에 대해, 관찰 p-value 와 기대 p-value 를 비교하여 QQ (quality-quality) plot을 그려 연관성 분석의 분포를 테스트하였다. 실험군과 대조군 사이의 유전자형과 집단 계층(population structure)의 차이가 보이지 않았다. 생 데이터(raw data) 에 대해 1차 품질 관리(quality control) 과 필터링을 통해 유전자형의 call rate가 95% 미만이며, minor-allele frequencies가 5% 미만, H.W.E. 테스트의 p-value가 0.001보다 작은 유전적 변이(SNP)들을 제외한 후, 남은 312,978개의 단일염기다형으로 연관성 분석(association test)을 실시한 결과, p-value < 1 X 10-4 인 54개의 SNP가 정상군과 TDI-유발성 천식 환자에서 유의성있는 차이를 나타냄을 확인하였다(하기 표 2a 및 표 2b 참조).A genome-wide association study was performed on 84 TDI-induced asthma patients and 263 healthy controls not exposed to TDI using an Affymetrix 500K gene chip microarray. For the initial analysis of unrelated control and control samples, the distribution of correlation analysis was tested by drawing a quality-quality (QQ) plot by comparing the observed p-value with the expected p-value. There was no difference in genotype and population structure between the experimental and control groups. First-class quality control and filtering of raw data results in genotyping of less than 95% genotype, less than 5% minor-allele frequencies, and less than 0.001 p-value in HWE tests. After excluding the SNPs, the association test with the remaining 312,978 monobasic polymorphisms revealed that 54 SNPs with p-value <1 X 10 -4 were found in normal and TDI-induced asthma patients. It was confirmed that there was a significant difference (see Table 2a and Table 2b below).

Figure 112009021641276-pat00001
Figure 112009021641276-pat00001

* OR: 각 분석 모델에 따른 공통 유전자형에 대한 위험 유전자형의 오즈 비율, MAF: 소수 대립인자 빈도(minor allele frequency), 95%U: upper bound, 95%L: lower bound* OR: odds ratio of risk genotype to common genotypes for each analytical model, MAF: minor allele frequency, 95% U: upper bound, 95% L: lower bound

Figure 112009021641276-pat00002
Figure 112009021641276-pat00002

* OR: 각 분석 모델에 따른 공통 유전자형에 대한 위험 유전자형의 오즈 비율, MAF: 소수 대립인자 빈도(minor allele frequency), 95%U: upper bound, 95%L: lower bound* OR: odds ratio of risk genotype to common genotypes for each analytical model, MAF: minor allele frequency, 95% U: upper bound, 95% L: lower bound

표 2a 및 2b로부터, CTNNA1과 CTNNA3 두 개의 유전자가 여러 번에 걸쳐 중복되어 나타남을 알 수 있다. CTNNA3는 염색체 10q21에 위치하며 알파 T 카테닌 (α T-catenin)의 한 종류이며 CTNNA3 3개의 SNP (rs10762058, rs7088181, 및 rs4378283)은 성별, 나이로 보정한 로지스틱 회귀분석 회기분석에서 유의성 있는 결과가 나왔다(하기 표 3 참조).From Tables 2a and 2b, it can be seen that the two genes of CTNNA1 and CTNNA3 overlap several times. CTNNA3 is located on chromosome 10q21 and is a type of alpha T-catenin, and three SNPs (rs10762058, rs7088181, and rs4378283) of CTNNA3 have significant results in logistic regression regression analysis by gender and age. (See Table 3 below).

Figure 112009021641276-pat00003
Figure 112009021641276-pat00003

* 상기 표 3에서 rs4378283의 유전자형은 상보적인 염기로 표기된 것이다* Genotype of rs4378283 in Table 3 is expressed as a complementary base

또한 두 개의 SNP (rs10762058 and rs7088181) 에서 강한 연관불균형 (linkage disequilibrium, LD)(D'> 0.9, 도 1 참조)를 보였다. 또한 두 개 유전자 변이의 소수의 반수체형(haplotype)을 가진 haplotype HT2 [GG]의 빈도가 TDI-유발성 천식 환자에서 0.372, 대조군에서 0.242로 빈도수에서 차이를 보이며 TDI-유발성 천식 발생과 연관성이 있는 것으로 보인다 (p = 0.0005, OR = 1.852, 95% CI = 1.273-3.694; 표 3). Haplotype 2를 가진 그룹이 그렇지 않은 그룹보다 메타콜린 PC20 레벨이 유의하게 낮았다(도 2 참조)The two SNPs (rs10762058 and rs7088181) also showed strong linkage disequilibrium (LD) (D '> 0.9, see FIG. 1). In addition, the frequency of haplotype HT2 [GG] with a few haplotypes of the two gene mutations was 0.372 in TDI-induced asthma patients and 0.242 in controls, which was associated with the incidence of TDI-induced asthma. It appears to be ( p = 0.005, OR = 1.852, 95% CI = 1.273-3.694; Table 3). Groups with Haplotype 2 had significantly lower levels of methacholine PC 20 than those without (see FIG. 2).

(3) CTNNA3의 fine mapping 과 연관성 분석(3) Fine mapping and correlation analysis of CTNNA3

앞선 결과에서 CTNNA3 동일 유전자의 여러 다양한 유전자 변이가 p-value <0.0001 에서 유의성 있게 나온 것을 토대로, CTNNA3 의 또 다른 유전적 변이를 찾아보기 위해 CTNNA3 주변 지역인, CTNNA3 의 코딩 서열의 상위지역(upstream) 2kb과 하위지역(downstream) 1kb에 대해 DNA direct sequencing을 실시하였다(도 1 참조). 이 결과로 기존에 알려진 5개의 SNP (rs35289132, rs10997784, rs1941996, rs2924307, 및 rs1786929)와 알려지지 않은 5개의 SNP를 발견하였다 (표 4 참조). Recessive 분석 모델에서 downstream지역에 있는 rs1786929이 TDI-유발성 천식과 유의한 연관성을 보였다 (p = 0.015-성별, 나이로 보정, OR = 1.783, 95% CI = 1.042-3.052; 표 5). rs1786929에서 CT 또는 CC 유전자형을 가진 그룹이 TT 유전자형을 가진 그룹에 비해 CK19에 대항하는 IgG수치가 유의하게 높음을 보여주고 있다 (표 6). 따라서, p value가 10-2 이하인 rs1786929 (서열번호 55), rs700617 (서열번호 56), rs6860780 (서열번호 57), 및 rs6596456 (서열번호 58) 또한 TDI-유발성 천식의 진단에 유용하게 사용될 수 있으며, 이들 서열의 다형성 부위는 각각 251번째, 254번째, 747번째, 301번째 염기이며, 위험대립인자는 소수대립인자 즉, C, A, G, 및 G이다.Based on the previous findings, several different gene variants of the same gene of CTNNA3 were found to be significant at p-value <0.0001. DNA direct sequencing was performed for 2 kb and downstream 1 kb (see FIG. 1). As a result, five known SNPs (rs35289132, rs10997784, rs1941996, rs2924307, and rs1786929) and five unknown SNPs were found (see Table 4). In the recessive analysis model, rs1786929 in the downstream region was significantly associated with TDI-induced asthma (p = 0.015-gender, age corrected, OR = 1.783, 95% CI = 1.042-3.052; Table 5). In rs1786929, the group with CT or CC genotype showed significantly higher IgG against CK19 than the group with TT genotype (Table 6). Thus, rs1786929 (SEQ ID NO: 55), rs700617 (SEQ ID NO: 56), rs6860780 (SEQ ID NO: 57), and rs6596456 (SEQ ID NO: 58) with a p value of 10 −2 or less may also be usefully used for the diagnosis of TDI-induced asthma. The polymorphic sites of these sequences are 251, 254, 747, and 301 bases, respectively, and the risk alleles are minor alleles, namely C, A, G, and G.

Figure 112009021641276-pat00004
Figure 112009021641276-pat00004

* MAF: 소수 대립인자 빈도* MAF: prime allele frequency

Figure 112009021641276-pat00005
Figure 112009021641276-pat00005

Figure 112009021641276-pat00006
Figure 112009021641276-pat00006

(4) CTNNA1의 발견과 TDI-유발성 천식 후보 유전자로의 가능성(4) Discovery of CTNNA1 and its potential as a TDI-induced asthma candidate gene

본 연구에서 TDI-유발성 천식 표현형과 연관성을 보이는 다수의 유전적 변이를 가지는 (rs1828187, rs10515504, rs10043478, rs9327827, rs288016, rs176382, rs288033, rs10038162) CTNNA1을 후보 유전자로 선정하였다. CTNNA1 유전자 지역을 coding regions (exons 5-10)과 untranslated regions (UTRs)을 sequencing 을 이용하여 fine-mapping을 실시하였다 (도 3). 염기서열(sequencing) 분석 지역은 LD 지도를 기초로 하여 선정하였다. 연관된 SNP간의 LD 블록 안에서 exon SNP 만을 선택하였다. 이 결과 알려진 4개의 유전자 변이 (rs700617, rs6860780, rs6596456, rs2292268; 도 3 참조)를 발견하였다. 이들 중 3개의 단일염기다형들(rs700617, rs6860780, rs6596456)이 TDI-유발성 천식과 유의한 연관성을 보였다. 그러나 CTNNA1 유전자의 3개의 단일염기다형들은 TDI-유발성 천식의 중간표현형과 유의한 연관성을 보이지 않았다.In this study, CTNNA1 was selected as a candidate gene (rs1828187, rs10515504, rs10043478, rs9327827, rs288016, rs176382, rs288033, rs10038162) with multiple genetic variations associated with the TDI-induced asthma phenotype. Fine-mapping of CTNNA1 gene regions by sequencing coding regions (exons 5-10) and untranslated regions (UTRs) (FIG. 3). Sequencing regions were selected based on LD maps. Only exon SNPs were selected in the LD block between the related SNPs. As a result, four known gene variants (rs700617, rs6860780, rs6596456, rs2292268; see FIG. 3) were found. Three of these monobasic polymorphs (rs700617, rs6860780, rs6596456) were significantly associated with TDI-induced asthma. However, the three monobasic polymorphisms of the CTNNA1 gene did not show a significant association with the intermediate phenotype of TDI-induced asthma.

(5) CTNNA3와 CTNNA1의 생체외 (ex vivo) 기능 연구(5) Study of ex vivo function of CTNNA3 and CTNNA1

TDI-유발성 천식 환자의 말초혈액으로부터 만든 Epstein-Barr Virus - 변형 림프구 세포주 (transformed lymphoblastoid cell line) 에서 유전자 다형성에 따른 CTNNA3 유전자의 mRNA 발현 차이를 분석한 결과, rs10762058과 rs7088181 두 개의 단일염기다형으로 구성된 반수체형 HT2 [GG] 를 가진 그룹이 가지지 않은 그룹에 비해 낮은 mRNA 발현을 보였다(p=0.04; 도 4).Analysis of mRNA expression differences of CTNNA3 gene by polymorphism in Epstein-Barr Virus-transformed lymphoblastoid cell line produced from peripheral blood of TDI-induced asthma patients showed that rs10762058 and rs7088181 The group with the haplotype HT2 [GG] constructed showed lower mRNA expression than the group without (p = 0.04; FIG. 4).

3. 고찰3. Consideration

Affymetrix 500K GeneChip 마이크로어레이를 이용하여 84명의 TDI-유발성 천식 환자와 263명의 정상인을 대상으로 전체 게놈 연관성 연구를 진행한 결과 TDI(Toluene diisocyante) 천식에 연관된 2개의 CTNNA 유전자인 CTNNA3와 CTNNA1를 발견하였으며, CTNNA3 유전자의 두 개의 단일염기다형들(rs10762058, rs7088181)은 TDI-유발성 천식 질환에서 염증반응과 기도 과민증의 지표를 나타내는 표현형인 메타콜린(methacholine) PC20 수치와 연관성을 보였고 유전자 발현 차이와 연관성을 보였다. 이 결과는 CTNNA3 유전자의 유전자 다형성에 따라 유전자 발현의 차이를 보이고 궁극적으로는 기도 과민증에 차이를 주게 되어 TDI-유발성 천식의 발생에 중요한 인자로 작용함을 시사한다. A total genome association study of 84 TDI-induced asthma patients and 263 normal subjects using the Affymetrix 500K GeneChip microarray revealed two CTNNA genes, CTNNA3 and CTNNA1, associated with toluene diisocyante (TDI) asthma. , Two monobasic polymorphisms of the CTNNA3 gene (rs10762058, rs7088181) have been associated with methacholine PC 20 levels, a phenotype of inflammatory response and airway hypersensitivity in TDI-induced asthma disease, The relationship was shown. This result suggests that the gene expression of CTNNA3 gene varies according to gene polymorphism and ultimately to airway hypersensitivity, which is an important factor in the development of TDI-induced asthma.

CTNNA3 유전자의 다른 단일염기다형 rs1786929는 TDI-유발성 천식의 중간형 표현형인 사이토케라틴 CK19에 대항하는 혈청 특이 IgG 수치와 연관성을 보였다. TDI-유발성 천식의 병인기전에서 기도 상피세포에 노출된 TDI가 CK19의 발현을 증가시키고, 기도로 유입된 이소시아네이트는 사이토케라틴에 결합하여 기도 염증을 일으키는 자기항원 (autoantigen)으로 역할을 한다는 보고가 있다. (Choi et al, Ann Allergy Asthma Immunol 2004; 93: 293-8). 이 연구에서 CK19에 대항하는 혈청 특이 IgG의 수치는 TDI에 노출된 근로자 중 TDI-유발성 천식 환자에서 더 높게 나타났다. 이상의 결과를 종합해 볼때, CTNNA3 유전자의 단일염기다형 rs1786929는 상피세포 손상과 기도 염증을 증가시키는 위험 인자라는 것을 시사한다. CTNNA3외에 TDI-유발성 천식의 유전적 인자로 CTNNA1유전자의 단일염기다형들이 발견되었다. Another monobasic polymorphism rs1786929 of the CTNNA3 gene was associated with serum specific IgG levels against cytokeratin CK19, an intermediate phenotype of TDI-induced asthma. In the pathogenesis of TDI-induced asthma, TDI exposed to airway epithelial cells increases the expression of CK19, and isocyanates introduced into the airways have been reported to act as autoantigens that bind to cytokeratin and cause airway inflammation. have. (Choi et al, Ann Allergy Asthma Immunol 2004; 93: 293-8). In this study, serum specific IgG levels against CK19 were higher in TDI-induced asthma patients among workers exposed to TDI. Taken together, the single-nucleotide polymorphism rs1786929 of the CTNNA3 gene is a risk factor that increases epithelial cell damage and airway inflammation. In addition to CTNNA3, single nucleotide polymorphisms of the CTNNA1 gene have been discovered as a genetic factor of TDI-induced asthma.

CTNNA1이나 CTNNA3 유전자들의 천식의 병인기전에 대한 연구는 보고되지 않았다. 그러나 유사 단백질인 CTNNAL1은 천식의 생쥐 모델(mouse model)에서 천식 진행에 영향을 미치는 것으로 보고 되어 있다 (Xiang et al. J Cell Biochem 2008; 103:920-30). 특히 Balb/c 생쥐 모델에서 CTNNAL1의 낮은 mRNA 발현이 기도과민증과 연관성을 보였다 (Xiang et al. J Cell Biochem 2008; 103:920-30). TDI-유발성 천식 병인기전에서 CTNNA3의 역할이 본 연구에서 명확 하지 않지만, CTNNAL1과의 상동 관계 (homology)는 CTNNA3 의 발현의 감소가 TDI와 같은 독성물질에 의한 기도 과민증 증가에 의해 TDI-유발성 천식의 진행에 기여함을 시사한다.No studies of the pathogenesis of asthma in the CTNNA1 or CTNNA3 genes have been reported. However, the similar protein CTNNAL1 has been reported to affect asthma progression in the mouse model of asthma (Xiang et al. J Cell Biochem 2008; 103: 920-30). In particular, low mRNA expression of CTNNAL1 was associated with airway hypersensitivity in the Balb / c mouse model (Xiang et al. J Cell Biochem 2008; 103: 920-30). Although the role of CTNNA3 in the TDI-induced asthma etiology is not clear in this study, the homology with CTNNAL1 suggests that a decrease in the expression of CTNNA3 is caused by increased airway hypersensitivity by toxic substances such as TDI. Suggests that it contributes to the progression of asthma.

도 1은 CTNNA3에 대한 전체 게놈 연관성 분석 결과의 요약 및 연관 비평형 구조를 나타낸다.1 shows a summary of the overall genome association analysis results for CTNNA3 and the association non-equilibrium structure.

도 2는 CTNNA3 반수체형에 의한 기관지 수축(초기 메타콜린 PC20)의 정도를 나타낸다.2 shows the extent of bronchial contraction (initial methacholine PC 20 ) due to CTNNA3 haplotype.

도 3은 CTNNA1에 대한 전체 게놈 연관성 분석 결과의 요약 및 연관 비평형 구조를 나타낸다.3 shows a summary of the overall genome association analysis results for CTNNA1 and the association non-equilibrium structure.

도 4는 CTNNA3 반수체형에 의한, TDI-유발성 천식 환자로부터 얻은 Epstein-Barr virus (EBV) 세포 중에서의 CTNNA3 mRNA 발현을 나타낸다.4 shows CTNNA3 mRNA expression in Epstein-Barr virus (EBV) cells obtained from TDI-induced asthma patients by CTNNA3 haplotype.

