한국인 정신분열병 환자의 HLA-DQA1,HLA-DQB1 HLA-DRB1 대립유전자 빈도

신규성,이민수,김영리,김영태,조윤정 대한신경정신의학회 2000 신경정신의학 Vol.39 No.4

연구목적: 저자들은 PCR-SSOP 방법으로 한국인 정신분열병 환자에서 HLA-DQA1, HLA-DQB1 및 HLA- DRB1과 정신분열병의 감수성과의 상관성을 밝히고자 하였다. 방법: DSM-IV 에 의거하여 정신분열병으로 진단된 환자군 128명과 정상대조군 160명에 대해 polymerase chain reaction-sequence specifc oligonucleotide probes(PCR-SSOP) 방법을 이용하여 HLA-DQA1, HLA-DQB1, HLA-DRB1 대립유전자의 빈도를 분석하였다. 결과: HLA-DQB1□04는 환자군에서 14.6%로 정상대조군의 8.2%보다 높은 빈도를 보였고 (p=0.028), HLA-DRB1□14는 환자군에서 11.8%로 정상대조군으 5.5%보다 높았으며 (p=0.01), HLA-DRB□15는 환자군에서 2.0%로 정상대조군의 7.1%보다 낮은 빈도를 보였고(p=0.007), HLA-DRB□16은 환자군에서 1.6%로 정상대조군의 4.8%에 비해 유의하게 낮았다(p=0.043). 결론: 한국인 정신분열병 환자에서 HLA-DQB1□04와 HLA-DRB1□14S는 질병 발생의 감수성 인자로 작용을 하고, HLA-DRB1□15와 HLA-DRB1□16은 방어적인 역할을 할 수 있다고 할 수 있으나, 다른 인종에 관한 외국의 연구자들의 결과와는 상이한 양상을 보였다. Objectives: The aim of this study was to investigate the correlation between HLA-DQA1,HLA-DQB1 and HLA-DRB! alleles and disease susceptibility in Korean schizophrenic patients. Methods: HLA-DQA1, HLA-DQB1, and HLA-DRB! allele typing were performed using polymerase chain reaction-sequence specific oligonucleotide probes(PCR-SSOP) method in 128 Korean schizophrenic patients diagnosed by DSM-IV criteria, who were not blood-related, and 160 normal blood bank donors. Results: The HLA-DQB1□04 allele frequency was 14.6% in schizophrenic patients, which was significantly higher than that of normal controls which was 8.2%(p=0.028). HLA-DRB1□14 allele frequency was 11.8% in patients, which was also more frequent than that of normal controls which was 5.5%(p=0.01). HLA-DRB1□15 allele frequency was 2.0% in patients, which was significantly lower than that of normal controls which was 7.1%(p=0.007) and HLA-DRB1□16 allele frequency was 1.6% in patients, which was also lower than that of normal controls which was 4.8%(p=0.043). Conclusion: Schizophrenia in Korea had positive correlation with HLA-DQB1□04 and HLA-DRB1□14, and negative correlation with HLA-DRB1□15 and HLA-DRB1□16. These findings support the association of the HLA-DQB1 and HLA-DRB1 with schizophrenia in Korean population, which was different from other study results in other different ethnic groups.

한국인의 HLA-DQB1 유전자빈도와 DRB1과의 연관성 조사

임영애,곽연식 대한임상병리학회 1999 대한임상병리학회지 Vol.19 No.5

한국인 정신분열병과 HLA-DRB1 대립유전자의 관련성

황나영,김종원,오흥범,조지희,오선영,홍진표,박종익,이동은 大韓神經精神醫學會 2000 신경정신의학 Vol.39 No.5

연구목적: 유전이 정신분열병의 중요한 원인이라는 것은 널리 인정되어 왔다. 본 연구는 한국인 정신분열병과HLA-DRB1 유전자좌와의 관련성을 알아보고 외국인 대상의 보고들과 비교함으로써 한국인 정신분열병의 유전적 특성을 밝히고자 시행하였다. 방법: 정신분열병 환자 70명을 대상으로 HLA-DRB1 대립유전자를 고해상도 수준까지 분석하였다. 저해상도 수준의 HLA-DR결과는 정상 한국인 2,000명의 연구 보고와 비교하였으며 고해상도 수준의 HLA-DRB1 결과는 정상 한국인 229명의 연구 보고와 비교하였다. 결과: 저해상도 수준에서는 HLA-DR11이 정신분열병 환자군에서 9.0%, 정산인에서는 3.8%의 빈도를 보여 환자군에서 통계적으로 유의하게 높은 빈도를 보였으며(p=0.005), 고해상도 수준에서는 HLA-DRB1*1101이 환자군에서 9.0%로 정상인의 1.8%보다 유의하게 높은 빈도를 보였다(p<0.001). 결론: 본 연구에서는 한국인 정신분열병과 HLA-DR11(HLA-DRB1*1101)이 양적 상관관계를 보여 백인에서 DR4와 부정적 상관관계를 보인 결과나 일본인에서 DR1(DRB1*0101)과 양적 상관관계를 보인 결과와 상이하였다. 이러한 한국인 정신분열병 환자의 유전적 특성은 가족연구 혹은 더 많은 수의 환자를 대상으로 한 관련연구를 통하여 재확인되어야 할 것이다. 중심단어:정신분열병·HLA-DRB1·관련연구. Objective: A genetic predisposition is widely accepted in schizophrenia. This study was intended to fine any association of HLA-DRB1 alleles with korean schizophrenics and thereby compare the results of other ethni groups. Method: The subjects were 70 unrelated Korean patients. Low and high resolution typing of HLA-DRB1 alleles were performed. The comparison groups were 2,000 unrelated healthy Koreans for low resolution HLA-DR and 229 unrelated healthy Koreans for HLA-DRB1 alleles. Results: Gene frequencies of HLA-DR11(patients 9.0%, healthy control 3.8%, p=0.005) and HLA-DRB1*1101(patients 9.0%, healthy control 1.8%, p<0.001) were significantly higher in Korean schizophrenics. Conclusion: The frequency of HLA-DR11(HLA-DRB1*1101) is significantly higher in Korean schizophrenics than in healthy Koreans. HLA-