<110> AJOU UNIVERSITY INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Polynucleotides comprising single nucleotide polymorphism, microarrays and diagnostic kits comprising the same, and analytical methods using the same <130> DP090042 <160> 58 <170> KopatentIn 1.71 <210> 1 <211> 582 <212> DNA <213> Homo sapiens <400> 1 tttcacttaa ttattttggg tttgctatta tatatagaaa ttactcacaa atattttttc 60 tgcttttcta atatttagct gtattatttc tgtctcatgg tatgcagctt tgagcagctg 120 aagttaaata gaagtggtat caggagatac acggagacac agttcagtat tttgagtccc 180 tggatcgagt tcagctccca tctctcagcc ttcctaagtc acatagccac tcagagcctc 240 tgactcctcc atgcaaagtg gaggtgataa tgccttcctt atagattttc ctgagatgta 300 gatgcaatat ctggcatgca ctaggggatg agtaaatggc aactatagta aaactaacta 360 tcactgttat cttcctgatg awtgtcatat acctctttat tctgatgtct ttttaacaat 420 ctctaagatt tctccaccaa gaatacattg gctgttgggg gttctgtgtg agcctaacca 480 ctcctcctca ttgcctctag atttcaagct aattgggaag aagacacaga tcccagagga 540 aattaacatg caatattcac ttaattgctg ttttggtggt at 582 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tggcaggggt gattgtgggc cttgcaatct 840 actatactga gtcactgatt caaatgcaaa tctcagccag aagcaccctt acagtgtaac 900 accccaaaac aatgtttctc ctgggcaccc tgtggcctac tcaaatgaac gcataaaatt 960 aactgtcaca gtctataatg gagtataaca tgcggcactg cctggtacac cagtcttcag 1020 ctctgtcatt agaaacccta gggcttgaac atgtttcagg gaaaaaaaaa a 1071 <210> 3 <211> 201 <212> DNA <213> Homo sapiens <400> 3 atactaactg gccacttccc ctttgtccct gaagtggaag gaaacattca gacccatcat 60 atccctttaa caagcatgcc aggttataag cctgtatgca rgtgatttct ggagaatcca 120 tgtttcactt gtgactgtct ctttgtaaaa cacaggacga agggaaagat atggttaaat 180 ccaagtcaag ctcctttagg g 201 <210> 4 <211> 1136 <212> DNA <213> Homo sapiens <400> 4 gacagtctaa cagcaatcct gaggaggcta aactcctatc cacctgctgc ctaacactgg 60 gcaggcttac atgcctgctc catcattctg atttcaaaac cactactgct ccatcaggcc 120 agcatcactt caacaaatac ataaacatgc atctttctgg tattagagat taagaacttg 180 cctgctaaat actgcaatgc rcaatgccag gatagctcat aaatgggaag tacttcaaac 240 ctctttgaaa gcaacacaaa tataactggg gtaagatgtc tttctcagag ttatgaagat 300 cttttaaact ccttatcttg aaccgtaaga aaatcacaaa ttaatttttg acaaagtgtt 360 ttcaaattaa ataaatgctg ctctacaaca tggatgaact tggagggcat tatactaagt 420 gaaatagaca cagagaaaac tattgcatga tttttacatg ttctctaata aataaaaaca 480 agagagtaga aaggtgggtt accatatggt gggagtaggg gacacttatg tcaaggaata 540 caaagttgca gttatgcagg atgaataaat ctagaactct tggccagcca tggtggctca 600 cacctgtaat cccaacactt tgggaagcca aggcaggtgg atcacttgag gccaggtgtt 660 cgagaccagc ctggccaata gcacggaacc ccatctctac taaaaataca aaaattagct 720 aggcttagta acacaagcct ctaaacccag ctattatgtt tgggaggctg gagcatgaaa 780 atcacttgaa tcagggacgc agaggttgca gtgagctgtg atcgtaccag tgcactccag 840 cctgggtgac agagcaaaaa ataagtaaat aaaaaatcta gagctctaat ctacagcatg 900 aagcctatag tcaatagcac tgtattgtat ttggaaaact tgctaagaga gtagatttta 960 ggccctctta ccacccacac aaggtaactc taagataaca gatatgttaa atggcttcac 1020 tgtagtaatc atttaactat gtatatctaa atatcacctt gtatacctta aacatataca 1080 gtaaaaataa aatttattaa ataaaaaata aaaataaatg ccgctgtcaa aaaagc 1136 <210> 5 <211> 501 <212> DNA <213> Homo sapiens <400> 5 ttactgatac aaactgctag ccagtaaaaa ctgaaatttg tcattggggc ttctctcaag 60 ccacatccca ctctcagaag atcctaaaaa gccagtttgc acatgtaaaa ctcttcattc 120 aaaccacgaa atcttcatga tatcttttta cttaaaagta aagttttatt agttattgat 180 gacctctcat cagcaaacct ccaaaataca taatcatagt atagaatggg aatttagcta 240 tcactctcag raaaatacac ctgcccactt ctaagccacg tagtccagtc tggggccaga 300 taaggccctc ctggccatgg gaaggactga cttccatccc cagggtcctg gacgctgggc 360 tggcactctc aaatgggacc ctctggggaa ggctggcaca gttgctcttc atcagagggc 420 caactttgaa atagaggaga cagggagcct tcccccacct tctcccctta catgcaggca 480 gggggtagag gggcaagggc t 501 <210> 6 <211> 501 <212> DNA <213> Homo sapiens <400> 6 ataattactt gatcataatc aaatgggaaa aaaaatcaag tgtttagtgt tttattctcc 60 cttattcatg ttttcaaaag agaacttcac cttgagaaaa acactcttgg agtaacatgt 120 cccatagagc tacttactga ttcaatattt actctccctt tacattaacg gaatcccaat 180 aattgaggga agcaatatgc ccagttaaaa tctacacacc aagcctactt ttcagctagg 240 gataaccatg ygatgttggt cagtaagatg tacgtagaag tccttgggta gaaatgcaga 300 gaaaagctct tcatataaga taggggatgg gatgtaggga taaactaaac ttgtttgcaa 360 cactttgcct tttgcttttc tagaacatag aatatgaaca taattgttta agcagctata 420 tcttaacttc cagggaaaat ctaaaagaat cacaaaatcc tttgccctga tattttaatg 480 ccaccaacca tacacctata a 501 <210> 7 <211> 1658 <212> DNA <213> Homo sapiens <400> 7 cctaggagag tgcatgaaaa gatacgtctg gaatagagaa actacttaga gtttggaacc 60 aatttgtaca ggtccttaaa taacagtatc tttaaaccaa catcccttac ctgtgcctat 120 tgccccagat gagaatgtca ttaccttgag tgaagaaatt aggataagtt cctagcattt 180 tccaaagcgt tgtctacagg tgtttcaatt tcatcttctc atgttaactc ctcagcccaa 240 tccattctgg cctccgaccc ttacacaaca tggaattatt cctcttaagg tcacacatgg 300 cttccttgtt gccaaattaa tggacccgcc tttctgacct cattctgttt taagtgacat 360 ttgacagaat tagcagttcc tttccttgag aaacaccaca tcctcagctt tgggaaagcc 420 agacggtttt tcctcctgcc actttggcca ctgctcttca atcttcctta ctagctcctc 480 tgcccatccc caatatctac atggcagagt tcctcaagat cttgcacaaa tcttattctc 540 tccctctaca cacccaatct gctggtctca cctttcccat ggcttacata tggtccatat 600 gataccatct ccctaattta catctctagc ttagacctgt ccttcaagtt ctagtctttg 660 taatctaata tcttatttgg tatattcact tggatgtctc acaagaggcc agacttacag 720 atgagaatat tattactttg cagatgagaa tattattaaa agaagtctga tattgacttc 780 ttgattttac ttcaaaatat gtttctcatc tacttctctc tcaatgaatg gtaagctaag 840 aacctgagga aaaaaaacct ttactcttcc ctctccctta cctcccaaat cagtctatct 900 gtaattcctg ttaattctat ttcaaaatca tatcttgttt attgctcccc atctccatgg 960 ccaccactgt agtccagaac agcactgttt ttctcacaga atgtctccta atcagtttct 1020 tgctccttct gttgccctct gctaattcat tatacccaaa gcagcagagt aaactttcaa 1080 aaattaaaaa tgtaaaccaa atcttgttaa catctgctta ataccctgca gggtttccca 1140 ttataattgg aatgaaatct aaaggcttta catgccttag cctctcatta tgtctcctct 1200 tggacctctc tcctgcygtt tgccacacac cagctgcact ggccttcttt caattcctat 1260 aacaggccaa gttctatgtc tgggaggctt ttctcaaggg tattcatatg gttggctgtt 1320 tctcatcctt tggggtcttg gctttaaact tccgcagctc agaaagagcc tcttcaccac 1380 tcacctgagt agagtccttt ccccacattg ccactgctct attccatgac agcatgattt 1440 ctttgtttca tagtactttg caatggcaaa tggcatcttc atattaagaa cttctagttt 1500 ttctttttct aatcccttat ttcttggaag ttattatttc cttttatctc tgtaaggatc 1560 ctaaccattt acgttgcatt ttatgtgttg ctttttctga ggccttctct tattttttag 1620 ttccttttca tctccaagtt cgtcttcact ccctgccc 1658 <210> 8 <211> 601 <212> DNA <213> Homo sapiens <400> 8 tcttaggtac tccagtgtat ctaatagttt tacctaccca gatgtgttcc tgatgatgat 60 gctggtttca cttgcaaatt cccatataat gcttagccct ctggtttggg tattttaatt 120 ttactggata atgatcgtgg tgattttaaa catttcctgt tgcttgttaa actgcatgcc 180 cgattcagct ccaaataaca gcttttacac gcaagtgaaa atttagctcc tagtatttaa 240 caactactat aattttaaaa tctactttca attaagaaaa ccttgtaatt ctaaaaagtg 300 rttatgttcc aaagaagtgc tgaaatgtca actgaataca agtccacttt atgtctggca 360 ggaactgttc agttgtcgtg tggcttagca ttgaaaagct cgctccaaag tgctactgac 420 aggcctggtc tagtgtggca tttaatattt ccctttatac atttccccat ggtgtcagaa 480 caatctccag taatcaaaag aggtgaaaag agctagaata aaatattcgt taaatctaaa 540 catacacaat tgacgtgttc aagaaaatgt gcataaggag tgtattattg attttaacaa 600 t 601 <210> 9 <211> 601 <212> DNA <213> Homo sapiens <400> 9 agcagtatca gaaatggtta taaagagaac cttaagtttt aaggttcata gtgtgtgaat 60 cctttcagat aagccagata actctttttt ctctcttctc tttttattta gccaattagg 120 ctaattatat atatattcca aggctatgtg ccagttcaac ccagagctgc tttcagttca 180 gcttttgtat tatttaagtt gtaagcccta gttttgtaat tcccaagaaa aaaggatatt 240 gtcttaagaa ctgagattct gttgctgaaa tgctgtaact gtagtaatgt aaaccattgt 300 stccatgatc atgtttcctg tgttgtagat tatgtaactg catggcttac atgaggggtc 360 ctcatgtaag tgcagcaagt ctaccgtaag cttcattaga tttaagtgta caagagaata 420 aaaagcaatc tatttaatac ctttttggta gaaataaaat caaattttta caatttaatc 480 attagctccg caaagctgtc atggaccacg tttcagattc tttcctggaa accaatgttc 540 cacttttggt attgattgaa gctgcaaaga atggaaatga gaaagaagtt aaggagtatg 600 c 601 <210> 10 <211> 801 <212> DNA <213> Homo sapiens <400> 10 gtcacccctg ctggagtgca gtggcaggat ctcagctcac tgcaacctct gcctcctggg 60 ttcaagcaat tctcctgcct cagcctccca agtagctggg attacaggca catgctacaa 120 cacccatcta atttttttgt attttttcta gagacggggt ttcaccatgt tggccaggct 180 ggtcttgaac tcctgacctc atgatcctcc cgccttggcc tccaaaagtg ctgggattac 240 aggtgtgagc caccacaccc agaccagaaa agccattttt atgacagtat atctgaggag 300 ttcatcaaga gcatatactt gtctgggatg atgtaattga gttggcacgt cccttaagag 360 ctacagtgca cgagaacaga aagaattcat tattgccaaa ratttctaga ggacatgaat 420 ataagctttt tcttgaaata tgcatagaat ttgatgtgag aaacaagggg tagagatatt 480 taaaaagaga gtgatggcag ttaataatct tggcatgtcc ccgccattgt ggaagtatta 540 acttaagtgt tgtggaaggt gccttttggc ccacatcaga aaaaaaaaaa aaaagttaga 600 aataaaattt taggtgaaat caaattcctc cagagttcaa gaaggtaaac tgagtgaaga 660 agactggggc tataatgaga cagagtggaa gagactatgg catggtagag accatggcca 720 aggctcagtg aaaaagagga caccactaag ctccagccaa ttcccgtgaa aattatgttg 780 gtcaaaactc cactggccac a 801 <210> 11 <211> 601 <212> DNA <213> Homo sapiens <400> 11 ctactgaaat tgtttgttcc cacctcagca ctgctatatc taatttacac tgtacttata 60 aaaagaataa atatttaagg gaactcagaa aatggagctg gagcagggcc cctgtagtct 120 ataaaaacct agttgtcttc tggagaccaa ataattcact gcaatccact cacatgcctt 180 tgaagaggct tctcacccct tgtcaccaga tgtctggcag tttgtgactg gaactaccca 240 ctccatgcct ggatggctgg atgtgaggag gacaggcctc cctcctgcat aatagcatcc 300 rgagagaacc ccagaaaagc ccattaaaca tttatttagg taaaatcact gtgtcattaa 360 cttatctcca tacacacaca gaaagggaac taaaatagat tttaatggag caactaggag 420 ctttctaatt tttcctcttt tgtttgatga gcaatcaatt caagtgtgtg cactgggtac 480 atgtgggggt acccgtaatt ggggagtgtg ctgtattaga gggtgttttg tgaacaccag 540 ttaatagaaa aaagaatacc caacatgcac acaccacttt atgggtttgc aaagcatttc 600 c 601 <210> 12 <211> 601 <212> DNA <213> Homo sapiens <400> 12 caggatattc cacttggccc cagtgtgact actcaagaat gggaaggagt caggagtctg 60 actttttaag ggttctcatg tgagggtgat gttcctgctt aagaggaggg gatttgacgg 120 cgacttctct tggcctccat tccttgtcat gtggggtaat ctgactcaag gatgcctcca 180 tgacagtttc atcatatatg gcaccagctg ttgttggagt gggaactggg tcttctctgc 240 agtcagggga agttggaagc attcagaaga tgcccagagc atctggagcc tagttgacac 300 rgtactttat gatggcagat ggaggcacat gtcgcaggag attccggagt ggttcggtgt 360 cagcacccct gcaaggcggg gtcttgttag ttgacctaag agattccatt ccaatgtgct 420 gaagatggat tttcaacttg gcctttgcgg aggctaagaa agattcattg caaatttctg 480 tttacttgtc tggctttcgt gggatagcca gtgttttccc ttgttttagg ttatctttgg 540 ctggagggca agaaaaatag tcaatgatgt cttggaagtt taagcctaca ctatatggct 600 c 601 <210> 13 <211> 661 <212> DNA <213> Homo sapiens <400> 13 tcctttgcct atagattcct gcttcccttc cctcttttcg cgcgcgcgcg cacacacaca 60 tttttgcata ggtgtttgcc tgatcaaagt gggatcattg ttcacaaatg ttcacaaacc 120 tgcatcatct tattcatcag taactcatgg aaatccttgc aagccttctg gtttacctct 180 aatttgttca ttttattgct sactacacta tgtatttgac cactcccctc ccatgtgttg 240 tgtgttttta tttcagtgtg ctaacagtag gcattatttg ttttaatttt gctgatctga 300 tgagtgtgaa gcagttgttc attattactt tttttttttt gtctcgaact cctgacctga 360 agttatcctc ccgcctcggc ctcccaaagt gcttgggatt ataggcgtga gccactgcac 420 ccggcctgct cattattaaa gttgcatttc ccttgaccac tgttgaattc aaataatctt 480 tttaatgtac ttgtaagtca ttggatttgc ttttttatga agtgtctgtt tgtattcttt 540 gcccattttc tactgtcatt tgtatgtttt tctttgccgg agctcttggt atattatagc 600 tatttgtctt ttgacattgc gtgtgttttc ccccgccttt tttaatcctt cctagccagc 660 g 661 <210> 14 <211> 1335 <212> DNA <213> Homo sapiens <400> 14 ataatcttgc catgaggctt taatgaataa caagtacaaa atgcccagtt cataagagtt 60 cctttaaaaa gattagtaca aggtgctgtg agattttttt aaaatgaatc agatatgatt 120 atgtcctcat ggaacttact atctaggaga ataaataata catacataaa agtaatcata 180 atactcaatt tttagaactc ytattatgac ctggatatat gtattcattt tacagatgag 240 gaaactaagg ctcagagaag gaaagtgact tgactaaggt cacaaaagta ggaaattgca 300 aaactagaat ttgaaccttt atctgctcaa ctgcacgttg cattaatata acataggcac 360 ttatttttaa acctttaaaa gtcttatagt cagtaaatac actcaacaca ggtacagatt 420 taaaacttcc tatacatata agactataag acacctatac aaattttata gtacagggtc 480 aggggaaggt gatgccagta ctcccttagc tgccccagct ggtatctcag taggtaatgt 540 gtcccctcat tccactgggc ccaggtcagc actagggact cacctatgag ttgcagtcct 600 tgtggcctag actatctctc aaagtttatt tggggctcca gagcactcta gcccatggtg 660 gtgagggttg tggaaactca agttctgact gtggaaattg gcaattcccc tctggctagg 720 gctggtttaa aagctccctc catgggtgtg tgtaagctga atttggtttg gttttccttt 780 ctgctctagc aggacagtgc tgagttcaat tactcacaat tgctgtgctc tccctctttc 840 cagcatacag aattgctctc cacaccactc tgcagctgcc agaggatctg ggaggggagg 900 gctggtgctg gctagtcaag actgtttttc ctgccacttc agggcattat tcagtgatat 960 gaagtcaaaa ccaggcactg tgagtgctca cccgattttt ggttcttaca aaggtgtttt 1020 ttttgtgtgt gtagatagtt gtcaaattgg tatccttgca ggagagatga tcggtggagt 1080 tttctattct acaatcttac tcttccccaa agtcctctgc ctgcattttt aatttttgcc 1140 aagctagtat gtgtgaaaac atatctttct ttggtttcaa tttgaaatat cttgagtagt 1200 ttaagcattt atttacatat ttatgaaaat gttcatagtt cttctatgaa aacctgatca 1260 tgccttttac tcatttttct actaggttat tcactgactt actgactttt agattttttt 1320 tttctagata ttaaa 1335 <210> 15 <211> 601 <212> DNA <213> Homo sapiens <400> 15 aaacattaaa ttgtacacta tcaatgggtg aattttaggt gacctatatc agtatataat 60 ctgtatcagt agataattat cttatatatt tgtaaaatta tttaaagata tttacatgcg 120 tttcacatgt cagtttgcta atgatgtgat atgtatttta aattatattt cctgtaggag 180 ttcaggcaat ttgttcatct tacatgaagt aaagagtatt tttcccattt tgaaacacgg 240 cctgtgtctg ttattgccac cagaattaca tggtctacat taaatcctat attgtgtaca 300 ytgttgacct ctttaatctt ctgactttgt atgggacaaa ctaatggcct acaattttct 360 gtgactattt catttaaatt atacaaatgt tgaatgaagg attgctgaat taaaaatagt 420 taaaaaaaaa cccctcaaat tatactgaac aggtgtcatt tcaagctgag tgtttttcat 480 ttgggggcag ggtgtcttct ctctgaaaaa gtgttagatc tctacattat gtacattgtt 540 agcccttaaa gatttttgaa tggtttggat tattagaaga ttctgcatat aatcacctag 600 a 601 <210> 16 <211> 1064 <212> DNA <213> Homo sapiens <400> 16 tttattttta tagccagatg tgataatgtg cctctttctc ccccagcatt tgtccaggtc 60 agaaaaggcc ctctggagac tctagaatag gtcaagctgt ggtctcctga ggaaggatat 120 tcagaatttt cattctaact gctagagttt atagtggctc ttaatgaagt ctttcaattt 180 gaggaatctt ccatgaagac tatacctagg atatgactgc ttttcatcac ccccactttt 240 actaccttag ttcaaaccac cttcaaatgc tagggttact gcagtagcct cccaactaac 300 cacctttctt cgccctttcc cctcattttc tgtggactat tctcracaca gtacctccta 360 cgttcccttg aaaagataaa tctgatcaca tgatgactcc tgcttaaagc attcaatgac 420 tcctcatcaa actaaaagct aacatccttc taataacctc aaaggcccat ttccctatta 480 tctcatggac ctcaaacctc atcttgttac tgtcctccaa gctcacacag ctctatcatc 540 tgtggtcttt ttcaccatgc tgattctttc cttaaacatc agtttctcag ggaggccttc 600 cttgactacc tcatatgaag ctgcaatcac ctctctgcac tactttctct gctttgattc 660 cagagcagtg actaccatgg gatatataat acccacgtaa attaatatat atatatatat 720 atatattttt taatatctgt ctctccaata aagaaaggtt aagctctgtg agagcatgag 780 tttgtgtctg tcggtttcac tgttatttcc atagcaccca gaaagtgcct ggcagtttgc 840 aggagtttga tgaacatttt ttgactatta aatgaaagtt cttcctggtt cctttaacca 900 accagtgata atgtcttcct cccttgagat gccgtcgcag gttgtctgta tgcctttctg 960 aactgatagc acagcaagga gactggacct gattaagcag gggaaacctt tggctgggga 1020 tgcaatagac atagaacaca gttaatgggc tagagaagag acag 1064 <210> 17 <211> 953 <212> DNA <213> Homo sapiens <400> 17 taaacacaca cacacaatct ttaaacacac acacacacgc atgcacacgc acaccacacc 60 ccgccctcag tttaaattga gaagggagtc tggggattag atatacttat gaaaggttag 120 acttctgttt tttgtttagt tgttgagact gggtcttgct ctgttgccca gactggaatg 180 cagagttgca gttttggctt tctgcaacct ctgcctcctg ggctcaagcg attctcccac 240 ctcagcctcc caagtagctg cgactacagg tgcatggcac cacacctgcc taatttttgt 300 atttattgta gagatggggt tttgccatgt tgcccaggct ggtctcaaac tcctgggctc 360 aagcgaccct aaagtgctgg gattacaggc gtgagccact gctctgagcc ctgttatttg 420 taactagcat tttaactaac tgaataccaa gaaaagatta agaagactat taagtggaac 480 acattaggaa agtgggggat gcagaacaat taagattcaa tatatgacat gttaaagtta 540 gaatgtttat tagtcgtcca agtagagatg acaagtccag gggaatggtc caggctggaa 600 acataaattt agaagtcatc atccgtgaat acaggtattt aaagtcacta gcctagatga 660 gatcaccaag ggaatgggtg tagatgggag atgagactca cagaaccatc ctttcctcct 720 aaaccagtct gagaaatctt taaacaatac ctrtaaaatg gcagtcacgg aaaaaaaagg 780 ataggtttca agggaagcat tccctcaaca tcaaagccac ttgaacaagt catgtgctat 840 tggaaaacaa ataggaatat ggtcagctta attcatgaaa atgactggaa acgacatatc 900 aaaggaattt ttaatcaatg aagaatacac atgtatacca tttaggaatt cag 953 <210> 18 <211> 601 <212> DNA <213> Homo sapiens <400> 18 tgaggtggga ggatggcttg agaccaggag tttgagacca gcctgggcag catagcaaga 60 ccccatctct acaaaaaatg agaaattgtt taagagcgag aaaagatact acactgtgca 120 gccagacaag accatgatgt ttatacattt aatctccaat ccacatacac agtgccattc 180 ttgaaatgat ctgtgacaaa ttcagtttcc cctgataact aaatagcatg tagtaatagt 240 aaaagaaagg tgaaggtgaa tttcacttta tgtgggggca ctgttcactg gtatacctgc 300 raccactcca cactgctcag ctgaatgaac cttgattggc taatggaggg agacagagac 360 tcccagtttc agaaaaagtt attttccatt ccatccacag gaatgagtca tcactgggcc 420 catctacccc tttgctgagg atgccacagg atgtggtcgt gtgattagtt ccatggagtt 480 aagccaccgc tggtccagta tccagttact tacagccaaa agcatcccta actatgaagt 540 atattatgaa tatcattaaa atgctaatac aaactttcta attagaatat taataataaa 600 a 601 <210> 19 <211> 596 <212> DNA <213> Homo sapiens <400> 19 gtctgggttg acatcactct gtcactaatc aacagaaaat tgtcaggagg gtcccacata 60 ctctagttag acatagagca aatttcctgc cctttgtttt acttacgtcc ctattgtcac 120 aggttataat actggcccta agtgtgtatt tgcttcaaat aattatattt tgggagacat 180 tgggttgact gtatcatgtt yctacacatt tttttttttg agacggagtt tcactctttt 240 gcccaggctg gagtgcagtg gcacgatctc agctcactgc aacttctgcc ccccaaggtt 300 caggcgattc tcatacctca gcctcccgag tagctgggat cataggcgcc cgccaccacg 360 cctggccaat ttttgtattt ccagtagaaa cggggtttca tcatgttggc caggctggtc 420 tcaaactcct gacctcaggc gatccacctg ccttggcctc ccaaagtgct aggattacag 480 gcatgagcca ctgcacccgg ccatgtttct ccatttttta agggcctgaa gtctgttgag 540 tagagctgcc tatgtgaatt tcatattttt tctttttacc catgtgctac ttatag 596 <210> 20 <211> 501 <212> DNA <213> Homo sapiens <400> 20 tcccaaagtg ctgggattac aggcgtgagc caccgtgccc ggcctggcct aaggtcttat 60 taactctcct ccatttcaga catgaccccc tgtggagtta tagctgcaac aatagcagag 120 acaggattta gccaatgcag ggtgcttttc cagccctagc ttaacctttc cattcattct 180 aaatgaaata aaatctccac aggtaaccca aggactgaaa taggcttcag gtaagaagtg 240 agtgaacttt rtatttttcc tgagcttggt ggaatgagtg tttggaaaag ttaaatggtt 300 taactactga aaaccaccca ggccacaggc atatgattca ttttgtgtga ccttagactt 360 tttcttggaa gatttggggc cagaaaatag gaagccaaaa atagcttcat tgggatcaaa 420 tatttttctt tctggaaacc agaaaactat tcagttctgt aagttccaac aagttcctca 480 ttaacatcac tatttctcta c 501 <210> 21 <211> 1001 <212> DNA <213> Homo sapiens <400> 21 tgcatagtct cctcatgtcc caggaaacac ccagatggca gggcatgtga cctcactcaa 60 ccacaccaat tatagccagg taagcaatgc ctctagaact tctggcccag tagctctgca 120 tctgtgtgta ctcagctaga gcatgcagaa ttccattggt ctgggaaaca cctaggtgaa 180 agagttcatg aggttgctca cctccatcac tagtagtcag gtgggcaata cctgttagag 240 cttctgaccc agcggtcctg cttctgtggg aattcaggta gtaggtagag cctcttgttg 300 tcccaggaag cacccataca agagggcagg tgtcccccac aattactgct gctgatagcc 360 gggcaagcca aacctgctag aactttctgc ccagcagttc tactgctggc tgaatttgct 420 gggcagcata tcctgctact gccttggaaa cacccagact acagggcaga caactccagt 480 caccgctacc tccaatagtc rgatgggcca tacctgttta gagcttccaa tcagtatccc 540 cccttccatc tgaattctac tgacaggtgt aaccctgggc tgctccagaa agtatataga 600 caacacatta gggctagcct gtcaaggata ttgcttgttt gccaacagtg gcccctgcct 660 gagaaagccc catggaccag aacaatcaac aatagaaaca aggatatgga gatagtaatt 720 ggagacaaaa cacaaaccat ccactattcc aaacccagga gtggactaga attgaagcca 780 gtcaaccaaa gccacgtaat atcatactca ctcacaggag aaaaaagcaa acaattccat 840 ccaaaggaca gcaacttcaa ataataaagg aatatcagtc cacacaaatg agaaagaatg 900 agtgctacaa gtctggcaac tcaaaagtga gagtgccttc ttctttccaa atgactgcac 960 tagtactcca gcaaagttta ttaactaggc tgaaatggct a 1001 <210> 22 <211> 1001 <212> DNA <213> Homo sapiens <400> 22 gctgggacta caggcgcccg ccaccacacc cagctaattt ttttttttgt atttttagta 60 gagacggggt ttcaccatgt tagccaggat ggtctcgatc tcctgacctc gtgatctgcc 120 cgcctcagcc tcccaaagtg ctgggattac aggcgtgagc cactgcgccc ggcccaaaac 180 tcacatgttt ctatgacagg gattgacgtt gattacaaaa gaatacattt gttggtagca 240 tatttcgttt attgttgcga aattacacaa taatacagtt aaaattctct gaagtaatgg 300 ccatcacctc tctgaaaaat gacaccaagc attcaacatt ttatctcgtg ttttagtttt 360 ccatggctgc tttgaaaaat tgcaatgaac ttaatggctt acaacaatac acactgatta 420 tcttacagtt ctgtacatta gaagtccagc attggtcctg ctgggctaaa atcaaggttg 480 gcagggctgt gttttcttcc rgaggctcga gggataaatc tgtttccttg ccttttccaa 540 cttctggagg ccgcccacat tcctcggctc ttggcctctc cctccgtctt caaagccaga 600 atagtgggtt gaatcctttt cacacagaat cactctgact tctccttctg cctcctcttc 660 tcccactttt aagacctttt gattacattg ggcctactca gataatccag aatattctcc 720 ccattccaag gtctttaact taatcacttc tgcaaagccc actttgccag gtaagataac 780 ctattggtgg gttctgggga ttaggatgtg gcattttggg gaggccatta ttctgtctac 840 cacaccaact ggcacacttg ttctgtgtgt atgtgtgcat gtgtgtctgt ctgtctgcct 900 gtctgtctgg ggtaattaca taggggcctc agacctttga actgatcagg agagtatgta 960 atttggggtg agggggtgga agtggaattc tgcccattgc t 1001 <210> 23 <211> 1055 <212> DNA <213> Homo sapiens <400> 23 agatgtgtgc acgagaaacg gccagttgcc agtagtgtgc aaactcgtgg cttaaacagg 60 tcccaagagc ctttcatcca ttgatttgtc cttccgtacc tctcttttgg gatgcgtgca 120 tgtctagggg gtcacttttc cattcccctg accccagcac cccaccctca gtctctctcc 180 agcgtcggct gagctcctac tgccatcttg tggccgttca cgtaaggtgc accagagagg 240 cggagcccct gctgtccttg tcctaggact tgatttgcag agatttggga ggcttcctga 300 ctctggggtg ctcatttcct tcacaaacag aaaaagaaaa gtcactcctg ggcacattgc 360 tgtcatgtgt gaggctggaa gcactcccta cgatgggayt ctctcaactg tccctatttg 420 catctctagt cctcacgtag tgcaattcac tgtgtgagtg tgtgtgtgtg agagagtggg 480 tgtgagtttg cgtgagtgtg agagtgtgcg tgtgtgtgtg agagtatgtg tgtgtgtgag 540 agtgagtgtg cgtgcgtgtg tgtgtgtgtg tgtgtgtgtg tctgtgatta ttggtaaggg 600 gaaggtacaa gaagcagggt aggcactgat gctagtacta tacttcaaag tcctcaagga 660 agaagtctcg ttttgagcca aggatttggg tgtttctaga gagagggaaa acgtgagctc 720 cagagctcat gaaaagctcc atcacaacaa aggattgtct tgtcttttta gccacatcct 780 cccattcaca ttgcagcata ttgagatctt ggcactgtct ccactctttc tttggcatat 840 ggctttcaat ttgagctccc tgaggtgaag aaccattcaa gtccacaacc tgcatctcac 900 acagggctga gcctagggaa ggtattaaat gtttcttgaa tgagagaacc ttatcttcat 960 tcagatgctc tgtggtcagc atatcctgtc gattcttctt ccagaaatca ttttcctatc 1020 cctagccccc tctctttatt cccagtgtca atgga 1055 <210> 24 <211> 1498 <212> DNA <213> Homo sapiens <400> 24 aacttttttt atgtttcaca aatattgaaa actaggtcaa cagattctta ccagtttgac 60 tcttttgatt gtgacttttg tgtcaacatt tttgtgaggt ttgcatagtt ttgtcttgat 120 tgtatgtcac agcttatttg ttaatacttc ctgcactgat aggcatttgg cttgttttct 180 gttagaaatc tttcagggta atgctgtcat acacattctt ttacctgttt attttaatta 240 ttattatact ttaagttctg aggtacatgt acagaatgtg caggtttgtt acataggtat 300 acacatgcca tggtggtttg ctgcacctat caatccatca tctacatgaa gtatttctcc 360 taatgctatc cctcccctaa ccccctcccc tagacaggcc ctggtgtgtg atgttcccct 420 ccctgtgtcc ttgtgttctc attgtccagc tcccacctat gagtgagaac atgtggtgtc 480 tggttttctc ttcttgtgtt agtttgctga gaatgatggt ttccagcttc atccatgtcc 540 ctgcaaagga catgaactca tcccttttta tggctgcata gtatttcatg gtgtatatgt 600 gccacatttt ctttatccag tctattattg ataagcattg gggttggttc caagtctttg 660 ctattgtgaa tagtgctgca ataaactttc atgtgcatgt gtctctatag tagaatgatt 720 tacaatcctt tggttatgta cccagtaatg agatggctgg gtcaaatggt atttctggtt 780 ctagatccct gaggaattgc cacactgtct tccacaatgg ttgaactaat tgacactacc 840 accaacagtg taaaagcatt cctatttcgc cacatcctct ccagcatctg ttgtttcctg 900 actttttaat gattgccatt ctaactggtg tgagatggta tctcattatg gttttgattt 960 gcatttctct aatgaccagt gatgatgagc tttttctcat atgtttgttg gctgcataaa 1020 tgtcttcttt tgagaagtgt ctgttcatat cttttgccca ctttttgatg gggttatttg 1080 ttttttttct tgtaaatttg tttaagttct ttgtagattc tggatattag ccctttgtca 1140 gatggataga ttgcaaaaag tttctcccat tctgtagttt gcctgttcag tctgatgata 1200 gtttcctttg agctctcata ttttaagaat tgtataaaag tgtagtttct tagatcataa 1260 gttatgccca aataaagctt tagtgtgtgt attttccrac aattttccaa ggtaattgta 1320 tcaatataaa atctcattgg cagttccaga tatttcatat caaccacaac ttgaaattgt 1380 cagtccattt atgatagtga tttgtttcaa tatataacag aattataaat tacaatgtta 1440 tatccatacc tataaccaat tataaaatat tactgtcatt gttctaaaat aaaagtgt 1498 <210> 25 <211> 985 <212> DNA <213> Homo sapiens <400> 25 tccccacagc agagaaatga ctttgcaaag aatgggaggc aggtttgcct taagcagttc 60 ccagattgat ttttcccttt agcttactga tttgggggtc ccaagattta ttttcctttc 120 acatatgtat cttatggttt tttgtttttg tggttgttgt tattttattt attttttgag 180 acggcgtctc gctctgtcac ccaagctgga gtgcagtggc acaacctcgg ttgactgcaa 240 cctccacctc ctgggttcaa gcaattctcc taccttgcct cgcaagtagc tgggattaca 300 ggcacccgcc accatgcccg gctaattttt gtatttttgg tagagatggg gtttcaccat 360 gtagccaggc tggtctcgaa ctcctgacct caagtgatct gcccacctcc gcctccaaaa 420 atgttaggat tacaggcatg ggccacagtg cccggccatt aatcttatgt ttaaagtact 480 tctaattcac atgtgtgtaa tcagcaagca catggacagg agaggttcca aaaaaaaaag 540 gaggttgtaa ctcccctcct ctaacagcca gagaatctac cataccagtt aaatatgctg 600 tctctggagg gagagtttcc cactgctgaa ggatccaata cagacatgac aataaagatt 660 acaagtgaaa gggatttaca caccagacta agaacctatg attctatgag aaaggaccac 720 tcactctggt gtgaagagat gggatcagat tccctgcgga gaagaaaaaa cttgactcag 780 aaaagagcat ctccagggaa aaggaaagct caaagcaaat agcacccaat aagacaagtg 840 gtaaatcact gggtaacrac cataaaaagg atcgacaaaa agctgcagaa acaaacttgc 900 cctgccttac ctcttccagg tggtgtttat gactctgcag catgctaagc tggcctgtgt 960 agtcaagcta cctaaaaatc atgca 985 <210> 26 <211> 601 <212> DNA <213> Homo sapiens <400> 26 gcatcagtgc aatcaagagt aattattttt tgaaggcctc tgaggaagtg ggcactaatg 60 cttgcagtat catggtgccc agagagcaca gccccttcca ggtcaccagc catctttctc 120 acctgcccac tctttgggtt caagaggttc aggctgtgga accaaagaag acatggagtt 180 tgccttaaaa ttggtagagt gcagagttcc cattgatgga attgtgtatc attttttggt 240 ctttatcttt ctttagctaa aagggctaca tatctatttt tctaaacttt ctcttggttt 300 ygctgtagag cagctttttt ccgcaaacat atgactttga cttaaagtgg caatactact 360 tctggaaggt actgtccata tgatctgttt caattttcat tgctttagat gttcatgata 420 aggcaaagga gaagtaaaat ctaacctgtc tcctctctgt aaatggtttt aagcaaatta 480 actgagtcaa gtggcagggc ttagatggct gtagttgtct gcattcctcc acatgagagt 540 ttgcttttca tatgtattgc tgattaggga gagttattcc cctacttgga gaagcaaatg 600 t 601 <210> 27 <211> 701 <212> DNA <213> Homo sapiens <400> 27 aaacttccac acagtaggca cagatggtac aaaagagggc tgcctgatct caaactagtg 60 gttgtggtgt cagtcttagc ctacctcttc gaatagtggg aatcagagac attttagttg 120 ttaatacaag taactgtggt aggaaagata ataatttatt ctcctaacaa atccagagat 180 acttctcact gttctacgaa rtcttggctc tgctgggttc tctgtggaag ttaactgctc 240 caagtgtttt tcttttctct tctcttctct tccgctcccc tcccctcccc tcttttctct 300 tttctctttt ttgagagagt ctcgctctgt tgtccaggct ggagtgcagt ggcgccatct 360 cagctcactt caacctccac ctcctgagtt caagcaattc tcatgcctca gcctcccaag 420 cagctgggat tacaggggcg tgccaccacg ctgggccaat ttttgtattt ttagtagagg 480 tgaggtttca ctatgtggcc aggggtgggt ctcccaactc ctggcctcaa gcagtccgcc 540 cacctcggcc tcccaaactg ctggtattac aagcatgagc caccacaccc agcctctttc 600 tttttttggg acatggtctt gcagtcatgg cttgctgcag cctcgacctt ctgggctcaa 660 gctattctcc caactcagcc ttccaattag ctgggactat a 701 <210> 28 <211> 601 <212> DNA <213> Homo sapiens <400> 28 gatcccagat tcctgtgggc tatctccccg catggctggc cacacggcag gtttgaaatc 60 aatacttgct ggttcaccac ctaactgtgg accctcagtg tccctccctc gctcatccct 120 cttgctcggg gtccgtgtgt gcatccagcc agtcaagtgc cttgttgcca tggctcaggg 180 gctcatcaga acagggaaga ttttatccac tcacagggta gccgtgggag gtggagagac 240 tctgtaagct ttgacacaca ggggattctc attacagtga tgttattaca ggtgtctgga 300 yggttgtcat tagagactgg aagtggggcc caaatctctt actcatgtag agagcctttg 360 gaaaaagcca tttggaaaat gcctcgagaa ccactgcagc ttcctccttt gtattagagg 420 cccttgccct ctaacacaaa gttgcggatg cctagacccc agctaaaggc tttctgaggt 480 tactgtctcc atcaccagca gtgttagcag ctgccagggc tcagccctcc tgaggtttca 540 gcaccagggt gagggtgact catggggtag atgaggggca accatagttg aagctgactt 600 c 601 <210> 29 <211> 601 <212> DNA <213> Homo sapiens <400> 29 gaatgtaagt gttcttaact tttctgtaga ataaacaccc caaagagatc ccagattcct 60 gtgggctatc tccccgcatg gctggccaca cggcaggttt gaaatcaata cttgctggtt 120 caccacctaa ctgtggaccc tcagtgtccc tccctcgctc atccctcttg ctcggggtcc 180 gtgtgtgcat ccagccagtc aagtgccttg ttgccatggc tcaggggctc atcagaacag 240 ggaagatttt atccactcac agggtagccg tgggaggtgg agagactctg taagctttga 300 yacacagggg attctcatta cagtgatgtt attacaggtg tctggacggt tgtcattaga 360 gactggaagt ggggcccaaa tctcttactc atgtagagag cctttggaaa aagccatttg 420 gaaaatgcct cgagaaccac tgcagcttcc tcctttgtat tagaggccct tgccctctaa 480 cacaaagttg cggatgccta gaccccagct aaaggctttc tgaggttact gtctccatca 540 ccagcagtgt tagcagctgc cagggctcag ccctcctgag gtttcagcac cagggtgagg 600 g 601 <210> 30 <211> 1001 <212> DNA <213> Homo sapiens <400> 30 aaaagcgatg cttgcaaaag atccttggac ttcgttgctg gaggagctta gaaggaaatg 60 cagcagaatt ttggatgtca caggaggaga atgttccaag gagaggtcaa cagtgataag 120 tttggacttt gctgctggag gagcttacaa ggaaacacag cagaattttg gatgtcacag 180 gaggagaatg ttccaaggag aggtcaaaag tgataaatgt tgaccactga gaggttaaat 240 aacaactgaa cagttcttcg gatttagcaa gaacggcttc attgcagtgt tacagtgaac 300 actagaatgt ggtaggttaa ttaatgagtg ggttgtgagg aagtggaggc agccaacact 360 tcttctcaaa caatttgctg tgaatgggaa gagagagtta agtggtggta gctggagaag 420 aagctgaaat gaaaataaag aatgttatgt caggtgactg agaaggtagg aggaaggaat 480 gggaagtgga gaacagctga yagcattagc cttatatgga aatatggtag ttgttacggt 540 tgttcgtaga tactttgttt tcccccatgc atatggtagt gtcaggctgt tcagactgcc 600 ataaccatca gatgggcagc atatacacca tacaaatttt tttctcacag ttatgggagc 660 tgggaagtcc aagatcaagg tgacctcaga tccgtgtctg gtgaggccca ctttctcgga 720 gatggcactt ctctgtcttc acatgattca agggacaaac gagctccctt ggacctatgg 780 atttttgatt ttgtcatctc ttcaaacccc accttccttg tatcatcaca atggtgataa 840 ggtttcaaca taagaatttt gtggggatac aaacatgcag acctagcagg taggatttaa 900 ctttcctaat attttgaact cagcatggcc acatgactaa ctttagcctg tgaaatgcaa 960 ggagatgtgt gtcattgcta ggcagaagct tgcagcacca t 1001 <210> 31 <211> 1335 <212> DNA <213> Homo sapiens <400> 31 gcccagttca taagagttcc tttaaaaaga ttagtacaag gtgctgtgag atttttttaa 60 aatgaatcag atatgattat gtcctcatgg aacttactat ctaggagaat aaataataca 120 tacataaaag taatcataat actcaatttt tagaactcct attatgacct ggatatatgt 180 attcatttta cagatgagga aactaaggct cagagaagga aagtgacttg actaaggtca 240 caaaagtagg aaattgcaaa actagaattt gaacctttat ctgctcaact gcaygttgca 300 ttaatataac ataggcactt atttttaaac ctttaaaagt cttatagtca gtaaatacac 360 tcaacacagg tacagattta aaacttccta tacatataag actataagac acctatacaa 420 attttatagt acagggtcag gggaaggtga tgccagtact cccttagctg ccccagctgg 480 tatctcagta ggtaatgtgt cccctcattc cactgggccc aggtcagcac tagggactca 540 cctatgagtt gcagtccttg tggcctagac tatctctcaa agtttatttg gggctccaga 600 gcactctagc ccatggtggt gagggttgtg gaaactcaag ttctgactgt ggaaattggc 660 aattcccctc tggctagggc tggtttaaaa gctccctcca tgggtgtgtg taagctgaat 720 ttggtttggt tttcctttct gctctagcag gacagtgctg agttcaatta ctcacaattg 780 ctgtgctctc cctctttcca gcatacagaa ttgctctcca caccactctg cagctgccag 840 aggatctggg aggggagggc tggtgctggc tagtcaagac tgtttttcct gccacttcag 900 ggcattattc agtgatatga agtcaaaacc aggcactgtg agtgctcacc cgatttttgg 960 ttcttacaaa ggtgtttttt ttgtgtgtgt agatagttgt caaattggta tccttgcagg 1020 agagatgatc ggtggagttt tctattctac aatcttactc ttccccaaag tcctctgcct 1080 gcatttttaa tttttgccaa gctagtatgt gtgaaaacat atctttcttt ggtttcaatt 1140 tgaaatatct tgagtagttt aagcatttat ttacatattt atgaaaatgt tcatagttct 1200 tctatgaaaa cctgatcatg ccttttactc atttttctac taggttattc actgacttac 1260 tgacttttag attttttttt tctagatatt aaacttctgt cagttaattg cccttaagct 1320 tcctgcttcc actag 1335 <210> 32 <211> 692 <212> DNA <213> Homo sapiens <400> 32 cccttcgact atgctgggtg tttattgcct ttgatatttt tactaacctg gtgggtgtga 60 aatgggatct cactgtggtt ttcctttgca tttgctcatt ctgaatgagg ttgagcttcc 120 tttcatatgt ttatgggtta ttctctttca atgaatgctt actcttgtct ttggccattt 180 ttttcccatc ggattgtctg tctcattctt actgatgtac agtgcttata tattctggct 240 atcaatctta tgatgtttca tacatgatgc aaataccttc ttccactttg aggagtgtag 300 gtatttttaa aggagttttt cctttgtttc caaatagttt gcttctgcta acttaaggga 360 agcttttggt ttataaaggc ttttggtttt ttgtcagaat taggtcccag atgtgcctaa 420 ctacctctcc catggaggga taaatacatt tatgaacggt ttttggaata tgtcttcttt 480 taaacagcaa gsataagagg aatgggaatc tgcattgata tattatttat gaaaaactat 540 catccaatgc ctatattctc cctggtagcc ttagaggtgg aaaaacataa tttgtatgta 600 tataatactg tttataaata agataagtcc aaatcacttc tagaaaaatt ttccatttag 660 ttataaaaat tttaaagttt gcatctttaa aa 692 <210> 33 <211> 1001 <212> DNA <213> Homo sapiens <400> 33 ggaatattaa acattccatt atttcctata caaactatgc ctcagggtca gcaaatagtt 60 gatgataatt ttttttcttt atgaaagttt tccagctaaa ttatggaaaa gaaaatacat 120 aatggaaaca gtacagaaga gagggacata ttttaaatga catcatatgg atttaactga 180 aacctgaagc atcagaattg aaatctaaag catcagaaat catagtagga gacaaatcaa 240 ctaatttgct catcaagtaa gttgatagga aaaaaatgaa acatgttcat tgagaaatgt 300 gagactgtta agaagaacat ccacctagat cttatttgga tcatcattta aacacacaca 360 caatgcacac acactcacag acacacacac agacacacat aaaatctggg aaatgggtca 420 ttcactgtat taaaaaaatt gacatcttta tgagttttgt tagttttgtt tggggtctcc 480 aagagcactg ccagactcaa ygatttacaa aaaatatctc acaagactca gaagagttat 540 tatatttacc gttataattt atcatagtga aatgatacaa tgtaaaatca gcttatgggg 600 aaaagttaaa agaagccagg cacacacttc caggagtttt atcctcgtgc agtcttaaga 660 acacacttaa ttctcccagt aattacatgt gacagtatgt gcaaagtctt atgactcaaa 720 gaagccttcc tgagccttgg tatccagagt tttggttggg catctgtcat gtatgcatga 780 cctaagctat tctgacatga aaactgatct aagctactca acctccaaaa acaggtgttc 840 acataaatca tagtgttagt ataaattatc tgatcaaact gttactacat ggcccaaagc 900 ctgaagcata caaaaatcct tgtcttaaga agaatattcc aagggcttag catgcatctt 960 ctagaatcca gccaagaacc attcctaaag acagatcttt c 1001 <210> 34 <211> 601 <212> DNA <213> Homo sapiens <400> 34 cactctctct cacactcaca cactcactct ctctctctct cgtaatttgt cagggatacc 60 atattttccc ttttaacaaa tcattcctta aaaagcagca gcgatataaa cttgtcacta 120 atcttaattg tatgttttaa ttctatgttt aaatgttcct ctatattaca gatactgctt 180 tgtccctgag agcccctaat ttttcagcca ttttctacat agagagtgat agaggaaaga 240 aagcagcaca atgatttgtt aagcctgtat taaatgcctt taaacttttc aaccttgcag 300 yttaagcaca ggcaaaagga tgagacggaa catgttcaag actgtacatg ccgatcattg 360 actaaatgtt aaaagtcaac atgaaaatct atatctgaga agaaaggtta ctgcctaccc 420 aaaatagccc tccacaaaaa taattctggc aactcaatcc agatattcaa ccaatttcca 480 gcacaagctt tgattcaatc acattctctt tttctaatca gtatgtttct ccaccttata 540 atgtatatgt tcatttaatt gttgaaattg acagaaacaa tttttaaagt acttttcagc 600 a 601 <210> 35 <211> 1807 <212> DNA <213> Homo sapiens <400> 35 tgggagctac agtatggaac ctggtattcg atgtgtagtt tatggaccaa tatcaccacc 60 accacctggg agcttgttag aaatatagaa tcttgtgctc cactgcagaa ttattgaatc 120 agaatctgca ttctaacaag accaccaggt gattcataca cacattaaag tttgagaggc 180 actgatatag agcactgctc atcaaatttt gcaacatatt agaatcatgt gggagctttt 240 aaaaatctga tatcccatga ttatatatta acagcaacaa aaatttggtg cccttgctac 300 atatactgtg ccagttaagt cagaatatct tgagatgaga cccaggcatt agtatttttt 360 tattgtgatg aaatacacag aacataaaat ttgcaatttt aaccatattt aagtatatac 420 tttagtgatg ttatgtacgt taacattgtt gtacaaccat caccaccatc taccttcaga 480 acttcttcat cttcccatat ggaaactcca taatccacta aacactaact cccatttccc 540 cctataccca gcccctggca accaccattc tgctttctac ctctatgaat ctgactactc 600 tggacacctc gtagaagtgg aacatacagt gtttgtccct ttgcgactgg cttatttcac 660 ttagcataat gtcttcaaga tttacccacc ttgtactctg tgtccgaatt tctttccttt 720 tatttatttt ttattttttc tttcttccta tataaaagca attccttcat ttttaaagct 780 gaataatatt gcactgtatg catatatcac attttgttta tccattcaac cgttgatgga 840 cacttgggat gcttctgcct tttggctatt gtgaataata cttctatgaa catgggtata 900 caaatatctg ttcatgtctc ttttctcaat tcttttgtgt atatgcccaa gtggaattgc 960 tagatcatat gacaattcta attggaattt tttgaggaat tgccatactg tttttcacag 1020 cagctgcatt attttacatt tctgccagca gtgcacaagg attccaattt ctctacatcc 1080 tcaccaacac tttttttctg tttttgtttt ttattacagc catcctaatg ggtgtgaaat 1140 ggtatctcat tgtggtttcg atttgcatat ccctaatgat tagtgatgtt tcatgtactt 1200 attgagcatt tgtatatctt cggagaaatg tctattcaag tcatttgttt tgagtcaggt 1260 tgtttagttt ttttgttgtt gagttgtagg agttctttat atattctgga tattaatacc 1320 ttgttagata tatgatttgc aaatattttc tcccattctg tgagtcctct tttcactctt 1380 ttgatagtgt ccttggatgt acaaaagttt ttaattttca tgcagtctgt tttagctatt 1440 ttttcttttg ttgcctgtgc ttttgctgtc ttatccaaga aactattgtc aggcatgaga 1500 atttttttaa agctccccag atgattccaa tgcacagcca agattgagca gtgtttctca 1560 aattttaaca crcattggaa taatctgaaa tcttgttaaa atgcagattc tgatttatta 1620 agtctggagt gggatccaag attctgcatt tccaacaagc tcctaagtga tgccgatgca 1680 ctggtctgcc gactgctctg agtagccagg gtggagaaga gcatttaaat gatttccttt 1740 atctgaaccc cccaaaaaga gggtaaatat tatatttaca gaccttcttc taagcttcct 1800 caccgta 1807 <210> 36 <211> 507 <212> DNA <213> Homo sapiens <400> 36 ggagaaaatt aaaacctgat tgttgagctt ttagtgctta tattcaagat agtttaacac 60 ttccctaaaa tttcacagcc attatttatt atactaccat gaaaatcata taaataaata 120 ccacaaattc cacaaacaca ttaaggaaac caaagataac ataacagtta ctaaatcaac 180 aagtcttagc aactcttcct rtaactcgtt ttcatggatt caaagaagaa aacagtcaag 240 caaagttagc actgtaaaat aaaattaaga acattcatat actactttat actttaccac 300 atcttcctct tcattggttt gatttagtag gtgtatatca caagaaatca ctcaaaatat 360 aagttaatgt tgactttgaa gggacatgaa ggcctttctt gatttggatg gcaactgaat 420 gggtgcacac agatgtaaaa attcacttag ctgtacactg aaggtgtgca ctacgctgtg 480 taagttacat gccagtgaaa aagtaaa 507 <210> 37 <211> 601 <212> DNA <213> Homo sapiens <400> 37 ggcatccaat ctttttgctc tagactttgg atgttgaaat ctggattcat acttgatgta 60 aacaggatga atctcttttg cctacagcct ttaaaatatg gttatctagt tttggtcaaa 120 agtctcacca ttaagttcat tgttaaattg aataaactat ctgaaatctg ggggaatgag 180 aaaatggata ttttgggtaa ttacatactc tgttggataa ccaaacataa catatatggg 240 ctcttcaggt ttcaagtcag tagaaggtaa tgtgacattt tctgatcaga ctgttgggat 300 yttttgttag ttgcacctca tgtttacctc tgtgactagc cttcaccaag cagccatccc 360 ttccttgaac cgatccctct ctctcatgcc cctttccttg gtacattctc ttccttttgt 420 ccagaaatac tttttctctt ctttctgttt agatgtcacc tcttctgtga agcccttagt 480 tccttcacaa gaatctcccc aatccaattg cttgctcttt tatactccta taacattttt 540 ttggtaattt tttcatagtg gtaaaatata cataacatac gatttaaatt ttatccattt 600 t 601 <210> 38 <211> 601 <212> DNA <213> Homo sapiens <400> 38 ttgtcttgat atattaccta tcagattcct ttaatcagtg gtctgtgtgt gtggtgagca 60 ctcatctcca ttataatctc ctctgccccc acctattgcc acgaagtcct aggtctttgc 120 agatgatcaa attttggaga agaaacaaat ttactctgca taatagaggg agaaaaactt 180 agaaagccca gggcaaggag aaggggctga ggagcagaaa tgggagaaag acagactcca 240 ttcattcaga cagatggtgg aaacttgtgt gcaatgcgca tgcagaaacc ctataaaaat 300 rttctgcagt gtcaactacc ggtatgaatt ctctgagtaa attgctgttg tggattccaa 360 agaagaggta gagattcata tctagtctgc ataaggttgg acaaaggcag cagttgtggt 420 ggtcagatgt gaagaggatg gcattagaag aaatccttgg acatcacaga cttctacacg 480 cactggaact ggggttctta ggggctgggt ttcaaaagga tcaaagcaat ttaatttgga 540 tctccagggg tgcctgtagc tactttggtt tccatatgta taagaacaaa ctatatgttg 600 g 601 <210> 39 <211> 845 <212> DNA <213> Homo sapiens <400> 39 aggttatacg gcacgcgatg ctggatgacc tctgagagct gaggacctca tcctgtaacc 60 acaaagaact gaatccaaca aacagtgcgc ttagaagagg acttcaagcc acagatggtg 120 gcagctcctg ctgacacctt catcagaatt tgagtagaag accccctaaa ctgtgcctgg 180 atttctgagt caccaaatct gtgagataat aaatgtgttg ttttaagctg gtaaatttgt 240 gatattaata tttattaaaa acagtaaatg aatacaaaag tcaatgtaaa ctaaaattcc 300 atagtagaga tgaagtcctg tgaattttag ggagaatatg acactgtttt tcaccaataa 360 caaaattcac tactagtgga gtaaagaact ctggagtaag acttagagct gtgtgacttt 420 tggcaagtaa ttcaacctct ttttgcctca gtttcttcac atacaaaatg ggaatgattt 480 tattatttgt gagggttcag kgacagaata catttctaat gctcagttca gttgctgtca 540 catagtaagc tccatataat attattatta atgtcattgc tattgctaac ataattacta 600 ccatcattaa tttaactaag agaaacatgt ccgtatcatc agctacatac ataatgcttt 660 gcctaggctg aaaaataaat aaataaataa gatagaaata ttaaatggac ttacagagat 720 tgcagatgat tgcaagtttg caatcaacaa ggcttttaaa tcattcactc attttaaaag 780 accccttcaa atagttttca ttacaatgtc cagggcaggt aattcaaaga aagaggtctt 840 ggtgc 845 <210> 40 <211> 2477 <212> DNA <213> Homo sapiens <400> 40 tgcatccgtg ttttcaataa ctagaccctt gttttcagac ttggaatttt ttttttcagt 60 cattggtgga ttttctgtct aacattttat gaaaattttc aagcatccaa caaagttcaa 120 ataattttta cttggaatag ttttggtttt ttttttggag acagagtctt gctctgtcac 180 ccaggctgga gtacaacagt ggtgtgatct tggcttcctg tgacttccgc ttccctggtt 240 caagcgattc ttctgcctca gccccccaag tagctggggt tacaggtgtg tgccaccacg 300 cccgcctaat ttttgtattt ttagtagaga tggggtttca ccatgttggc caggctcgtc 360 ttaaactcct gacctcaggt gatccaccca ccttggcctc ccaaagtgct gggattacag 420 gcgtgagcca ccgcctccgg tcttacttgg catagtttta tacccttcac ctagattgtc 480 aatgacattt tttgatattt tcttcacttt atatccatcc atccctccgt ctgtctatcc 540 atgttattat ttagatgcat ttccgagtaa aatgcagaca cgggtatact cccctataca 600 cttcagcata tcattggagt ttggtatttg tttacggttt ttcctgtttg atgtaaaatt 660 tacatacaat gaaatgtaca cacgtcaagt gtacttttgc tgagttttga catatgcatg 720 cacccatgga acccaacccc gtgaagagct agaccatcac catcactgac agctctgaca 780 gctacctcgc accttgccca ggtggtcttc accccttgtc cccttagagg caaccactgt 840 ttggattttt tccgttataa ataagttttc ctattctaga attttatgta aatagaatca 900 tacagtatat aattgtgctg gggcctccag tgctaccccc aggctgaatg attcattagc 960 aggactcaca gaacttagaa aaggtattac actcccagtt agacttatta ctgtgaaaga 1020 ataaagatta aattcagcga agagaggaga cacatggggc aaagtctagg agaagacagg 1080 catgaacttc cagttgtccc ttcgaaatgg agtcctactg ggcacacttg attctcccag 1140 cgatgatgtg tgacaacaca tgggaagcat tggccaccag ggaagctcac tggagcctca 1200 gtgtccaggg tttttgtgta gacattagca cctgtgtgac tgactttagc gactcagtct 1260 ccagccccac agagtccaaa stgatacagc tgggccaggg ccgcagggat acagaaacag 1320 gtgttcactg taagccaagc tgttagcgta aatgatctgg tcagactgag agagcagggc 1380 ccgaggcctt gagcatacaa aaccccttat caggtagaac attgcagtgg ctcagaggtt 1440 atctcccagg agccagtcct gaagacaggc cttttttgga atgtacaggg tttgagcaac 1500 ctagtcctgc tgagttaacc ctttccgtca cagtagtctt ttgtgtaagg cttcttttac 1560 ccaacgtaat gtttttgaga ctcatccata ttattgcatg tatcagcagt gttgttcatt 1620 tttattgcag aatagtattc cattgagtga acagaccaca gtttatccat tcacatgttg 1680 ttgatacctg gattgtgacc agtttcagtc tattatgagc aaatctgcta tgaacattct 1740 tacacagttc ttttgggtaa atacctagca gcgaaattac tgggtcatag ggtacatgta 1800 tgttcacctt tgtaaaattc tgccagacct ttttttcaga gggattgcaa tattttacac 1860 gtcctccatc tgctgcagct gttcagtatc ctcaccagac cttggtgtta tcagtctttt 1920 taattctcac cattctggtg ggtatgaaat cgtatctcat tgtgtatttc agtttctttc 1980 tttctttttt tttttttttt ttgagacaga gtctcgctct gttgcccagg ctggaataca 2040 gtggtgcaat ctcagcccac tgcaacctct gcctctcggg ttcaagtgat tctactgcct 2100 cagactcctg agtagctgag attacaggcg gccgccaccg tgccgggctg attgttgtat 2160 ttttagtaga gatgggattt tgaccatgtt ggccaggctg gtctcgaact cctgaactca 2220 ggcgatccgc ccaccttgac ctcccaaagt gctgggatta caggcatgag ccaccgcacc 2280 tggcctcagt ttcttttcaa tttagaaagg tcaacatcta gtcctaagag agatgacagc 2340 atgtttcttc taggatctga aaacacagat ccaatgattt gatgtatcct tgcaaatttt 2400 cctattttaa tttaaaatgg gggaagacaa agaaggagaa ggaggaagag agtttcctaa 2460 gggagctggt gaactgg 2477 <210> 41 <211> 524 <212> DNA <213> Homo sapiens <400> 41 ccctccagat tcaggctcct tggagaaggc aggctccagc cttggtctca gaatcatcac 60 taaagtcaga taagaagata ataatagtaa tggctacaac agagtagcag aaaccacagg 120 ttccattttt aagcacctaa ttgtgtctag attcaggctg ggcatgtttc atatctcctc 180 tcactcattt ctcctgacag ycctggagag gatactgaag ccgagaacag tgggtcgcta 240 tactcaaggt ctccaggcta gaaagtgggg gggcttcctc caagggctaa gggacttcaa 300 gccctgtcct tcccactgta ccacgttgcc ttggtgatgc tccttttgca ctggccccac 360 atggccagct ggattcttct ggtcacagga gatggcgtgg ctgttgggct gtggggcagg 420 agggaggcag ctctacctgg agccaccacc ctgctccgac ttgctctagg tatcagcatt 480 acactgtggg agccagagga gccctgtgct ttctgatagg ccca 524 <210> 42 <211> 592 <212> DNA <213> Homo sapiens <400> 42 gaataacaaa gtagaaatga aataaaatga caacctaggc aaaactgacc agatgctgaa 60 agcagatgga gaacttaaag gaaagtatta aaagagcagg tttataatgc tacagctggt 120 gattaaaata tctcactatc taatcaggca atagcatctg gcctgctgca attcagaggt 180 tttcaaacag tagggaccac aatttaattt aattatcaaa attgaatttg taaagctagc 240 caatgagtag aaattcagaa gaccctgcca cagtatcccc caacttttca cgataagaaa 300 ttaaacataa taaaacatgc cttttgataa ttagactcca tatattgcaa aactaaagtt 360 tgataaaagt ttaatcaaac tcagtgggtg tcattaaaaa ggcaataatc aaatgattac 420 ataaataata acaaacttct gcatttccct caaattgtct aaggaaaaaa cagataagtt 480 gtmatttgag gaacaacagg cagaaatatg cagcattaaa attatctaga tcaaaatttt 540 aaaagctatg atgcccatga ttatttctat ctccatttta attcacaatt tc 592 <210> 43 <211> 425 <212> DNA <213> Homo sapiens <400> 43 aacttcatta gtctctgtgc aaggagagac ttttgcagag agtttttcat aatattgaaa 60 gaagttgcca gagaagttgg agagggccta aagcaccatt ccgttgtgcc atcgacacca 120 cacttctgat catggaagga gcatgcaatt aggcagaaat gagcttaggt tcaggttggg 180 ccatctgtga atggaacatt cttgggcaag ttactaaatc tytctaattc gtgtgttgtg 240 tatctgggat ttcagtggag ttttataaac agttaaatga gattatgtca agtctatatg 300 cacagttgct ggcatataat aagaccttga aacttgtgtt aacagcagtg tcagaattag 360 aacccacatc ttcttttcct ttttattgca tccttctgcc accaactcca acccttgtct 420 tctag 425 <210> 44 <211> 601 <212> DNA <213> Homo sapiens <400> 44 ctgtttattg gtgggagagg gtcattcacc tcttttgacc tgatcaaaga taagaatcac 60 tttctcacaa aaatgcacat aaacatcccg cctaattttg gcacatattt tatcttattg 120 tattagaaat tgacttcttc acacagaaaa aaaatcctat aaaaaatttt cttctctcat 180 tcttgtttat tcacgtaaat ggagtaatct aaaataaatt cagtgagcaa atacaaaaga 240 aaaaaattaa aattcttccc ccaaagcaaa tttcaacata aaggctgcca ttacttgact 300 kgagaagaaa ttacagcata gtcttacatg gtaatatgct tgtcatttgt ggtaagtcta 360 tcaattttga tagcaacaaa tgtaagaaag cccagattaa caaaagtatg ttgtcgcaaa 420 tgaataggtt taagtccaga tgcactggat ttctctagga cccttcaagc taatgcagtt 480 gcatcatttc ctcacatcta caaagttggt catctttgca aagtctgcat catctatgtt 540 gcatatgtca gcaaggaaat ggttaaaata accattccaa ttttaaggtc aaaccagttt 600 a 601 <210> 45 <211> 604 <212> DNA <213> Homo sapiens <400> 45 ctcttctgtg tttcaagcag gtaagtgggt tccctattga agttctgtca ccctttggga 60 aaggaacatt tgtgtgagta ataggtgaga aaaggaaaag tttagaggaa gcatgatgga 120 cttgagagtc tacctgaaga agccaccctt ctatcaacat ccctactgaa aaggaaagca 180 cacttctagg ttgcctacaa tgtgtgcaca catatgcaca cataacacgc atgcactcat 240 taatgaaagc ttgtaagaga gctgcaaggg caagaagtca gttttgytca cctccaacag 300 gacagagata tcttgaatat taaatgatgt aagaccggta tcaagggcct tccccccata 360 ctctgctgcc gggatccttc tcaagccaag tgcccccatg caattcatcg agtgactggc 420 cccgactcca gcctactcca cgtgtcctgc tgccccaacc ctcccttctg ccatcaatgc 480 tcctgccatc aatgcacaat gtgatccaga gaaaggaggc acacatccct tctttatacc 540 gctctgaacc atgaactaca tcttttaatc acggacacac tgcatcacat ggttgcttcc 600 ttaa 604 <210> 46 <211> 701 <212> DNA <213> Homo sapiens <400> 46 agatatggta cagtgcctgt actcggcttg caacttatgt tgaggtgatt cccactcaca 60 ttggcccttg tccttgtcag ccctctgtgc cacagttgac agagccaagg ggccaaagaa 120 gctgtgccct tgggttgtcc gtgattggca cctcttgatg aggtgaagat atcattccta 180 atatatttct tttcatgtat yctttgataa aactaaatgc agttcaaatt ttattaaaac 240 atttaaaact ttttttttat ttttgaaaca gagtcttgct ctgtcaccca ggatggagtg 300 caatggtgcc atcttggctc actgcagcct ctgcctccca ggttcaagcg attctcctgt 360 ctcagcctcc caagtagctg ggattacagg tgcccaccac catgcctggc taatttttgt 420 atttttagta gagatggggt ttcaccatgt tggtcaggct ggtctcgaac tcctgacctt 480 aggtgatcta cccaccttgg cctcccaaag tgctgggatt acaggcatga gtcactgcgc 540 ctggcctatt aaaaacattt tatgttgtgt gagtctgata gccaacttct aactagagtt 600 gtgcttcttc agtaatctga gtaggtaaga ctcccctttt ggaagtcaaa ttctacaaac 660 tccagtgccc acaggaacca ggaaggtaac ataaataaga g 701 <210> 47 <211> 601 <212> DNA <213> Homo sapiens <400> 47 tggctacttt agctggaact gtcatcacca gacatgaaca cgttagctca cagaagaggt 60 agaggtctac aggcaaacac gacagtagcg aagctgaggc tggccccagg gagcatctat 120 accaaggcac caccgggaag gctgcggcag actgtgccat gcgctgtctg ttgggcctgg 180 agcaccacga gaaggaaggc ggcgtgggga gagtgaagct gcactgaggt tctgctaaga 240 ccgctgtgaa ctttcacata caagactttg cgtgggtgta tcatttcagt tctcctgggt 300 rtatgcttaa gaatagaatc actacaattt tcaaccattc ctgttattat taagaaagta 360 atacatgctt gtaggaaacg gtcaaacaac acagcagaga acaggggagg aagtgtgggg 420 acacccactg catttcccat ccacagagac agcaactcag gagattagtt tgcatccttt 480 ccatagcttt ttatatgcac acacatattt attttgtaaa tacaattatt ctatacatat 540 tgttctacaa attgttatat aactctgcct acgttgtggc catattccta agtcagaaca 600 c 601 <210> 48 <211> 601 <212> DNA <213> Homo sapiens <400> 48 gagagtgtgt gtgtgtgtgt gtgtgtgtgt gaaacagaca tgggcttatg tttacgaaga 60 tctctttgta catgtgtttg aaaggtgact gcaagaatga gtaaaatagg ttacatttac 120 atttcttggt ctcctccaca ctccctgatg ctaaacaaga tgctgcaaga atgaaaaata 180 caacttttgt gtaaactttg taatctagtt catagagaaa ttggccaaca gctacacgca 240 cctaaaggaa gaggggacat acatttggag aaacatattc atgtgtgcta gttcaagaag 300 raagcagcta gctctttgcc tttgaagatt tcaatattca ctttgttgaa ggtgaccagg 360 tgatccctct tagatacttc gataattcag atacatccaa tacaagatgg atcttcataa 420 aattcaattt gttatttcaa tctggaaatg cattatctct tccttgagga aaataaattg 480 tgtaaggaca ggtgctattt tctttatctc tgcccaaagc ttcatcctag ggctcagaaa 540 tgctaaagga ctttgtacaa ggaaatgaag ctaaaagctt gctaccttaa ttataggatt 600 t 601 <210> 49 <211> 401 <212> DNA <213> Homo sapiens <400> 49 atatcttgtc cccatttttc tatgtgctga actgatcatc actgtgaatg tattactaag 60 tggaagtttt aaggttaaga tccttatgga ataactacag cagtcctatc ttcccccact 120 agatacatgc ttcaccatcc cctgaaagat ttatatagaa ggacactgtg gcaacatgtg 180 accttttgaa actgctccct yggaaggaat tctaatgtcc tcctatctat gttacctgct 240 gtgtacctac cactggggaa agatgctgaa aatttaatga attgcagaaa agctgtgcaa 300 gcttctcttt tggaagaacc ttggagaaga gagaggccga cagaaagaaa actttcaaag 360 aaattacact gccctcaagg gtggcatcta cagaggacag t 401 <210> 50 <211> 1001 <212> DNA <213> Homo sapiens <400> 50 gtatcaagca aattgtttga tagactcaga agacttttct gaggggccag aggttgctga 60 acaaatttaa atagaacaag caggggaaga aaaatttaag tgacatgtca gttggttctg 120 cttcagttgg ttctactgac aggttcaaat acattatccc ctttggaaaa aaagaaatat 180 gtgcattgtg taattctagg aaatctctcc caagaaggtg agtcagggct gaaggtacaa 240 gtaaaaattc atgataatgg actaaggtat ctaattggaa aggcaacagt aaggttttgt 300 gcacagtcat gggtcggtta gagatttcca ccatgtttaa ggtttctgca ctccaaggaa 360 ggggcccttt aaggaggtgg aatttaaaac agataaagtt gctccagtat caattaaagc 420 cttggtcttt tcaccattag tagttaaatt catttcacca agggcattag aaggaaagga 480 aaggaccctg gaatttcctc raagcagtct tactctgatg gttctgtcat ggccttttct 540 tccagttgcc acttgagctt tctggaatcc tttttgatgt gaccaggatt cttacaataa 600 aaacgtacat ttctctgatc tggtgagggc tgaaactgct gtttttgaaa tccctgttgt 660 ggattggcca actgttgcta cttgaaagct tataatccta gcagatttag acttttcttt 720 tttgtggaga aggccacaat attaactaga tcacatatct gagtggttgc tcaatttatc 780 tgatgtcact taacgagggt aacaaactct tagtcaaggc cgttaagaaa agctgagctt 840 aacatagatt catttttttc tattattaac actgttatca gacacaccaa agtattgttt 900 aaatgtcttt ttgaatcatt caaaattatc taaatctgtt atgttaggac cttggcagca 960 ttgccaaatt ttacccaatc tatatgtttt ggaaagactt t 1001 <210> 51 <211> 1001 <212> DNA <213> Homo sapiens <400> 51 ggagaaaaat caggattaca gttttgacga tatcctgcca atcagaggaa gcctcatagc 60 tatttcttag tgtttggttt tagaaaggca attatgcctt taactctatc agagttgatg 120 gaaaacccct ccttagatat tgaatgaccc aaacatttaa cttgttcttg gcataactgg 180 agtttttctt tagagagttt gtgacatttg cctgtgagtt gccttagaag atgcaggcac 240 ccccatatga gtgagcatat gtgatatttg tctttctgtg cctggcttaa ataagctact 300 taatataatg tcctccagtt ccatctgcat tgttgcaaat gataggattt caatcttttt 360 tatggctgaa taatattcca ttgcatgtat gtgccacatt ttctttatct attcatctat 420 ggatggacac ctaggttgat tccatatctt ggctattgta aatagtgctg cagtaaacat 480 gggagtgtgg atgttctttt sataaacttg ttaccagaag ctgggaaggg tagtggggag 540 agggataaaa agggggtggt taatgagtaa aaaaatacag ttagatagaa gaaataagat 600 ctagtatttg gtagcacaat agggttacta tttttttttt ttttttgaga caaaatctca 660 ctctgttgcc caagctggag tgcactggca tgatcttggc tcactgcaac ctccacctcc 720 cgggttcaag cagttctccc acctcagctt cctgagtagc tgggactaca agcacgtgcc 780 accatgctca gctaattttt gtattttttg gtagagacgg ggtttcacta tgttggccca 840 gctggtcttg aactcctgac cttgtgatcc acccgccttg gcctcccaaa gtgctgggat 900 tacaggcatg agccaccgtg cccagctggg agactattgt taacaataat ttattgtata 960 ttttaaatgt ttgaggtagt agataactct aattaccctg a 1001 <210> 52 <211> 1001 <212> DNA <213> Homo sapiens <400> 52 aaaggcaaca gtaaggtttt gtgcacagtc atgggtcggt tagagatttc caccatgttt 60 aaggtttctg cactccaagg aaggggccct ttaaggaggt ggaatttaaa acagataaag 120 ttgctccagt atcaattaaa gccttggtct tttcaccatt agtagttaaa ttcatttcac 180 caagggcatt agaaggaaag gaaaggaccc tggaatttcc tcaaagcagt cttactctga 240 tggttctgtc atggcctttt cttccagttg ccacttgagc tttctggaat cctttttgat 300 gtgaccagga ttcttacaat aaaaacgtac atttctctga tctggtgagg gctgaaactg 360 ctgtttttga aatccctgtt gtggattggc caactgttgc tacttgaaag cttataatcc 420 tagcagattt agacttttct tttttgtgga gaaggccaca atattaacta gatcacatat 480 ctgagtggtt gctcaattta yctgatgtca cttaacgagg gtaacaaact cttagtcaag 540 gccgttaaga aaagctgagc ttaacataga ttcatttttt tctattatta acactgttat 600 cagacacacc aaagtattgt ttaaatgtct ttttgaatca ttcaaaatta tctaaatctg 660 ttatgttagg accttggcag cattgccaaa ttttacccaa tctatatgtt ttggaaagac 720 ttttgggatg gcatctaaaa gctctctggc taaagcgcta gcttctattc tgttgtatac 780 cttcatttgc tctattaaag ttttccagag gattttgcca attagcattt ttaatccatt 840 tggtgtccct ctcttctgaa atcaatagtc cccctagtag ctgggaccac aggcacgtgc 900 caatatgcct gtcaaatttt tgtatttttt gaagagatgg gctcaagcaa tccacctgcc 960 ttggcctccc aaaatattgg aattacaggc gtgaaccact g 1001 <210> 53 <211> 601 <212> DNA <213> Homo sapiens <400> 53 agatcggtcc tgccccttgg ctgggctgcc tggacttcac ttcatcatct ctaaaatgag 60 attaaagatt gtttctccct catgggaagg ctccgggatt cagtgagctt atgcctgttt 120 aggaaagtgt ctggcacagg gtcactgccc ttgtgccatc acatctgccc agatgaaatc 180 aggtaatcag ctgacgcacc cggagtgccc atcgcgcatg cgtgctgtgc cccatgggaa 240 aggggcgtca gatgtgactc tgccctcaag gaatccgcat ctagcaggag aaagaaaacc 300 sgacactttg gagataaata gagagctaga aggccagcgg gacccccgct tccccacggc 360 gcggacatcc tggagggcga gcagctgccg ggcggggcac gctgtcagcc aaccctgcct 420 aatctcctgg cagacagagc tgagagaaag cagaatctgg tattcattgt gcggttgttt 480 ctaatttcct tctgctttcg agatcctctt ctaagggaga acaatgccct gaatgatggg 540 gcacaagctt ccttggctgg gcacccaccc agctgtggca gaggccgggc actcacaggg 600 c 601 <210> 54 <211> 601 <212> DNA <213> Homo sapiens <400> 54 tctccgagat ccagcctgct gtctagggta ctcgtgcatg tgagtaaaac ttccaagaat 60 gccacctccc tacgtatctc ccctacactg ctctcctcct gcattccctg tgactctaaa 120 gtgaggccta aggctctgat gggatcaccc agcttccacc acacactcca tgctttcctc 180 tgccccaccc tgatgagatg aggtgattct ttccctggtg agggagcgtc tggcagctgt 240 tgcctggttc ctcctccctg ttggttctgt cctggttgct gaggaccata agaccttgca 300 stgtatgcct gtttgtgatt ggaacaaaac gaggtgactg gggcttgtta ggccccagtc 360 ctagtgaaag tagtaggcaa gttatctaaa cacgatctca gacagagggt cctcaagata 420 gaagcccatt ggcaatcctg gggtacaagg agatggtgag tgttgtgatt gttacagaaa 480 gctagttatc caactggggc cacagaccag ggctagattt ctagttgggt gacctgatgg 540 tttgctccat aagactgcgt tgtagctcca gaaattccta ctgtttgaag tccagactgg 600 t 601 <210> 55 <211> 501 <212> DNA <213> Homo sapiens <400> 55 ttgggaaaat gagacaacaa actatatccc aaagtgagtt atattaataa taacagaagt 60 gtaagttctg tatgacccta tttttacaaa cataaaaata catttttatc agcttgcaat 120 tgtaattaaa aggaaaatgg cagtttgaaa aatcttttga cgttgagtaa aatataactg 180 catgaactgt accattgaac tatgaagcag ttaatggcaa tgaagctgga gtgattttaa 240 taacgttctt ytaaataaaa gtcactgggg tcattttaca actccagtca ctgtgttcat 300 tcctagttga gttcataatg gacttcataa tagtcttaga gtctagtgta cctctctctg 360 tcattctctc tctctttttc tctcccctga tgacctgcct ctctctgtct ttcaaaaatg 420 tccttaacag aaactctttg gaggccataa gttttgtttt cattttttct cattcataga 480 gttctgattc acagacttta a 501 <210> 56 <211> 754 <212> DNA <213> Homo sapiens <400> 56 tccctagcac cctgctctct attcagcaca aggccagcag tggacatcgt cgtcttgcat 60 tattcaggtt tataggccaa tactgaaatc tatcttattc atcatcccgt gagcagggga 120 aacatcatta gggttttcta taccaggatg atagtgagca tgtagtagtt tttgtttttt 180 tgtgttgttt gtttgctttg taattttgtt ttcttttgtt tttggagtat tcactatgaa 240 gataagaaag ggtragaata aaatgcccca aatgaccaga ggaatagaga tagaagtcag 300 gtccctcaaa tttgttggag gagggggaca agctgggagg ggggacgtgc tgggggcggg 360 gcgggaacaa gcccaaaaag ggacagctgc tgcggtgcct cttttgtgtt tgtaaatgtc 420 ctccccgcaa ggtggctcta gcctgtaatc ccagcacttt gggaggctga ggaggatttc 480 ttgagcccat gagtttgaga ccagcctggc aacatagtga gactctgtgt ctgtagttcc 540 agctactccg gaggctgagg tgggagggtc ggttgtccag ggatttgagg ctgcagtggg 600 ccgtgatcgc gacactccac cccagcctgg gcgacagagg gagaccccgt cttaaaaaaa 660 aaaaaaagtc cttgatcaag agggcttcgg gtgtttccat ctgtggagtg aggggacggg 720 ttaggtgaat tctaggggcg cttccacctc acat 754 <210> 57 <211> 955 <212> DNA <213> Homo sapiens <400> 57 ctgtggcatc ctgtcccaaa tttcacaaaa ctcttacaat aaaattatgt aacttggctg 60 ggcgcggtgg ctcacgcctg taatcccagc actttgggag gccgaggcgg gcggatcacg 120 aggtcaggag atcgaggcca tcccggctaa aacggtgaaa ccccgtctct actaaaaata 180 caaaaaatta gccgggcgta gtggcgggcg cctgtagtcc cagctacttg ggaggctgag 240 gcaggagaat ggcgtgaacc cgggaggcgg agcttgcagt gagccgagat cccgccactg 300 cactccagcc tgggcgacag agcgagactc cgtctcaaaa aaaaaaaaaa aaaaaaaaaa 360 aaaaaattat gtaacttgat aaaaaataat actcataata agtcttactc tgtttgactg 420 tatctcttca tgatctttct atcgttggtt ggtataggta catatatcta tatagagttg 480 taatcaagat gctaggcagt ttgttttgtc ttttatttaa tgccttattt agtgctgtgc 540 taagtacttt acatacatta tccgatttaa tcctcaaaac aatgataaga aaggtactgt 600 tactgctctt ctttgacaga aggggaacct tagccctgag ggtttaaaat aaggtcataa 660 aatagccagg agaaagtaga agtgggtgtg gggtggattc agatctaggt ctgtgtgatt 720 ccaaagctca gaatcttacc taccaarcca tactgccttc tttgtgattg actctcaact 780 agattgttaa tgaaaataat gtgtctaatt aatagaaatt ctaacttttc agcatttacc 840 agcaaatttt tatatgagta aagcccatat aaagagtgct ccaatttctt gttttattta 900 ctcttgtagg aattgaaaga tgttggccat cgtgatcaga tggctgcagc tagag 955 <210> 58 <211> 601 <212> DNA <213> Homo sapiens <400> 58 gctgagctcc tgtctttagt actagggcat tgttcattat gttctggaaa ttcccttcct 60 acctatgtaa acctaatcta ctctttcttc aggccccaca tttgtttttc atctctttgc 120 tgaaggccat ttcaaactac atcatcttac attatttctt tggtgcttga agttttgtgc 180 cttattgtat actcccttga attgttgttt aattgcattt cttttatcca ttttattctg 240 caactaggtt tttaagcctt tggaacatga caactcctta aaaatattca ttcatggtct 300 rgtataatgc tgcaagaggt gctcagtaaa tgcttgctta atgaactcat gctggtttgt 360 aggaatgaat aaaatgaata attttggatt ttcatggtgc taaggaggta atagtgtggt 420 ggaaaaaacc aaagaccttt acccttatgg gccttacatt ctacagtgga tgaaggagga 480 ggctgtgtgg tttatttcta cttcctatta gatctttcac tatacagatg acatttgttg 540 aaaaaattaa accaaatact ctggaataag caattaagtg aaagtgatat cttagagcag 600 a 601 <110> AJOU UNIVERSITY INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> polynucleotides comprising single nucleotide polymorphism,          microarrays and diagnostic kits comprising the same, and          analytical methods using the same <130> DP090042 <160> 58 <170> KopatentIn 1.71 <210> 1 <211> 582 <212> DNA <213> Homo sapiens <400> 1 tttcacttaa ttattttggg tttgctatta tatatagaaa ttactcacaa atattttttc 60 tgcttttcta atatttagct gtattatttc tgtctcatgg tatgcagctt tgagcagctg 120 aagttaaata gaagtggtat caggagatac acggagacac agttcagtat tttgagtccc 180 tggatcgagt tcagctccca tctctcagcc ttcctaagtc acatagccac tcagagcctc 240 tgactcctcc atgcaaagtg gaggtgataa tgccttcctt atagattttc ctgagatgta 300 gatgcaatat ctggcatgca ctaggggatg agtaaatggc aactatagta aaactaacta 360 tcactgttat cttcctgatg awtgtcatat acctctttat tctgatgtct ttttaacaat 420 ctctaagatt tctccaccaa gaatacattg gctgttgggg gttctgtgtg agcctaacca 480 ctcctcctca ttgcctctag atttcaagct aattgggaag aagacacaga tcccagagga 540 aattaacatg caatattcac ttaattgctg ttttggtggt at 582 <210> 2 <211> 1071 <212> DNA <213> Homo sapiens <400> 2 taaaatcagt gcagctcaga cttgtccata gagaagtctt tcttgatgat cacaggattt 60 ctttcctgaa atctcacggt ccattttatt acttaagtct gtgtattact caggttctcc 120 atagaaacag aaccatttta tgtgtatata aatgaggaat gacccatgca attatggagg 180 ctgagaagcc cacaatatgc cttctgcagg ctggagaccc actaaatctg gtsgtataat 240 ttaacctgca tctgaaggcc tgagaaccca ggagaaccaa taatgtaagt ttcagtccaa 300 gggcaggaga aatgtgatga gacattccag ctcaagcagt gaagcaggaa aaagagggat 360 aaattcatac acatacacac acacacatat atacatatat atatatatat atatatacac 420 acacacatat aaatataatt tttttttttt gagatggagt ttcactcttg ttgcccaggc 480 tggagtgcaa tgtcacgatc tcggctcact gcaacctctg cctccggaat tcaagcaatt 540 ctccggcctc agcctctcga gtagctggga ttacaggtgt gtgccatcac actctgctaa 600 tttttgtatt attagtagag atggggtttc accatatcgg ccaggctggt atcgaacccc 660 tgacctcagg tgatacaccc acctcagcct cctaaagtgc tgggattacg gggtgagcca 720 cggcgcccag ccaaagaggg atgaattctt acttcctctg ccttttgctc tattctggga 780 cctcaataga ttggatgata ccaatcactt tggcaggggt gattgtgggc cttgcaatct 840 actatactga gtcactgatt caaatgcaaa tctcagccag aagcaccctt acagtgtaac 900 accccaaaac aatgtttctc ctgggcaccc tgtggcctac tcaaatgaac gcataaaatt 960 aactgtcaca gtctataatg gagtataaca tgcggcactg cctggtacac cagtcttcag 1020 ctctgtcatt agaaacccta gggcttgaac atgtttcagg gaaaaaaaaa a 1071 <210> 3 <211> 201 <212> DNA <213> Homo sapiens <400> 3 atactaactg gccacttccc ctttgtccct gaagtggaag gaaacattca gacccatcat 60 atccctttaa caagcatgcc aggttataag cctgtatgca rgtgatttct ggagaatcca 120 tgtttcactt gtgactgtct ctttgtaaaa cacaggacga agggaaagat atggttaaat 180 ccaagtcaag ctcctttagg g 201 <210> 4 <211> 1136 <212> DNA <213> Homo sapiens <400> 4 gacagtctaa cagcaatcct gaggaggcta aactcctatc cacctgctgc ctaacactgg 60 gcaggcttac atgcctgctc catcattctg atttcaaaac cactactgct ccatcaggcc 120 agcatcactt caacaaatac ataaacatgc atctttctgg tattagagat taagaacttg 180 cctgctaaat actgcaatgc rcaatgccag gatagctcat aaatgggaag tacttcaaac 240 ctctttgaaa gcaacacaaa tataactggg gtaagatgtc tttctcagag ttatgaagat 300 cttttaaact ccttatcttg aaccgtaaga aaatcacaaa ttaatttttg acaaagtgtt 360 ttcaaattaa ataaatgctg ctctacaaca tggatgaact tggagggcat tatactaagt 420 gaaatagaca cagagaaaac tattgcatga tttttacatg ttctctaata aataaaaaca 480 agagagtaga aaggtgggtt accatatggt gggagtaggg gacacttatg tcaaggaata 540 caaagttgca gttatgcagg atgaataaat ctagaactct tggccagcca tggtggctca 600 cacctgtaat cccaacactt tgggaagcca aggcaggtgg atcacttgag gccaggtgtt 660 cgagaccagc ctggccaata gcacggaacc ccatctctac taaaaataca aaaattagct 720 aggcttagta acacaagcct ctaaacccag ctattatgtt tgggaggctg gagcatgaaa 780 atcacttgaa tcagggacgc agaggttgca gtgagctgtg atcgtaccag tgcactccag 840 cctgggtgac agagcaaaaa ataagtaaat aaaaaatcta gagctctaat ctacagcatg 900 aagcctatag tcaatagcac tgtattgtat ttggaaaact tgctaagaga gtagatttta 960 ggccctctta ccacccacac aaggtaactc taagataaca gatatgttaa atggcttcac 1020 tgtagtaatc atttaactat gtatatctaa atatcacctt gtatacctta aacatataca 1080 gtaaaaataa aatttattaa ataaaaaata aaaataaatg ccgctgtcaa aaaagc 1136 <210> 5 <211> 501 <212> DNA <213> Homo sapiens <400> 5 ttactgatac aaactgctag ccagtaaaaa ctgaaatttg tcattggggc ttctctcaag 60 ccacatccca ctctcagaag atcctaaaaa gccagtttgc acatgtaaaa ctcttcattc 120 aaaccacgaa atcttcatga tatcttttta cttaaaagta aagttttatt agttattgat 180 gacctctcat cagcaaacct ccaaaataca taatcatagt atagaatggg aatttagcta 240 tcactctcag raaaatacac ctgcccactt ctaagccacg tagtccagtc tggggccaga 300 taaggccctc ctggccatgg gaaggactga cttccatccc cagggtcctg gacgctgggc 360 tggcactctc aaatgggacc ctctggggaa ggctggcaca gttgctcttc atcagagggc 420 caactttgaa atagaggaga cagggagcct tcccccacct tctcccctta catgcaggca 480 gggggtagag gggcaagggc t 501 <210> 6 <211> 501 <212> DNA <213> Homo sapiens <400> 6 ataattactt gatcataatc aaatgggaaa aaaaatcaag tgtttagtgt tttattctcc 60 cttattcatg ttttcaaaag agaacttcac cttgagaaaa acactcttgg agtaacatgt 120 cccatagagc tacttactga ttcaatattt actctccctt tacattaacg gaatcccaat 180 aattgaggga agcaatatgc ccagttaaaa tctacacacc aagcctactt ttcagctagg 240 gataaccatg ygatgttggt cagtaagatg tacgtagaag tccttgggta gaaatgcaga 300 gaaaagctct tcatataaga taggggatgg gatgtaggga taaactaaac ttgtttgcaa 360 cactttgcct tttgcttttc tagaacatag aatatgaaca taattgttta agcagctata 420 tcttaacttc cagggaaaat ctaaaagaat cacaaaatcc tttgccctga tattttaatg 480 ccaccaacca tacacctata a 501 <210> 7 <211> 1658 <212> DNA <213> Homo sapiens <400> 7 cctaggagag tgcatgaaaa gatacgtctg gaatagagaa actacttaga gtttggaacc 60 aatttgtaca ggtccttaaa taacagtatc tttaaaccaa catcccttac ctgtgcctat 120 tgccccagat gagaatgtca ttaccttgag tgaagaaatt aggataagtt cctagcattt 180 tccaaagcgt tgtctacagg tgtttcaatt tcatcttctc atgttaactc ctcagcccaa 240 tccattctgg cctccgaccc ttacacaaca tggaattatt cctcttaagg tcacacatgg 300 cttccttgtt gccaaattaa tggacccgcc tttctgacct cattctgttt taagtgacat 360 ttgacagaat tagcagttcc tttccttgag aaacaccaca tcctcagctt tgggaaagcc 420 agacggtttt tcctcctgcc actttggcca ctgctcttca atcttcctta ctagctcctc 480 tgcccatccc caatatctac atggcagagt tcctcaagat cttgcacaaa tcttattctc 540 tccctctaca cacccaatct gctggtctca cctttcccat ggcttacata tggtccatat 600 gataccatct ccctaattta catctctagc ttagacctgt ccttcaagtt ctagtctttg 660 taatctaata tcttatttgg tatattcact tggatgtctc acaagaggcc agacttacag 720 atgagaatat tattactttg cagatgagaa tattattaaa agaagtctga tattgacttc 780 ttgattttac ttcaaaatat gtttctcatc tacttctctc tcaatgaatg gtaagctaag 840 aacctgagga aaaaaaacct ttactcttcc ctctccctta cctcccaaat cagtctatct 900 gtaattcctg ttaattctat ttcaaaatca tatcttgttt attgctcccc atctccatgg 960 ccaccactgt agtccagaac agcactgttt ttctcacaga atgtctccta atcagtttct 1020 tgctccttct gttgccctct gctaattcat tatacccaaa gcagcagagt aaactttcaa 1080 aaattaaaaa tgtaaaccaa atcttgttaa catctgctta ataccctgca gggtttccca 1140 ttataattgg aatgaaatct aaaggcttta catgccttag cctctcatta tgtctcctct 1200 tggacctctc tcctgcygtt tgccacacac cagctgcact ggccttcttt caattcctat 1260 aacaggccaa gttctatgtc tgggaggctt ttctcaaggg tattcatatg gttggctgtt 1320 tctcatcctt tggggtcttg gctttaaact tccgcagctc agaaagagcc tcttcaccac 1380 tcacctgagt agagtccttt ccccacattg ccactgctct attccatgac agcatgattt 1440 ctttgtttca tagtactttg caatggcaaa tggcatcttc atattaagaa cttctagttt 1500 ttctttttct aatcccttat ttcttggaag ttattatttc cttttatctc tgtaaggatc 1560 ctaaccattt acgttgcatt ttatgtgttg ctttttctga ggccttctct tattttttag 1620 ttccttttca tctccaagtt cgtcttcact ccctgccc 1658 <210> 8 <211> 601 <212> DNA <213> Homo sapiens <400> 8 tcttaggtac tccagtgtat ctaatagttt tacctaccca gatgtgttcc tgatgatgat 60 gctggtttca cttgcaaatt cccatataat gcttagccct ctggtttggg tattttaatt 120 ttactggata atgatcgtgg tgattttaaa catttcctgt tgcttgttaa actgcatgcc 180 cgattcagct ccaaataaca gcttttacac gcaagtgaaa atttagctcc tagtatttaa 240 caactactat aattttaaaa tctactttca attaagaaaa ccttgtaatt ctaaaaagtg 300 rttatgttcc aaagaagtgc tgaaatgtca actgaataca agtccacttt atgtctggca 360 ggaactgttc agttgtcgtg tggcttagca ttgaaaagct cgctccaaag tgctactgac 420 aggcctggtc tagtgtggca tttaatattt ccctttatac atttccccat ggtgtcagaa 480 caatctccag taatcaaaag aggtgaaaag agctagaata aaatattcgt taaatctaaa 540 catacacaat tgacgtgttc aagaaaatgt gcataaggag tgtattattg attttaacaa 600 t 601 <210> 9 <211> 601 <212> DNA <213> Homo sapiens <400> 9 agcagtatca gaaatggtta taaagagaac cttaagtttt aaggttcata gtgtgtgaat 60 cctttcagat aagccagata actctttttt ctctcttctc tttttattta gccaattagg 120 ctaattatat atatattcca aggctatgtg ccagttcaac ccagagctgc tttcagttca 180 gcttttgtat tatttaagtt gtaagcccta gttttgtaat tcccaagaaa aaaggatatt 240 gtcttaagaa ctgagattct gttgctgaaa tgctgtaact gtagtaatgt aaaccattgt 300 stccatgatc atgtttcctg tgttgtagat tatgtaactg catggcttac atgaggggtc 360 ctcatgtaag tgcagcaagt ctaccgtaag cttcattaga tttaagtgta caagagaata 420 aaaagcaatc tatttaatac ctttttggta gaaataaaat caaattttta caatttaatc 480 attagctccg caaagctgtc atggaccacg tttcagattc tttcctggaa accaatgttc 540 cacttttggt attgattgaa gctgcaaaga atggaaatga gaaagaagtt aaggagtatg 600 c 601 <210> 10 <211> 801 <212> DNA <213> Homo sapiens <400> 10 gtcacccctg ctggagtgca gtggcaggat ctcagctcac tgcaacctct gcctcctggg 60 ttcaagcaat tctcctgcct cagcctccca agtagctggg attacaggca catgctacaa 120 cacccatcta atttttttgt attttttcta gagacggggt ttcaccatgt tggccaggct 180 ggtcttgaac tcctgacctc atgatcctcc cgccttggcc tccaaaagtg ctgggattac 240 aggtgtgagc caccacaccc agaccagaaa agccattttt atgacagtat atctgaggag 300 ttcatcaaga gcatatactt gtctgggatg atgtaattga gttggcacgt cccttaagag 360 ctacagtgca cgagaacaga aagaattcat tattgccaaa ratttctaga ggacatgaat 420 ataagctttt tcttgaaata tgcatagaat ttgatgtgag aaacaagggg tagagatatt 480 taaaaagaga gtgatggcag ttaataatct tggcatgtcc ccgccattgt ggaagtatta 540 acttaagtgt tgtggaaggt gccttttggc ccacatcaga aaaaaaaaaa aaaagttaga 600 aataaaattt taggtgaaat caaattcctc cagagttcaa gaaggtaaac tgagtgaaga 660 agactggggc tataatgaga cagagtggaa gagactatgg catggtagag accatggcca 720 aggctcagtg aaaaagagga caccactaag ctccagccaa ttcccgtgaa aattatgttg 780 gtcaaaactc cactggccac a 801 <210> 11 <211> 601 <212> DNA <213> Homo sapiens <400> 11 ctactgaaat tgtttgttcc cacctcagca ctgctatatc taatttacac tgtacttata 60 aaaagaataa atatttaagg gaactcagaa aatggagctg gagcagggcc cctgtagtct 120 ataaaaacct agttgtcttc tggagaccaa ataattcact gcaatccact cacatgcctt 180 tgaagaggct tctcacccct tgtcaccaga tgtctggcag tttgtgactg gaactaccca 240 ctccatgcct ggatggctgg atgtgaggag gacaggcctc cctcctgcat aatagcatcc 300 rgagagaacc ccagaaaagc ccattaaaca tttatttagg taaaatcact gtgtcattaa 360 cttatctcca tacacacaca gaaagggaac taaaatagat tttaatggag caactaggag 420 ctttctaatt tttcctcttt tgtttgatga gcaatcaatt caagtgtgtg cactgggtac 480 atgtgggggt acccgtaatt ggggagtgtg ctgtattaga gggtgttttg tgaacaccag 540 ttaatagaaa aaagaatacc caacatgcac acaccacttt atgggtttgc aaagcatttc 600 c 601 <210> 12 <211> 601 <212> DNA <213> Homo sapiens <400> 12 caggatattc cacttggccc cagtgtgact actcaagaat gggaaggagt caggagtctg 60 actttttaag ggttctcatg tgagggtgat gttcctgctt aagaggaggg gatttgacgg 120 cgacttctct tggcctccat tccttgtcat gtggggtaat ctgactcaag gatgcctcca 180 tgacagtttc atcatatatg gcaccagctg ttgttggagt gggaactggg tcttctctgc 240 agtcagggga agttggaagc attcagaaga tgcccagagc atctggagcc tagttgacac 300 rgtactttat gatggcagat ggaggcacat gtcgcaggag attccggagt ggttcggtgt 360 cagcacccct gcaaggcggg gtcttgttag ttgacctaag agattccatt ccaatgtgct 420 gaagatggat tttcaacttg gcctttgcgg aggctaagaa agattcattg caaatttctg 480 tttacttgtc tggctttcgt gggatagcca gtgttttccc ttgttttagg ttatctttgg 540 ctggagggca agaaaaatag tcaatgatgt cttggaagtt taagcctaca ctatatggct 600 c 601 <210> 13 <211> 661 <212> DNA <213> Homo sapiens <400> 13 tcctttgcct atagattcct gcttcccttc cctcttttcg cgcgcgcgcg cacacacaca 60 tttttgcata ggtgtttgcc tgatcaaagt gggatcattg ttcacaaatg ttcacaaacc 120 tgcatcatct tattcatcag taactcatgg aaatccttgc aagccttctg gtttacctct 180 aatttgttca ttttattgct sactacacta tgtatttgac cactcccctc ccatgtgttg 240 tgtgttttta tttcagtgtg ctaacagtag gcattatttg ttttaatttt gctgatctga 300 tgagtgtgaa gcagttgttc attattactt tttttttttt gtctcgaact cctgacctga 360 agttatcctc ccgcctcggc ctcccaaagt gcttgggatt ataggcgtga gccactgcac 420 ccggcctgct cattattaaa gttgcatttc ccttgaccac tgttgaattc aaataatctt 480 tttaatgtac ttgtaagtca ttggatttgc ttttttatga agtgtctgtt tgtattcttt 540 gcccattttc tactgtcatt tgtatgtttt tctttgccgg agctcttggt atattatagc 600 tatttgtctt ttgacattgc gtgtgttttc ccccgccttt tttaatcctt cctagccagc 660 g 661 <210> 14 <211> 1335 <212> DNA <213> Homo sapiens <400> 14 ataatcttgc catgaggctt taatgaataa caagtacaaa atgcccagtt cataagagtt 60 cctttaaaaa gattagtaca aggtgctgtg agattttttt aaaatgaatc agatatgatt 120 atgtcctcat ggaacttact atctaggaga ataaataata catacataaa agtaatcata 180 atactcaatt tttagaactc ytattatgac ctggatatat gtattcattt tacagatgag 240 gaaactaagg ctcagagaag gaaagtgact tgactaaggt cacaaaagta ggaaattgca 300 aaactagaat ttgaaccttt atctgctcaa ctgcacgttg cattaatata acataggcac 360 ttatttttaa acctttaaaa gtcttatagt cagtaaatac actcaacaca ggtacagatt 420 taaaacttcc tatacatata agactataag acacctatac aaattttata gtacagggtc 480 aggggaaggt gatgccagta ctcccttagc tgccccagct ggtatctcag taggtaatgt 540 gtcccctcat tccactgggc ccaggtcagc actagggact cacctatgag ttgcagtcct 600 tgtggcctag actatctctc aaagtttatt tggggctcca gagcactcta gcccatggtg 660 gtgagggttg tggaaactca agttctgact gtggaaattg gcaattcccc tctggctagg 720 gctggtttaa aagctccctc catgggtgtg tgtaagctga atttggtttg gttttccttt 780 ctgctctagc aggacagtgc tgagttcaat tactcacaat tgctgtgctc tccctctttc 840 cagcatacag aattgctctc cacaccactc tgcagctgcc agaggatctg ggaggggagg 900 gctggtgctg gctagtcaag actgtttttc ctgccacttc agggcattat tcagtgatat 960 gaagtcaaaa ccaggcactg tgagtgctca cccgattttt ggttcttaca aaggtgtttt 1020 ttttgtgtgt gtagatagtt gtcaaattgg tatccttgca ggagagatga tcggtggagt 1080 tttctattct acaatcttac tcttccccaa agtcctctgc ctgcattttt aatttttgcc 1140 aagctagtat gtgtgaaaac atatctttct ttggtttcaa tttgaaatat cttgagtagt 1200 ttaagcattt atttacatat ttatgaaaat gttcatagtt cttctatgaa aacctgatca 1260 tgccttttac tcatttttct actaggttat tcactgactt actgactttt agattttttt 1320 tttctagata ttaaa 1335 <210> 15 <211> 601 <212> DNA <213> Homo sapiens <400> 15 aaacattaaa ttgtacacta tcaatgggtg aattttaggt gacctatatc agtatataat 60 ctgtatcagt agataattat cttatatatt tgtaaaatta tttaaagata tttacatgcg 120 tttcacatgt cagtttgcta atgatgtgat atgtatttta aattatattt cctgtaggag 180 ttcaggcaat ttgttcatct tacatgaagt aaagagtatt tttcccattt tgaaacacgg 240 cctgtgtctg ttattgccac cagaattaca tggtctacat taaatcctat attgtgtaca 300 ytgttgacct ctttaatctt ctgactttgt atgggacaaa ctaatggcct acaattttct 360 gtgactattt catttaaatt atacaaatgt tgaatgaagg attgctgaat taaaaatagt 420 taaaaaaaaa cccctcaaat tatactgaac aggtgtcatt tcaagctgag tgtttttcat 480 ttgggggcag ggtgtcttct ctctgaaaaa gtgttagatc tctacattat gtacattgtt 540 agcccttaaa gatttttgaa tggtttggat tattagaaga ttctgcatat aatcacctag 600 a 601 <210> 16 <211> 1064 <212> DNA <213> Homo sapiens <400> 16 tttattttta tagccagatg tgataatgtg cctctttctc ccccagcatt tgtccaggtc 60 agaaaaggcc ctctggagac tctagaatag gtcaagctgt ggtctcctga ggaaggatat 120 tcagaatttt cattctaact gctagagttt atagtggctc ttaatgaagt ctttcaattt 180 gaggaatctt ccatgaagac tatacctagg atatgactgc ttttcatcac ccccactttt 240 actaccttag ttcaaaccac cttcaaatgc tagggttact gcagtagcct cccaactaac 300 cacctttctt cgccctttcc cctcattttc tgtggactat tctcracaca gtacctccta 360 cgttcccttg aaaagataaa tctgatcaca tgatgactcc tgcttaaagc attcaatgac 420 tcctcatcaa actaaaagct aacatccttc taataacctc aaaggcccat ttccctatta 480 tctcatggac ctcaaacctc atcttgttac tgtcctccaa gctcacacag ctctatcatc 540 tgtggtcttt ttcaccatgc tgattctttc cttaaacatc agtttctcag ggaggccttc 600 cttgactacc tcatatgaag ctgcaatcac ctctctgcac tactttctct gctttgattc 660 cagagcagtg actaccatgg gatatataat acccacgtaa attaatatat atatatatat 720 atatattttt taatatctgt ctctccaata aagaaaggtt aagctctgtg agagcatgag 780 tttgtgtctg tcggtttcac tgttatttcc atagcaccca gaaagtgcct ggcagtttgc 840 aggagtttga tgaacatttt ttgactatta aatgaaagtt cttcctggtt cctttaacca 900 accagtgata atgtcttcct cccttgagat gccgtcgcag gttgtctgta tgcctttctg 960 aactgatagc acagcaagga gactggacct gattaagcag gggaaacctt tggctgggga 1020 tgcaatagac atagaacaca gttaatgggc tagagaagag acag 1064 <210> 17 <211> 953 <212> DNA <213> Homo sapiens <400> 17 taaacacaca cacacaatct ttaaacacac acacacacgc atgcacacgc acaccacacc 60 ccgccctcag tttaaattga gaagggagtc tggggattag atatacttat gaaaggttag 120 acttctgttt tttgtttagt tgttgagact gggtcttgct ctgttgccca gactggaatg 180 cagagttgca gttttggctt tctgcaacct ctgcctcctg ggctcaagcg attctcccac 240 ctcagcctcc caagtagctg cgactacagg tgcatggcac cacacctgcc taatttttgt 300 atttattgta gagatggggt tttgccatgt tgcccaggct ggtctcaaac tcctgggctc 360 aagcgaccct aaagtgctgg gattacaggc gtgagccact gctctgagcc ctgttatttg 420 taactagcat tttaactaac tgaataccaa gaaaagatta agaagactat taagtggaac 480 acattaggaa agtgggggat gcagaacaat taagattcaa tatatgacat gttaaagtta 540 gaatgtttat tagtcgtcca agtagagatg acaagtccag gggaatggtc caggctggaa 600 acataaattt agaagtcatc atccgtgaat acaggtattt aaagtcacta gcctagatga 660 gatcaccaag ggaatgggtg tagatgggag atgagactca cagaaccatc ctttcctcct 720 aaaccagtct gagaaatctt taaacaatac ctrtaaaatg gcagtcacgg aaaaaaaagg 780 ataggtttca agggaagcat tccctcaaca tcaaagccac ttgaacaagt catgtgctat 840 tggaaaacaa ataggaatat ggtcagctta attcatgaaa atgactggaa acgacatatc 900 aaaggaattt ttaatcaatg aagaatacac atgtatacca tttaggaatt cag 953 <210> 18 <211> 601 <212> DNA <213> Homo sapiens <400> 18 tgaggtggga ggatggcttg agaccaggag tttgagacca gcctgggcag catagcaaga 60 ccccatctct acaaaaaatg agaaattgtt taagagcgag aaaagatact acactgtgca 120 gccagacaag accatgatgt ttatacattt aatctccaat ccacatacac agtgccattc 180 ttgaaatgat ctgtgacaaa ttcagtttcc cctgataact aaatagcatg tagtaatagt 240 aaaagaaagg tgaaggtgaa tttcacttta tgtgggggca ctgttcactg gtatacctgc 300 raccactcca cactgctcag ctgaatgaac cttgattggc taatggaggg agacagagac 360 tcccagtttc agaaaaagtt attttccatt ccatccacag gaatgagtca tcactgggcc 420 catctacccc tttgctgagg atgccacagg atgtggtcgt gtgattagtt ccatggagtt 480 aagccaccgc tggtccagta tccagttact tacagccaaa agcatcccta actatgaagt 540 atattatgaa tatcattaaa atgctaatac aaactttcta attagaatat taataataaa 600 a 601 <210> 19 <211> 596 <212> DNA <213> Homo sapiens <400> 19 gtctgggttg acatcactct gtcactaatc aacagaaaat tgtcaggagg gtcccacata 60 ctctagttag acatagagca aatttcctgc cctttgtttt acttacgtcc ctattgtcac 120 aggttataat actggcccta agtgtgtatt tgcttcaaat aattatattt tgggagacat 180 tgggttgact gtatcatgtt yctacacatt tttttttttg agacggagtt tcactctttt 240 gcccaggctg gagtgcagtg gcacgatctc agctcactgc aacttctgcc ccccaaggtt 300 caggcgattc tcatacctca gcctcccgag tagctgggat cataggcgcc cgccaccacg 360 cctggccaat ttttgtattt ccagtagaaa cggggtttca tcatgttggc caggctggtc 420 tcaaactcct gacctcaggc gatccacctg ccttggcctc ccaaagtgct aggattacag 480 gcatgagcca ctgcacccgg ccatgtttct ccatttttta agggcctgaa gtctgttgag 540 tagagctgcc tatgtgaatt tcatattttt tctttttacc catgtgctac ttatag 596 <210> 20 <211> 501 <212> DNA <213> Homo sapiens <400> 20 tcccaaagtg ctgggattac aggcgtgagc caccgtgccc ggcctggcct aaggtcttat 60 taactctcct ccatttcaga catgaccccc tgtggagtta tagctgcaac aatagcagag 120 acaggattta gccaatgcag ggtgcttttc cagccctagc ttaacctttc cattcattct 180 aaatgaaata aaatctccac aggtaaccca aggactgaaa taggcttcag gtaagaagtg 240 agtgaacttt rtatttttcc tgagcttggt ggaatgagtg tttggaaaag ttaaatggtt 300 taactactga aaaccaccca ggccacaggc atatgattca ttttgtgtga ccttagactt 360 tttcttggaa gatttggggc cagaaaatag gaagccaaaa atagcttcat tgggatcaaa 420 tatttttctt tctggaaacc agaaaactat tcagttctgt aagttccaac aagttcctca 480 ttaacatcac tatttctcta c 501 <210> 21 <211> 1001 <212> DNA <213> Homo sapiens <400> 21 tgcatagtct cctcatgtcc caggaaacac ccagatggca gggcatgtga cctcactcaa 60 ccacaccaat tatagccagg taagcaatgc ctctagaact tctggcccag tagctctgca 120 tctgtgtgta ctcagctaga gcatgcagaa ttccattggt ctgggaaaca cctaggtgaa 180 agagttcatg aggttgctca cctccatcac tagtagtcag gtgggcaata cctgttagag 240 cttctgaccc agcggtcctg cttctgtggg aattcaggta gtaggtagag cctcttgttg 300 tcccaggaag cacccataca agagggcagg tgtcccccac aattactgct gctgatagcc 360 gggcaagcca aacctgctag aactttctgc ccagcagttc tactgctggc tgaatttgct 420 gggcagcata tcctgctact gccttggaaa cacccagact acagggcaga caactccagt 480 caccgctacc tccaatagtc rgatgggcca tacctgttta gagcttccaa tcagtatccc 540 cccttccatc tgaattctac tgacaggtgt aaccctgggc tgctccagaa agtatataga 600 caacacatta gggctagcct gtcaaggata ttgcttgttt gccaacagtg gcccctgcct 660 gagaaagccc catggaccag aacaatcaac aatagaaaca aggatatgga gatagtaatt 720 ggagacaaaa cacaaaccat ccactattcc aaacccagga gtggactaga attgaagcca 780 gtcaaccaaa gccacgtaat atcatactca ctcacaggag aaaaaagcaa acaattccat 840 ccaaaggaca gcaacttcaa ataataaagg aatatcagtc cacacaaatg agaaagaatg 900 agtgctacaa gtctggcaac tcaaaagtga gagtgccttc ttctttccaa atgactgcac 960 tagtactcca gcaaagttta ttaactaggc tgaaatggct a 1001 <210> 22 <211> 1001 <212> DNA <213> Homo sapiens <400> 22 gctgggacta caggcgcccg ccaccacacc cagctaattt ttttttttgt atttttagta 60 gagacggggt ttcaccatgt tagccaggat ggtctcgatc tcctgacctc gtgatctgcc 120 cgcctcagcc tcccaaagtg ctgggattac aggcgtgagc cactgcgccc ggcccaaaac 180 tcacatgttt ctatgacagg gattgacgtt gattacaaaa gaatacattt gttggtagca 240 tatttcgttt attgttgcga aattacacaa taatacagtt aaaattctct gaagtaatgg 300 ccatcacctc tctgaaaaat gacaccaagc attcaacatt ttatctcgtg ttttagtttt 360 ccatggctgc tttgaaaaat tgcaatgaac ttaatggctt acaacaatac acactgatta 420 tcttacagtt ctgtacatta gaagtccagc attggtcctg ctgggctaaa atcaaggttg 480 gcagggctgt gttttcttcc rgaggctcga gggataaatc tgtttccttg ccttttccaa 540 cttctggagg ccgcccacat tcctcggctc ttggcctctc cctccgtctt caaagccaga 600 atagtgggtt gaatcctttt cacacagaat cactctgact tctccttctg cctcctcttc 660 tcccactttt aagacctttt gattacattg ggcctactca gataatccag aatattctcc 720 ccattccaag gtctttaact taatcacttc tgcaaagccc actttgccag gtaagataac 780 ctattggtgg gttctgggga ttaggatgtg gcattttggg gaggccatta ttctgtctac 840 cacaccaact ggcacacttg ttctgtgtgt atgtgtgcat gtgtgtctgt ctgtctgcct 900 gtctgtctgg ggtaattaca taggggcctc agacctttga actgatcagg agagtatgta 960 atttggggtg agggggtgga agtggaattc tgcccattgc t 1001 <210> 23 <211> 1055 <212> DNA <213> Homo sapiens <400> 23 agatgtgtgc acgagaaacg gccagttgcc agtagtgtgc aaactcgtgg cttaaacagg 60 tcccaagagc ctttcatcca ttgatttgtc cttccgtacc tctcttttgg gatgcgtgca 120 tgtctagggg gtcacttttc cattcccctg accccagcac cccaccctca gtctctctcc 180 agcgtcggct gagctcctac tgccatcttg tggccgttca cgtaaggtgc accagagagg 240 cggagcccct gctgtccttg tcctaggact tgatttgcag agatttggga ggcttcctga 300 ctctggggtg ctcatttcct tcacaaacag aaaaagaaaa gtcactcctg ggcacattgc 360 tgtcatgtgt gaggctggaa gcactcccta cgatgggayt ctctcaactg tccctatttg 420 catctctagt cctcacgtag tgcaattcac tgtgtgagtg tgtgtgtgtg agagagtggg 480 tgtgagtttg cgtgagtgtg agagtgtgcg tgtgtgtgtg agagtatgtg tgtgtgtgag 540 agtgagtgtg cgtgcgtgtg tgtgtgtgtg tgtgtgtgtg tctgtgatta ttggtaaggg 600 gaaggtacaa gaagcagggt aggcactgat gctagtacta tacttcaaag tcctcaagga 660 agaagtctcg ttttgagcca aggatttggg tgtttctaga gagagggaaa acgtgagctc 720 cagagctcat gaaaagctcc atcacaacaa aggattgtct tgtcttttta gccacatcct 780 cccattcaca ttgcagcata ttgagatctt ggcactgtct ccactctttc tttggcatat 840 ggctttcaat ttgagctccc tgaggtgaag aaccattcaa gtccacaacc tgcatctcac 900 acagggctga gcctagggaa ggtattaaat gtttcttgaa tgagagaacc ttatcttcat 960 tcagatgctc tgtggtcagc atatcctgtc gattcttctt ccagaaatca ttttcctatc 1020 cctagccccc tctctttatt cccagtgtca atgga 1055 <210> 24 <211> 1498 <212> DNA <213> Homo sapiens <400> 24 aacttttttt atgtttcaca aatattgaaa actaggtcaa cagattctta ccagtttgac 60 tcttttgatt gtgacttttg tgtcaacatt tttgtgaggt ttgcatagtt ttgtcttgat 120 tgtatgtcac agcttatttg ttaatacttc ctgcactgat aggcatttgg cttgttttct 180 gttagaaatc tttcagggta atgctgtcat acacattctt ttacctgttt attttaatta 240 ttattatact ttaagttctg aggtacatgt acagaatgtg caggtttgtt acataggtat 300 acacatgcca tggtggtttg ctgcacctat caatccatca tctacatgaa gtatttctcc 360 taatgctatc cctcccctaa ccccctcccc tagacaggcc ctggtgtgtg atgttcccct 420 ccctgtgtcc ttgtgttctc attgtccagc tcccacctat gagtgagaac atgtggtgtc 480 tggttttctc ttcttgtgtt agtttgctga gaatgatggt ttccagcttc atccatgtcc 540 ctgcaaagga catgaactca tcccttttta tggctgcata gtatttcatg gtgtatatgt 600 gccacatttt ctttatccag tctattattg ataagcattg gggttggttc caagtctttg 660 ctattgtgaa tagtgctgca ataaactttc atgtgcatgt gtctctatag tagaatgatt 720 tacaatcctt tggttatgta cccagtaatg agatggctgg gtcaaatggt atttctggtt 780 ctagatccct gaggaattgc cacactgtct tccacaatgg ttgaactaat tgacactacc 840 accaacagtg taaaagcatt cctatttcgc cacatcctct ccagcatctg ttgtttcctg 900 actttttaat gattgccatt ctaactggtg tgagatggta tctcattatg gttttgattt 960 gcatttctct aatgaccagt gatgatgagc tttttctcat atgtttgttg gctgcataaa 1020 tgtcttcttt tgagaagtgt ctgttcatat cttttgccca ctttttgatg gggttatttg 1080 ttttttttct tgtaaatttg tttaagttct ttgtagattc tggatattag ccctttgtca 1140 gatggataga ttgcaaaaag tttctcccat tctgtagttt gcctgttcag tctgatgata 1200 gtttcctttg agctctcata ttttaagaat tgtataaaag tgtagtttct tagatcataa 1260 gttatgccca aataaagctt tagtgtgtgt attttccrac aattttccaa ggtaattgta 1320 tcaatataaa atctcattgg cagttccaga tatttcatat caaccacaac ttgaaattgt 1380 cagtccattt atgatagtga tttgtttcaa tatataacag aattataaat tacaatgtta 1440 tatccatacc tataaccaat tataaaatat tactgtcatt gttctaaaat aaaagtgt 1498 <210> 25 <211> 985 <212> DNA <213> Homo sapiens <400> 25 tccccacagc agagaaatga ctttgcaaag aatgggaggc aggtttgcct taagcagttc 60 ccagattgat ttttcccttt agcttactga tttgggggtc ccaagattta ttttcctttc 120 acatatgtat cttatggttt tttgtttttg tggttgttgt tattttattt attttttgag 180 acggcgtctc gctctgtcac ccaagctgga gtgcagtggc acaacctcgg ttgactgcaa 240 cctccacctc ctgggttcaa gcaattctcc taccttgcct cgcaagtagc tgggattaca 300 ggcacccgcc accatgcccg gctaattttt gtatttttgg tagagatggg gtttcaccat 360 gtagccaggc tggtctcgaa ctcctgacct caagtgatct gcccacctcc gcctccaaaa 420 atgttaggat tacaggcatg ggccacagtg cccggccatt aatcttatgt ttaaagtact 480 tctaattcac atgtgtgtaa tcagcaagca catggacagg agaggttcca aaaaaaaaag 540 gaggttgtaa ctcccctcct ctaacagcca gagaatctac cataccagtt aaatatgctg 600 tctctggagg gagagtttcc cactgctgaa ggatccaata cagacatgac aataaagatt 660 acaagtgaaa gggatttaca caccagacta agaacctatg attctatgag aaaggaccac 720 tcactctggt gtgaagagat gggatcagat tccctgcgga gaagaaaaaa cttgactcag 780 aaaagagcat ctccagggaa aaggaaagct caaagcaaat agcacccaat aagacaagtg 840 gtaaatcact gggtaacrac cataaaaagg atcgacaaaa agctgcagaa acaaacttgc 900 cctgccttac ctcttccagg tggtgtttat gactctgcag catgctaagc tggcctgtgt 960 agtcaagcta cctaaaaatc atgca 985 <210> 26 <211> 601 <212> DNA <213> Homo sapiens <400> 26 gcatcagtgc aatcaagagt aattattttt tgaaggcctc tgaggaagtg ggcactaatg 60 cttgcagtat catggtgccc agagagcaca gccccttcca ggtcaccagc catctttctc 120 acctgcccac tctttgggtt caagaggttc aggctgtgga accaaagaag acatggagtt 180 tgccttaaaa ttggtagagt gcagagttcc cattgatgga attgtgtatc attttttggt 240 ctttatcttt ctttagctaa aagggctaca tatctatttt tctaaacttt ctcttggttt 300 ygctgtagag cagctttttt ccgcaaacat atgactttga cttaaagtgg caatactact 360 tctggaaggt actgtccata tgatctgttt caattttcat tgctttagat gttcatgata 420 aggcaaagga gaagtaaaat ctaacctgtc tcctctctgt aaatggtttt aagcaaatta 480 actgagtcaa gtggcagggc ttagatggct gtagttgtct gcattcctcc acatgagagt 540 ttgcttttca tatgtattgc tgattaggga gagttattcc cctacttgga gaagcaaatg 600 t 601 <210> 27 <211> 701 <212> DNA <213> Homo sapiens <400> 27 aaacttccac acagtaggca cagatggtac aaaagagggc tgcctgatct caaactagtg 60 gttgtggtgt cagtcttagc ctacctcttc gaatagtggg aatcagagac attttagttg 120 ttaatacaag taactgtggt aggaaagata ataatttatt ctcctaacaa atccagagat 180 acttctcact gttctacgaa rtcttggctc tgctgggttc tctgtggaag ttaactgctc 240 caagtgtttt tcttttctct tctcttctct tccgctcccc tcccctcccc tcttttctct 300 tttctctttt ttgagagagt ctcgctctgt tgtccaggct ggagtgcagt ggcgccatct 360 cagctcactt caacctccac ctcctgagtt caagcaattc tcatgcctca gcctcccaag 420 cagctgggat tacaggggcg tgccaccacg ctgggccaat ttttgtattt ttagtagagg 480 tgaggtttca ctatgtggcc aggggtgggt ctcccaactc ctggcctcaa gcagtccgcc 540 cacctcggcc tcccaaactg ctggtattac aagcatgagc caccacaccc agcctctttc 600 tttttttggg acatggtctt gcagtcatgg cttgctgcag cctcgacctt ctgggctcaa 660 gctattctcc caactcagcc ttccaattag ctgggactat a 701 <210> 28 <211> 601 <212> DNA <213> Homo sapiens <400> 28 gatcccagat tcctgtgggc tatctccccg catggctggc cacacggcag gtttgaaatc 60 aatacttgct ggttcaccac ctaactgtgg accctcagtg tccctccctc gctcatccct 120 cttgctcggg gtccgtgtgt gcatccagcc agtcaagtgc cttgttgcca tggctcaggg 180 gctcatcaga acagggaaga ttttatccac tcacagggta gccgtgggag gtggagagac 240 tctgtaagct ttgacacaca ggggattctc attacagtga tgttattaca ggtgtctgga 300 yggttgtcat tagagactgg aagtggggcc caaatctctt actcatgtag agagcctttg 360 gaaaaagcca tttggaaaat gcctcgagaa ccactgcagc ttcctccttt gtattagagg 420 cccttgccct ctaacacaaa gttgcggatg cctagacccc agctaaaggc tttctgaggt 480 tactgtctcc atcaccagca gtgttagcag ctgccagggc tcagccctcc tgaggtttca 540 gcaccagggt gagggtgact catggggtag atgaggggca accatagttg aagctgactt 600 c 601 <210> 29 <211> 601 <212> DNA <213> Homo sapiens <400> 29 gaatgtaagt gttcttaact tttctgtaga ataaacaccc caaagagatc ccagattcct 60 gtgggctatc tccccgcatg gctggccaca cggcaggttt gaaatcaata cttgctggtt 120 caccacctaa ctgtggaccc tcagtgtccc tccctcgctc atccctcttg ctcggggtcc 180 gtgtgtgcat ccagccagtc aagtgccttg ttgccatggc tcaggggctc atcagaacag 240 ggaagatttt atccactcac agggtagccg tgggaggtgg agagactctg taagctttga 300 yacacagggg attctcatta cagtgatgtt attacaggtg tctggacggt tgtcattaga 360 gactggaagt ggggcccaaa tctcttactc atgtagagag cctttggaaa aagccatttg 420 gaaaatgcct cgagaaccac tgcagcttcc tcctttgtat tagaggccct tgccctctaa 480 cacaaagttg cggatgccta gaccccagct aaaggctttc tgaggttact gtctccatca 540 ccagcagtgt tagcagctgc cagggctcag ccctcctgag gtttcagcac cagggtgagg 600 g 601 <210> 30 <211> 1001 <212> DNA <213> Homo sapiens <400> 30 aaaagcgatg cttgcaaaag atccttggac ttcgttgctg gaggagctta gaaggaaatg 60 cagcagaatt ttggatgtca caggaggaga atgttccaag gagaggtcaa cagtgataag 120 tttggacttt gctgctggag gagcttacaa ggaaacacag cagaattttg gatgtcacag 180 gaggagaatg ttccaaggag aggtcaaaag tgataaatgt tgaccactga gaggttaaat 240 aacaactgaa cagttcttcg gatttagcaa gaacggcttc attgcagtgt tacagtgaac 300 actagaatgt ggtaggttaa ttaatgagtg ggttgtgagg aagtggaggc agccaacact 360 tcttctcaaa caatttgctg tgaatgggaa gagagagtta agtggtggta gctggagaag 420 aagctgaaat gaaaataaag aatgttatgt caggtgactg agaaggtagg aggaaggaat 480 gggaagtgga gaacagctga yagcattagc cttatatgga aatatggtag ttgttacggt 540 tgttcgtaga tactttgttt tcccccatgc atatggtagt gtcaggctgt tcagactgcc 600 ataaccatca gatgggcagc atatacacca tacaaatttt tttctcacag ttatgggagc 660 tgggaagtcc aagatcaagg tgacctcaga tccgtgtctg gtgaggccca ctttctcgga 720 gatggcactt ctctgtcttc acatgattca agggacaaac gagctccctt ggacctatgg 780 atttttgatt ttgtcatctc ttcaaacccc accttccttg tatcatcaca atggtgataa 840 ggtttcaaca taagaatttt gtggggatac aaacatgcag acctagcagg taggatttaa 900 ctttcctaat attttgaact cagcatggcc acatgactaa ctttagcctg tgaaatgcaa 960 ggagatgtgt gtcattgcta ggcagaagct tgcagcacca t 1001 <210> 31 <211> 1335 <212> DNA <213> Homo sapiens <400> 31 gcccagttca taagagttcc tttaaaaaga ttagtacaag gtgctgtgag atttttttaa 60 aatgaatcag atatgattat gtcctcatgg aacttactat ctaggagaat aaataataca 120 tacataaaag taatcataat actcaatttt tagaactcct attatgacct ggatatatgt 180 attcatttta cagatgagga aactaaggct cagagaagga aagtgacttg actaaggtca 240 caaaagtagg aaattgcaaa actagaattt gaacctttat ctgctcaact gcaygttgca 300 ttaatataac ataggcactt atttttaaac ctttaaaagt cttatagtca gtaaatacac 360 tcaacacagg tacagattta aaacttccta tacatataag actataagac acctatacaa 420 attttatagt acagggtcag gggaaggtga tgccagtact cccttagctg ccccagctgg 480 tatctcagta ggtaatgtgt cccctcattc cactgggccc aggtcagcac tagggactca 540 cctatgagtt gcagtccttg tggcctagac tatctctcaa agtttatttg gggctccaga 600 gcactctagc ccatggtggt gagggttgtg gaaactcaag ttctgactgt ggaaattggc 660 aattcccctc tggctagggc tggtttaaaa gctccctcca tgggtgtgtg taagctgaat 720 ttggtttggt tttcctttct gctctagcag gacagtgctg agttcaatta ctcacaattg 780 ctgtgctctc cctctttcca gcatacagaa ttgctctcca caccactctg cagctgccag 840 aggatctggg aggggagggc tggtgctggc tagtcaagac tgtttttcct gccacttcag 900 ggcattattc agtgatatga agtcaaaacc aggcactgtg agtgctcacc cgatttttgg 960 ttcttacaaa ggtgtttttt ttgtgtgtgt agatagttgt caaattggta tccttgcagg 1020 agagatgatc ggtggagttt tctattctac aatcttactc ttccccaaag tcctctgcct 1080 gcatttttaa tttttgccaa gctagtatgt gtgaaaacat atctttcttt ggtttcaatt 1140 tgaaatatct tgagtagttt aagcatttat ttacatattt atgaaaatgt tcatagttct 1200 tctatgaaaa cctgatcatg ccttttactc atttttctac taggttattc actgacttac 1260 tgacttttag attttttttt tctagatatt aaacttctgt cagttaattg cccttaagct 1320 tcctgcttcc actag 1335 <210> 32 <211> 692 <212> DNA <213> Homo sapiens <400> 32 cccttcgact atgctgggtg tttattgcct ttgatatttt tactaacctg gtgggtgtga 60 aatgggatct cactgtggtt ttcctttgca tttgctcatt ctgaatgagg ttgagcttcc 120 tttcatatgt ttatgggtta ttctctttca atgaatgctt actcttgtct ttggccattt 180 ttttcccatc ggattgtctg tctcattctt actgatgtac agtgcttata tattctggct 240 atcaatctta tgatgtttca tacatgatgc aaataccttc ttccactttg aggagtgtag 300 gtatttttaa aggagttttt cctttgtttc caaatagttt gcttctgcta acttaaggga 360 agcttttggt ttataaaggc ttttggtttt ttgtcagaat taggtcccag atgtgcctaa 420 ctacctctcc catggaggga taaatacatt tatgaacggt ttttggaata tgtcttcttt 480 taaacagcaa gsataagagg aatgggaatc tgcattgata tattatttat gaaaaactat 540 catccaatgc ctatattctc cctggtagcc ttagaggtgg aaaaacataa tttgtatgta 600 tataatactg tttataaata agataagtcc aaatcacttc tagaaaaatt ttccatttag 660 ttataaaaat tttaaagttt gcatctttaa aa 692 <210> 33 <211> 1001 <212> DNA <213> Homo sapiens <400> 33 ggaatattaa acattccatt atttcctata caaactatgc ctcagggtca gcaaatagtt 60 gatgataatt ttttttcttt atgaaagttt tccagctaaa ttatggaaaa gaaaatacat 120 aatggaaaca gtacagaaga gagggacata ttttaaatga catcatatgg atttaactga 180 aacctgaagc atcagaattg aaatctaaag catcagaaat catagtagga gacaaatcaa 240 ctaatttgct catcaagtaa gttgatagga aaaaaatgaa acatgttcat tgagaaatgt 300 gagactgtta agaagaacat ccacctagat cttatttgga tcatcattta aacacacaca 360 caatgcacac acactcacag acacacacac agacacacat aaaatctggg aaatgggtca 420 ttcactgtat taaaaaaatt gacatcttta tgagttttgt tagttttgtt tggggtctcc 480 aagagcactg ccagactcaa ygatttacaa aaaatatctc acaagactca gaagagttat 540 tatatttacc gttataattt atcatagtga aatgatacaa tgtaaaatca gcttatgggg 600 aaaagttaaa agaagccagg cacacacttc caggagtttt atcctcgtgc agtcttaaga 660 acacacttaa ttctcccagt aattacatgt gacagtatgt gcaaagtctt atgactcaaa 720 gaagccttcc tgagccttgg tatccagagt tttggttggg catctgtcat gtatgcatga 780 cctaagctat tctgacatga aaactgatct aagctactca acctccaaaa acaggtgttc 840 acataaatca tagtgttagt ataaattatc tgatcaaact gttactacat ggcccaaagc 900 ctgaagcata caaaaatcct tgtcttaaga agaatattcc aagggcttag catgcatctt 960 ctagaatcca gccaagaacc attcctaaag acagatcttt c 1001 <210> 34 <211> 601 <212> DNA <213> Homo sapiens <400> 34 cactctctct cacactcaca cactcactct ctctctctct cgtaatttgt cagggatacc 60 atattttccc ttttaacaaa tcattcctta aaaagcagca gcgatataaa cttgtcacta 120 atcttaattg tatgttttaa ttctatgttt aaatgttcct ctatattaca gatactgctt 180 tgtccctgag agcccctaat ttttcagcca ttttctacat agagagtgat agaggaaaga 240 aagcagcaca atgatttgtt aagcctgtat taaatgcctt taaacttttc aaccttgcag 300 yttaagcaca ggcaaaagga tgagacggaa catgttcaag actgtacatg ccgatcattg 360 actaaatgtt aaaagtcaac atgaaaatct atatctgaga agaaaggtta ctgcctaccc 420 aaaatagccc tccacaaaaa taattctggc aactcaatcc agatattcaa ccaatttcca 480 gcacaagctt tgattcaatc acattctctt tttctaatca gtatgtttct ccaccttata 540 atgtatatgt tcatttaatt gttgaaattg acagaaacaa tttttaaagt acttttcagc 600 a 601 <210> 35 <211> 1807 <212> DNA <213> Homo sapiens <400> 35 tgggagctac agtatggaac ctggtattcg atgtgtagtt tatggaccaa tatcaccacc 60 accacctggg agcttgttag aaatatagaa tcttgtgctc cactgcagaa ttattgaatc 120 agaatctgca ttctaacaag accaccaggt gattcataca cacattaaag tttgagaggc 180 actgatatag agcactgctc atcaaatttt gcaacatatt agaatcatgt gggagctttt 240 aaaaatctga tatcccatga ttatatatta acagcaacaa aaatttggtg cccttgctac 300 atatactgtg ccagttaagt cagaatatct tgagatgaga cccaggcatt agtatttttt 360 tattgtgatg aaatacacag aacataaaat ttgcaatttt aaccatattt aagtatatac 420 tttagtgatg ttatgtacgt taacattgtt gtacaaccat caccaccatc taccttcaga 480 acttcttcat cttcccatat ggaaactcca taatccacta aacactaact cccatttccc 540 cctataccca gcccctggca accaccattc tgctttctac ctctatgaat ctgactactc 600 tggacacctc gtagaagtgg aacatacagt gtttgtccct ttgcgactgg cttatttcac 660 ttagcataat gtcttcaaga tttacccacc ttgtactctg tgtccgaatt tctttccttt 720 tatttatttt ttattttttc tttcttccta tataaaagca attccttcat ttttaaagct 780 gaataatatt gcactgtatg catatatcac attttgttta tccattcaac cgttgatgga 840 cacttgggat gcttctgcct tttggctatt gtgaataata cttctatgaa catgggtata 900 caaatatctg ttcatgtctc ttttctcaat tcttttgtgt atatgcccaa gtggaattgc 960 tagatcatat gacaattcta attggaattt tttgaggaat tgccatactg tttttcacag 1020 cagctgcatt attttacatt tctgccagca gtgcacaagg attccaattt ctctacatcc 1080 tcaccaacac tttttttctg tttttgtttt ttattacagc catcctaatg ggtgtgaaat 1140 ggtatctcat tgtggtttcg atttgcatat ccctaatgat tagtgatgtt tcatgtactt 1200 attgagcatt tgtatatctt cggagaaatg tctattcaag tcatttgttt tgagtcaggt 1260 tgtttagttt ttttgttgtt gagttgtagg agttctttat atattctgga tattaatacc 1320 ttgttagata tatgatttgc aaatattttc tcccattctg tgagtcctct tttcactctt 1380 ttgatagtgt ccttggatgt acaaaagttt ttaattttca tgcagtctgt tttagctatt 1440 ttttcttttg ttgcctgtgc ttttgctgtc ttatccaaga aactattgtc aggcatgaga 1500 atttttttaa agctccccag atgattccaa tgcacagcca agattgagca gtgtttctca 1560 aattttaaca crcattggaa taatctgaaa tcttgttaaa atgcagattc tgatttatta 1620 agtctggagt gggatccaag attctgcatt tccaacaagc tcctaagtga tgccgatgca 1680 ctggtctgcc gactgctctg agtagccagg gtggagaaga gcatttaaat gatttccttt 1740 atctgaaccc cccaaaaaga gggtaaatat tatatttaca gaccttcttc taagcttcct 1800 caccgta 1807 <210> 36 <211> 507 <212> DNA <213> Homo sapiens <400> 36 ggagaaaatt aaaacctgat tgttgagctt ttagtgctta tattcaagat agtttaacac 60 ttccctaaaa tttcacagcc attatttatt atactaccat gaaaatcata taaataaata 120 ccacaaattc cacaaacaca ttaaggaaac caaagataac ataacagtta ctaaatcaac 180 aagtcttagc aactcttcct rtaactcgtt ttcatggatt caaagaagaa aacagtcaag 240 caaagttagc actgtaaaat aaaattaaga acattcatat actactttat actttaccac 300 atcttcctct tcattggttt gatttagtag gtgtatatca caagaaatca ctcaaaatat 360 aagttaatgt tgactttgaa gggacatgaa ggcctttctt gatttggatg gcaactgaat 420 gggtgcacac agatgtaaaa attcacttag ctgtacactg aaggtgtgca ctacgctgtg 480 taagttacat gccagtgaaa aagtaaa 507 <210> 37 <211> 601 <212> DNA <213> Homo sapiens <400> 37 ggcatccaat ctttttgctc tagactttgg atgttgaaat ctggattcat acttgatgta 60 aacaggatga atctcttttg cctacagcct ttaaaatatg gttatctagt tttggtcaaa 120 agtctcacca ttaagttcat tgttaaattg aataaactat ctgaaatctg ggggaatgag 180 aaaatggata ttttgggtaa ttacatactc tgttggataa ccaaacataa catatatggg 240 ctcttcaggt ttcaagtcag tagaaggtaa tgtgacattt tctgatcaga ctgttgggat 300 yttttgttag ttgcacctca tgtttacctc tgtgactagc cttcaccaag cagccatccc 360 ttccttgaac cgatccctct ctctcatgcc cctttccttg gtacattctc ttccttttgt 420 ccagaaatac tttttctctt ctttctgttt agatgtcacc tcttctgtga agcccttagt 480 tccttcacaa gaatctcccc aatccaattg cttgctcttt tatactccta taacattttt 540 ttggtaattt tttcatagtg gtaaaatata cataacatac gatttaaatt ttatccattt 600 t 601 <210> 38 <211> 601 <212> DNA <213> Homo sapiens <400> 38 ttgtcttgat atattaccta tcagattcct ttaatcagtg gtctgtgtgt gtggtgagca 60 ctcatctcca ttataatctc ctctgccccc acctattgcc acgaagtcct aggtctttgc 120 agatgatcaa attttggaga agaaacaaat ttactctgca taatagaggg agaaaaactt 180 agaaagccca gggcaaggag aaggggctga ggagcagaaa tgggagaaag acagactcca 240 ttcattcaga cagatggtgg aaacttgtgt gcaatgcgca tgcagaaacc ctataaaaat 300 rttctgcagt gtcaactacc ggtatgaatt ctctgagtaa attgctgttg tggattccaa 360 agaagaggta gagattcata tctagtctgc ataaggttgg acaaaggcag cagttgtggt 420 ggtcagatgt gaagaggatg gcattagaag aaatccttgg acatcacaga cttctacacg 480 cactggaact ggggttctta ggggctgggt ttcaaaagga tcaaagcaat ttaatttgga 540 tctccagggg tgcctgtagc tactttggtt tccatatgta taagaacaaa ctatatgttg 600 g 601 <210> 39 <211> 845 <212> DNA <213> Homo sapiens <400> 39 aggttatacg gcacgcgatg ctggatgacc tctgagagct gaggacctca tcctgtaacc 60 acaaagaact gaatccaaca aacagtgcgc ttagaagagg acttcaagcc acagatggtg 120 gcagctcctg ctgacacctt catcagaatt tgagtagaag accccctaaa ctgtgcctgg 180 atttctgagt caccaaatct gtgagataat aaatgtgttg ttttaagctg gtaaatttgt 240 gatattaata tttattaaaa acagtaaatg aatacaaaag tcaatgtaaa ctaaaattcc 300 atagtagaga tgaagtcctg tgaattttag ggagaatatg acactgtttt tcaccaataa 360 caaaattcac tactagtgga gtaaagaact ctggagtaag acttagagct gtgtgacttt 420 tggcaagtaa ttcaacctct ttttgcctca gtttcttcac atacaaaatg ggaatgattt 480 tattatttgt gagggttcag kgacagaata catttctaat gctcagttca gttgctgtca 540 catagtaagc tccatataat attattatta atgtcattgc tattgctaac ataattacta 600 ccatcattaa tttaactaag agaaacatgt ccgtatcatc agctacatac ataatgcttt 660 gcctaggctg aaaaataaat aaataaataa gatagaaata ttaaatggac ttacagagat 720 tgcagatgat tgcaagtttg caatcaacaa ggcttttaaa tcattcactc attttaaaag 780 accccttcaa atagttttca ttacaatgtc cagggcaggt aattcaaaga aagaggtctt 840 ggtgc 845 <210> 40 <211> 2477 <212> DNA <213> Homo sapiens <400> 40 tgcatccgtg ttttcaataa ctagaccctt gttttcagac ttggaatttt ttttttcagt 60 cattggtgga ttttctgtct aacattttat gaaaattttc aagcatccaa caaagttcaa 120 ataattttta cttggaatag ttttggtttt ttttttggag acagagtctt gctctgtcac 180 ccaggctgga gtacaacagt ggtgtgatct tggcttcctg tgacttccgc ttccctggtt 240 caagcgattc ttctgcctca gccccccaag tagctggggt tacaggtgtg tgccaccacg 300 cccgcctaat ttttgtattt ttagtagaga tggggtttca ccatgttggc caggctcgtc 360 ttaaactcct gacctcaggt gatccaccca ccttggcctc ccaaagtgct gggattacag 420 gcgtgagcca ccgcctccgg tcttacttgg catagtttta tacccttcac ctagattgtc 480 aatgacattt tttgatattt tcttcacttt atatccatcc atccctccgt ctgtctatcc 540 atgttattat ttagatgcat ttccgagtaa aatgcagaca cgggtatact cccctataca 600 cttcagcata tcattggagt ttggtatttg tttacggttt ttcctgtttg atgtaaaatt 660 tacatacaat gaaatgtaca cacgtcaagt gtacttttgc tgagttttga catatgcatg 720 cacccatgga acccaacccc gtgaagagct agaccatcac catcactgac agctctgaca 780 gctacctcgc accttgccca ggtggtcttc accccttgtc cccttagagg caaccactgt 840 ttggattttt tccgttataa ataagttttc ctattctaga attttatgta aatagaatca 900 tacagtatat aattgtgctg gggcctccag tgctaccccc aggctgaatg attcattagc 960 aggactcaca gaacttagaa aaggtattac actcccagtt agacttatta ctgtgaaaga 1020 ataaagatta aattcagcga agagaggaga cacatggggc aaagtctagg agaagacagg 1080 catgaacttc cagttgtccc ttcgaaatgg agtcctactg ggcacacttg attctcccag 1140 cgatgatgtg tgacaacaca tgggaagcat tggccaccag ggaagctcac tggagcctca 1200 gtgtccaggg tttttgtgta gacattagca cctgtgtgac tgactttagc gactcagtct 1260 ccagccccac agagtccaaa stgatacagc tgggccaggg ccgcagggat acagaaacag 1320 gtgttcactg taagccaagc tgttagcgta aatgatctgg tcagactgag agagcagggc 1380 ccgaggcctt gagcatacaa aaccccttat caggtagaac attgcagtgg ctcagaggtt 1440 atctcccagg agccagtcct gaagacaggc cttttttgga atgtacaggg tttgagcaac 1500 ctagtcctgc tgagttaacc ctttccgtca cagtagtctt ttgtgtaagg cttcttttac 1560 ccaacgtaat gtttttgaga ctcatccata ttattgcatg tatcagcagt gttgttcatt 1620 tttattgcag aatagtattc cattgagtga acagaccaca gtttatccat tcacatgttg 1680 ttgatacctg gattgtgacc agtttcagtc tattatgagc aaatctgcta tgaacattct 1740 tacacagttc ttttgggtaa atacctagca gcgaaattac tgggtcatag ggtacatgta 1800 tgttcacctt tgtaaaattc tgccagacct ttttttcaga gggattgcaa tattttacac 1860 gtcctccatc tgctgcagct gttcagtatc ctcaccagac cttggtgtta tcagtctttt 1920 taattctcac cattctggtg ggtatgaaat cgtatctcat tgtgtatttc agtttctttc 1980 tttctttttt tttttttttt ttgagacaga gtctcgctct gttgcccagg ctggaataca 2040 gtggtgcaat ctcagcccac tgcaacctct gcctctcggg ttcaagtgat tctactgcct 2100 cagactcctg agtagctgag attacaggcg gccgccaccg tgccgggctg attgttgtat 2160 ttttagtaga gatgggattt tgaccatgtt ggccaggctg gtctcgaact cctgaactca 2220 ggcgatccgc ccaccttgac ctcccaaagt gctgggatta caggcatgag ccaccgcacc 2280 tggcctcagt ttcttttcaa tttagaaagg tcaacatcta gtcctaagag agatgacagc 2340 atgtttcttc taggatctga aaacacagat ccaatgattt gatgtatcct tgcaaatttt 2400 cctattttaa tttaaaatgg gggaagacaa agaaggagaa ggaggaagag agtttcctaa 2460 gggagctggt gaactgg 2477 <210> 41 <211> 524 <212> DNA <213> Homo sapiens <400> 41 ccctccagat tcaggctcct tggagaaggc aggctccagc cttggtctca gaatcatcac 60 taaagtcaga taagaagata ataatagtaa tggctacaac agagtagcag aaaccacagg 120 ttccattttt aagcacctaa ttgtgtctag attcaggctg ggcatgtttc atatctcctc 180 tcactcattt ctcctgacag ycctggagag gatactgaag ccgagaacag tgggtcgcta 240 tactcaaggt ctccaggcta gaaagtgggg gggcttcctc caagggctaa gggacttcaa 300 gccctgtcct tcccactgta ccacgttgcc ttggtgatgc tccttttgca ctggccccac 360 atggccagct ggattcttct ggtcacagga gatggcgtgg ctgttgggct gtggggcagg 420 agggaggcag ctctacctgg agccaccacc ctgctccgac ttgctctagg tatcagcatt 480 acactgtggg agccagagga gccctgtgct ttctgatagg ccca 524 <210> 42 <211> 592 <212> DNA <213> Homo sapiens <400> 42 gaataacaaa gtagaaatga aataaaatga caacctaggc aaaactgacc agatgctgaa 60 agcagatgga gaacttaaag gaaagtatta aaagagcagg tttataatgc tacagctggt 120 gattaaaata tctcactatc taatcaggca atagcatctg gcctgctgca attcagaggt 180 tttcaaacag tagggaccac aatttaattt aattatcaaa attgaatttg taaagctagc 240 caatgagtag aaattcagaa gaccctgcca cagtatcccc caacttttca cgataagaaa 300 ttaaacataa taaaacatgc cttttgataa ttagactcca tatattgcaa aactaaagtt 360 tgataaaagt ttaatcaaac tcagtgggtg tcattaaaaa ggcaataatc aaatgattac 420 ataaataata acaaacttct gcatttccct caaattgtct aaggaaaaaa cagataagtt 480 gtmatttgag gaacaacagg cagaaatatg cagcattaaa attatctaga tcaaaatttt 540 aaaagctatg atgcccatga ttatttctat ctccatttta attcacaatt tc 592 <210> 43 <211> 425 <212> DNA <213> Homo sapiens <400> 43 aacttcatta gtctctgtgc aaggagagac ttttgcagag agtttttcat aatattgaaa 60 gaagttgcca gagaagttgg agagggccta aagcaccatt ccgttgtgcc atcgacacca 120 cacttctgat catggaagga gcatgcaatt aggcagaaat gagcttaggt tcaggttggg 180 ccatctgtga atggaacatt cttgggcaag ttactaaatc tytctaattc gtgtgttgtg 240 tatctgggat ttcagtggag ttttataaac agttaaatga gattatgtca agtctatatg 300 cacagttgct ggcatataat aagaccttga aacttgtgtt aacagcagtg tcagaattag 360 aacccacatc ttcttttcct ttttattgca tccttctgcc accaactcca acccttgtct 420 tctag 425 <210> 44 <211> 601 <212> DNA <213> Homo sapiens <400> 44 ctgtttattg gtgggagagg gtcattcacc tcttttgacc tgatcaaaga taagaatcac 60 tttctcacaa aaatgcacat aaacatcccg cctaattttg gcacatattt tatcttattg 120 tattagaaat tgacttcttc acacagaaaa aaaatcctat aaaaaatttt cttctctcat 180 tcttgtttat tcacgtaaat ggagtaatct aaaataaatt cagtgagcaa atacaaaaga 240 aaaaaattaa aattcttccc ccaaagcaaa tttcaacata aaggctgcca ttacttgact 300 kgagaagaaa ttacagcata gtcttacatg gtaatatgct tgtcatttgt ggtaagtcta 360 tcaattttga tagcaacaaa tgtaagaaag cccagattaa caaaagtatg ttgtcgcaaa 420 tgaataggtt taagtccaga tgcactggat ttctctagga cccttcaagc taatgcagtt 480 gcatcatttc ctcacatcta caaagttggt catctttgca aagtctgcat catctatgtt 540 gcatatgtca gcaaggaaat ggttaaaata accattccaa ttttaaggtc aaaccagttt 600 a 601 <210> 45 <211> 604 <212> DNA <213> Homo sapiens <400> 45 ctcttctgtg tttcaagcag gtaagtgggt tccctattga agttctgtca ccctttggga 60 aaggaacatt tgtgtgagta ataggtgaga aaaggaaaag tttagaggaa gcatgatgga 120 cttgagagtc tacctgaaga agccaccctt ctatcaacat ccctactgaa aaggaaagca 180 cacttctagg ttgcctacaa tgtgtgcaca catatgcaca cataacacgc atgcactcat 240 taatgaaagc ttgtaagaga gctgcaaggg caagaagtca gttttgytca cctccaacag 300 gacagagata tcttgaatat taaatgatgt aagaccggta tcaagggcct tccccccata 360 ctctgctgcc gggatccttc tcaagccaag tgcccccatg caattcatcg agtgactggc 420 cccgactcca gcctactcca cgtgtcctgc tgccccaacc ctcccttctg ccatcaatgc 480 tcctgccatc aatgcacaat gtgatccaga gaaaggaggc acacatccct tctttatacc 540 gctctgaacc atgaactaca tcttttaatc acggacacac tgcatcacat ggttgcttcc 600 ttaa 604 <210> 46 <211> 701 <212> DNA <213> Homo sapiens <400> 46 agatatggta cagtgcctgt actcggcttg caacttatgt tgaggtgatt cccactcaca 60 ttggcccttg tccttgtcag ccctctgtgc cacagttgac agagccaagg ggccaaagaa 120 gctgtgccct tgggttgtcc gtgattggca cctcttgatg aggtgaagat atcattccta 180 atatatttct tttcatgtat yctttgataa aactaaatgc agttcaaatt ttattaaaac 240 atttaaaact ttttttttat ttttgaaaca gagtcttgct ctgtcaccca ggatggagtg 300 caatggtgcc atcttggctc actgcagcct ctgcctccca ggttcaagcg attctcctgt 360 ctcagcctcc caagtagctg ggattacagg tgcccaccac catgcctggc taatttttgt 420 atttttagta gagatggggt ttcaccatgt tggtcaggct ggtctcgaac tcctgacctt 480 aggtgatcta cccaccttgg cctcccaaag tgctgggatt acaggcatga gtcactgcgc 540 ctggcctatt aaaaacattt tatgttgtgt gagtctgata gccaacttct aactagagtt 600 gtgcttcttc agtaatctga gtaggtaaga ctcccctttt ggaagtcaaa ttctacaaac 660 tccagtgccc acaggaacca ggaaggtaac ataaataaga g 701 <210> 47 <211> 601 <212> DNA <213> Homo sapiens <400> 47 tggctacttt agctggaact gtcatcacca gacatgaaca cgttagctca cagaagaggt 60 agaggtctac aggcaaacac gacagtagcg aagctgaggc tggccccagg gagcatctat 120 accaaggcac caccgggaag gctgcggcag actgtgccat gcgctgtctg ttgggcctgg 180 agcaccacga gaaggaaggc ggcgtgggga gagtgaagct gcactgaggt tctgctaaga 240 ccgctgtgaa ctttcacata caagactttg cgtgggtgta tcatttcagt tctcctgggt 300 rtatgcttaa gaatagaatc actacaattt tcaaccattc ctgttattat taagaaagta 360 atacatgctt gtaggaaacg gtcaaacaac acagcagaga acaggggagg aagtgtgggg 420 acacccactg catttcccat ccacagagac agcaactcag gagattagtt tgcatccttt 480 ccatagcttt ttatatgcac acacatattt attttgtaaa tacaattatt ctatacatat 540 tgttctacaa attgttatat aactctgcct acgttgtggc catattccta agtcagaaca 600 c 601 <210> 48 <211> 601 <212> DNA <213> Homo sapiens <400> 48 gagagtgtgt gtgtgtgtgt gtgtgtgtgt gaaacagaca tgggcttatg tttacgaaga 60 tctctttgta catgtgtttg aaaggtgact gcaagaatga gtaaaatagg ttacatttac 120 atttcttggt ctcctccaca ctccctgatg ctaaacaaga tgctgcaaga atgaaaaata 180 caacttttgt gtaaactttg taatctagtt catagagaaa ttggccaaca gctacacgca 240 cctaaaggaa gaggggacat acatttggag aaacatattc atgtgtgcta gttcaagaag 300 raagcagcta gctctttgcc tttgaagatt tcaatattca ctttgttgaa ggtgaccagg 360 tgatccctct tagatacttc gataattcag atacatccaa tacaagatgg atcttcataa 420 aattcaattt gttatttcaa tctggaaatg cattatctct tccttgagga aaataaattg 480 tgtaaggaca ggtgctattt tctttatctc tgcccaaagc ttcatcctag ggctcagaaa 540 tgctaaagga ctttgtacaa ggaaatgaag ctaaaagctt gctaccttaa ttataggatt 600 t 601 <210> 49 <211> 401 <212> DNA <213> Homo sapiens <400> 49 atatcttgtc cccatttttc tatgtgctga actgatcatc actgtgaatg tattactaag 60 tggaagtttt aaggttaaga tccttatgga ataactacag cagtcctatc ttcccccact 120 agatacatgc ttcaccatcc cctgaaagat ttatatagaa ggacactgtg gcaacatgtg 180 accttttgaa actgctccct yggaaggaat tctaatgtcc tcctatctat gttacctgct 240 gtgtacctac cactggggaa agatgctgaa aatttaatga attgcagaaa agctgtgcaa 300 gcttctcttt tggaagaacc ttggagaaga gagaggccga cagaaagaaa actttcaaag 360 aaattacact gccctcaagg gtggcatcta cagaggacag t 401 <210> 50 <211> 1001 <212> DNA <213> Homo sapiens <400> 50 gtatcaagca aattgtttga tagactcaga agacttttct gaggggccag aggttgctga 60 acaaatttaa atagaacaag caggggaaga aaaatttaag tgacatgtca gttggttctg 120 cttcagttgg ttctactgac aggttcaaat acattatccc ctttggaaaa aaagaaatat 180 gtgcattgtg taattctagg aaatctctcc caagaaggtg agtcagggct gaaggtacaa 240 gtaaaaattc atgataatgg actaaggtat ctaattggaa aggcaacagt aaggttttgt 300 gcacagtcat gggtcggtta gagatttcca ccatgtttaa ggtttctgca ctccaaggaa 360 ggggcccttt aaggaggtgg aatttaaaac agataaagtt gctccagtat caattaaagc 420 cttggtcttt tcaccattag tagttaaatt catttcacca agggcattag aaggaaagga 480 aaggaccctg gaatttcctc raagcagtct tactctgatg gttctgtcat ggccttttct 540 tccagttgcc acttgagctt tctggaatcc tttttgatgt gaccaggatt cttacaataa 600 aaacgtacat ttctctgatc tggtgagggc tgaaactgct gtttttgaaa tccctgttgt 660 ggattggcca actgttgcta cttgaaagct tataatccta gcagatttag acttttcttt 720 tttgtggaga aggccacaat attaactaga tcacatatct gagtggttgc tcaatttatc 780 tgatgtcact taacgagggt aacaaactct tagtcaaggc cgttaagaaa agctgagctt 840 aacatagatt catttttttc tattattaac actgttatca gacacaccaa agtattgttt 900 aaatgtcttt ttgaatcatt caaaattatc taaatctgtt atgttaggac cttggcagca 960 ttgccaaatt ttacccaatc tatatgtttt ggaaagactt t 1001 <210> 51 <211> 1001 <212> DNA <213> Homo sapiens <400> 51 ggagaaaaat caggattaca gttttgacga tatcctgcca atcagaggaa gcctcatagc 60 tatttcttag tgtttggttt tagaaaggca attatgcctt taactctatc agagttgatg 120 gaaaacccct ccttagatat tgaatgaccc aaacatttaa cttgttcttg gcataactgg 180 agtttttctt tagagagttt gtgacatttg cctgtgagtt gccttagaag atgcaggcac 240 ccccatatga gtgagcatat gtgatatttg tctttctgtg cctggcttaa ataagctact 300 taatataatg tcctccagtt ccatctgcat tgttgcaaat gataggattt caatcttttt 360 tatggctgaa taatattcca ttgcatgtat gtgccacatt ttctttatct attcatctat 420 ggatggacac ctaggttgat tccatatctt ggctattgta aatagtgctg cagtaaacat 480 gggagtgtgg atgttctttt sataaacttg ttaccagaag ctgggaaggg tagtggggag 540 agggataaaa agggggtggt taatgagtaa aaaaatacag ttagatagaa gaaataagat 600 ctagtatttg gtagcacaat agggttacta tttttttttt ttttttgaga caaaatctca 660 ctctgttgcc caagctggag tgcactggca tgatcttggc tcactgcaac ctccacctcc 720 cgggttcaag cagttctccc acctcagctt cctgagtagc tgggactaca agcacgtgcc 780 accatgctca gctaattttt gtattttttg gtagagacgg ggtttcacta tgttggccca 840 gctggtcttg aactcctgac cttgtgatcc acccgccttg gcctcccaaa gtgctgggat 900 tacaggcatg agccaccgtg cccagctggg agactattgt taacaataat ttattgtata 960 ttttaaatgt ttgaggtagt agataactct aattaccctg a 1001 <210> 52 <211> 1001 <212> DNA <213> Homo sapiens <400> 52 aaaggcaaca gtaaggtttt gtgcacagtc atgggtcggt tagagatttc caccatgttt 60 aaggtttctg cactccaagg aaggggccct ttaaggaggt ggaatttaaa acagataaag 120 ttgctccagt atcaattaaa gccttggtct tttcaccatt agtagttaaa ttcatttcac 180 caagggcatt agaaggaaag gaaaggaccc tggaatttcc tcaaagcagt cttactctga 240 tggttctgtc atggcctttt cttccagttg ccacttgagc tttctggaat cctttttgat 300 gtgaccagga ttcttacaat aaaaacgtac atttctctga tctggtgagg gctgaaactg 360 ctgtttttga aatccctgtt gtggattggc caactgttgc tacttgaaag cttataatcc 420 tagcagattt agacttttct tttttgtgga gaaggccaca atattaacta gatcacatat 480 ctgagtggtt gctcaattta yctgatgtca cttaacgagg gtaacaaact cttagtcaag 540 gccgttaaga aaagctgagc ttaacataga ttcatttttt tctattatta acactgttat 600 cagacacacc aaagtattgt ttaaatgtct ttttgaatca ttcaaaatta tctaaatctg 660 ttatgttagg accttggcag cattgccaaa ttttacccaa tctatatgtt ttggaaagac 720 ttttgggatg gcatctaaaa gctctctggc taaagcgcta gcttctattc tgttgtatac 780 cttcatttgc tctattaaag ttttccagag gattttgcca attagcattt ttaatccatt 840 tggtgtccct ctcttctgaa atcaatagtc cccctagtag ctgggaccac aggcacgtgc 900 caatatgcct gtcaaatttt tgtatttttt gaagagatgg gctcaagcaa tccacctgcc 960 ttggcctccc aaaatattgg aattacaggc gtgaaccact g 1001 <210> 53 <211> 601 <212> DNA <213> Homo sapiens <400> 53 agatcggtcc tgccccttgg ctgggctgcc tggacttcac ttcatcatct ctaaaatgag 60 attaaagatt gtttctccct catgggaagg ctccgggatt cagtgagctt atgcctgttt 120 aggaaagtgt ctggcacagg gtcactgccc ttgtgccatc acatctgccc agatgaaatc 180 aggtaatcag ctgacgcacc cggagtgccc atcgcgcatg cgtgctgtgc cccatgggaa 240 aggggcgtca gatgtgactc tgccctcaag gaatccgcat ctagcaggag aaagaaaacc 300 sgacactttg gagataaata gagagctaga aggccagcgg gacccccgct tccccacggc 360 gcggacatcc tggagggcga gcagctgccg ggcggggcac gctgtcagcc aaccctgcct 420 aatctcctgg cagacagagc tgagagaaag cagaatctgg tattcattgt gcggttgttt 480 ctaatttcct tctgctttcg agatcctctt ctaagggaga acaatgccct gaatgatggg 540 gcacaagctt ccttggctgg gcacccaccc agctgtggca gaggccgggc actcacaggg 600 c 601 <210> 54 <211> 601 <212> DNA <213> Homo sapiens <400> 54 tctccgagat ccagcctgct gtctagggta ctcgtgcatg tgagtaaaac ttccaagaat 60 gccacctccc tacgtatctc ccctacactg ctctcctcct gcattccctg tgactctaaa 120 gtgaggccta aggctctgat gggatcaccc agcttccacc acacactcca tgctttcctc 180 tgccccaccc tgatgagatg aggtgattct ttccctggtg agggagcgtc tggcagctgt 240 tgcctggttc ctcctccctg ttggttctgt cctggttgct gaggaccata agaccttgca 300 stgtatgcct gtttgtgatt ggaacaaaac gaggtgactg gggcttgtta ggccccagtc 360 ctagtgaaag tagtaggcaa gttatctaaa cacgatctca gacagagggt cctcaagata 420 gaagcccatt ggcaatcctg gggtacaagg agatggtgag tgttgtgatt gttacagaaa 480 gctagttatc caactggggc cacagaccag ggctagattt ctagttgggt gacctgatgg 540 tttgctccat aagactgcgt tgtagctcca gaaattccta ctgtttgaag tccagactgg 600 t 601 <210> 55 <211> 501 <212> DNA <213> Homo sapiens <400> 55 ttgggaaaat gagacaacaa actatatccc aaagtgagtt atattaataa taacagaagt 60 gtaagttctg tatgacccta tttttacaaa cataaaaata catttttatc agcttgcaat 120 tgtaattaaa aggaaaatgg cagtttgaaa aatcttttga cgttgagtaa aatataactg 180 catgaactgt accattgaac tatgaagcag ttaatggcaa tgaagctgga gtgattttaa 240 taacgttctt ytaaataaaa gtcactgggg tcattttaca actccagtca ctgtgttcat 300 tcctagttga gttcataatg gacttcataa tagtcttaga gtctagtgta cctctctctg 360 tcattctctc tctctttttc tctcccctga tgacctgcct ctctctgtct ttcaaaaatg 420 tccttaacag aaactctttg gaggccataa gttttgtttt cattttttct cattcataga 480 gttctgattc acagacttta a 501 <210> 56 <211> 754 <212> DNA <213> Homo sapiens <400> 56 tccctagcac cctgctctct attcagcaca aggccagcag tggacatcgt cgtcttgcat 60 tattcaggtt tataggccaa tactgaaatc tatcttattc atcatcccgt gagcagggga 120 aacatcatta gggttttcta taccaggatg atagtgagca tgtagtagtt tttgtttttt 180 tgtgttgttt gtttgctttg taattttgtt ttcttttgtt tttggagtat tcactatgaa 240 gataagaaag ggtragaata aaatgcccca aatgaccaga ggaatagaga tagaagtcag 300 gtccctcaaa tttgttggag gagggggaca agctgggagg ggggacgtgc tgggggcggg 360 gcgggaacaa gcccaaaaag ggacagctgc tgcggtgcct cttttgtgtt tgtaaatgtc 420 ctccccgcaa ggtggctcta gcctgtaatc ccagcacttt gggaggctga ggaggatttc 480 ttgagcccat gagtttgaga ccagcctggc aacatagtga gactctgtgt ctgtagttcc 540 agctactccg gaggctgagg tgggagggtc ggttgtccag ggatttgagg ctgcagtggg 600 ccgtgatcgc gacactccac cccagcctgg gcgacagagg gagaccccgt cttaaaaaaa 660 aaaaaaagtc cttgatcaag agggcttcgg gtgtttccat ctgtggagtg aggggacggg 720 ttaggtgaat tctaggggcg cttccacctc acat 754 <210> 57 <211> 955 <212> DNA <213> Homo sapiens <400> 57 ctgtggcatc ctgtcccaaa tttcacaaaa ctcttacaat aaaattatgt aacttggctg 60 ggcgcggtgg ctcacgcctg taatcccagc actttgggag gccgaggcgg gcggatcacg 120 aggtcaggag atcgaggcca tcccggctaa aacggtgaaa ccccgtctct actaaaaata 180 caaaaaatta gccgggcgta gtggcgggcg cctgtagtcc cagctacttg ggaggctgag 240 gcaggagaat ggcgtgaacc cgggaggcgg agcttgcagt gagccgagat cccgccactg 300 cactccagcc tgggcgacag agcgagactc cgtctcaaaa aaaaaaaaaa aaaaaaaaaa 360 aaaaaattat gtaacttgat aaaaaataat actcataata agtcttactc tgtttgactg 420 tatctcttca tgatctttct atcgttggtt ggtataggta catatatcta tatagagttg 480 taatcaagat gctaggcagt ttgttttgtc ttttatttaa tgccttattt agtgctgtgc 540 taagtacttt acatacatta tccgatttaa tcctcaaaac aatgataaga aaggtactgt 600 tactgctctt ctttgacaga aggggaacct tagccctgag ggtttaaaat aaggtcataa 660 aatagccagg agaaagtaga agtgggtgtg gggtggattc agatctaggt ctgtgtgatt 720 ccaaagctca gaatcttacc taccaarcca tactgccttc tttgtgattg actctcaact 780 agattgttaa tgaaaataat gtgtctaatt aatagaaatt ctaacttttc agcatttacc 840 agcaaatttt tatatgagta aagcccatat aaagagtgct ccaatttctt gttttattta 900 ctcttgtagg aattgaaaga tgttggccat cgtgatcaga tggctgcagc tagag 955 <210> 58 <211> 601 <212> DNA <213> Homo sapiens <400> 58 gctgagctcc tgtctttagt actagggcat tgttcattat gttctggaaa ttcccttcct 60 acctatgtaa acctaatcta ctctttcttc aggccccaca tttgtttttc atctctttgc 120 tgaaggccat ttcaaactac atcatcttac attatttctt tggtgcttga agttttgtgc 180 cttattgtat actcccttga attgttgttt aattgcattt cttttatcca ttttattctg 240 caactaggtt tttaagcctt tggaacatga caactcctta aaaatattca ttcatggtct 300 rgtataatgc tgcaagaggt gctcagtaaa tgcttgctta atgaactcat gctggtttgt 360 aggaatgaat aaaatgaata attttggatt ttcatggtgc taaggaggta atagtgtggt 420 ggaaaaaacc aaagaccttt acccttatgg gccttacatt ctacagtgga tgaaggagga 480 ggctgtgtgg tttatttcta cttcctatta gatctttcac tatacagatg acatttgttg 540 aaaaaattaa accaaatact ctggaataag caattaagtg aaagtgatat cttagagcag 600 a 601  

Claims (9)

삭제delete 삭제delete 삭제delete 삭제delete 서열번호 2의 DNA 서열로 구성된 폴리뉴클레오티드에서, 233번째 염기(다형성 부위)가 G이고, 상기 233번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드를 포함하는, 톨루엔 디이소시아네이트 유발성 천식 진단용 키트.In the polynucleotide consisting of the DNA sequence of SEQ ID NO: 2, the 233th base (polymorphic site) is G, comprising a polynucleotide consisting of 10 to 100 contiguous DNA sequences comprising the 233th base or a complementary polynucleotide thereof , Toluene diisocyanate-induced asthma diagnostic kit. 톨루엔 디이소시아네이트 유발성 천식 진단에 필요한 정보를 제공하기 위하여, (i) 검체로부터 핵산 시료를 얻는 단계; 및 (ii) 상기 핵산 시료로부터, 서열번호 2의 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드의 다형성 부위의 염기 서열을 분석하는 단계(단, 상기 다형성 부위는 233번째 염기를 의미한다)를 포함하는, 검체 중의 단일염기다형을 검출하는 방법.In order to provide information necessary for diagnosing toluene diisocyanate-induced asthma, (i) obtaining a nucleic acid sample from a sample; And (ii) analyzing the nucleotide sequence of the polymorphic site of the polynucleotide of SEQ ID NO: 2 or its complementary polynucleotide from the nucleic acid sample, wherein the polymorphic site means the 233th base. A method for detecting a monobasic polymorphic form. 제6항에 있어서, 상기 다형성 부위의 염기 서열을 분석하는 단계가 서열번호 2의 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드 서열로서 다형성 부위를 포함하는 서열(단, 상기 다형성 부위는 233번째 염기를 의미한다)을 주형으로 하는 프라이머 또는 프로브를 이용하여 수행되는 것을 특징으로 하는, 검체 중의 단일염기다형을 검출하는 방법.The method of claim 6, wherein analyzing the base sequence of the polymorphic site comprises a polynucleotide of SEQ ID NO: 2 or a complementary polynucleotide sequence thereof, including a polymorphic site, wherein the polymorphic site refers to the 233th base. A single base polymorphism in a sample, characterized in that performed using a primer or a probe as a template. 제6항에 있어서, 상기 다형성 부위의 염기 서열을 분석하는 단계가 서열번호 2의 DNA 서열로 구성된 폴리뉴클레오티드에서, 233번째 염기(다형성 부위)가 G이고, 상기 233번째 염기를 포함하는 10 내지 100개의 연속 DNA 서열로 구성된 폴리뉴클레오티드 또는 그의 상보적 폴리뉴클레오티드가 고정된 마이크로어레이에 상기 핵산 시료를 혼성화시키는 단계; 및 얻어진 혼성화 결과를 분석하는 단계를 포함하는 것을 특징으로 하는, 검체 중의 단일염기다형을 검출하는 방법.The method of claim 6, wherein the step of analyzing the base sequence of the polymorphic site is a polynucleotide consisting of the DNA sequence of SEQ ID NO: 2, the 233th base (polymorphic site) is G, 10 to 100 containing the 233th base Hybridizing the nucleic acid sample to a microarray to which a polynucleotide consisting of two consecutive DNA sequences or a complementary polynucleotide thereof is immobilized; And analyzing the obtained hybridization result. 제6항에 있어서, 상기 다형성 부위의 염기 서열을 분석하는 단계가 서열번호 2의 DNA 서열의 다형성 부위(단, 상기 다형성 부위는 233번째 염기를 의미한다)의 유전자형(genotype) 분석을 포함하는 것을 특징으로 하는, 검체 중의 단일염기다형을 검출하는 방법.The method of claim 6, wherein analyzing the base sequence of the polymorphic site comprises genotype analysis of the polymorphic site of the DNA sequence of SEQ ID NO: 2, wherein the polymorphic site means 233th base. Characterized in that a single base polymorphism in the sample.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101346476B1 (en) * 2012-06-15 2014-01-03 중앙대학교 산학협력단 Single Nucleotide Polymorphismic Marker Associated with Asthma Risk and Use Thereof
WO2019004748A3 (en) * 2017-06-30 2019-03-28 아주대학교산학협력단 Method for diagnosis of isocyanate occupational asthma using periostin

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* Cited by examiner, † Cited by third party
Title
Clinical and Experimental Allergy, Vol. 36, pp.1153-1160 (2006.09.04.)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101346476B1 (en) * 2012-06-15 2014-01-03 중앙대학교 산학협력단 Single Nucleotide Polymorphismic Marker Associated with Asthma Risk and Use Thereof
WO2019004748A3 (en) * 2017-06-30 2019-03-28 아주대학교산학협력단 Method for diagnosis of isocyanate occupational asthma using periostin

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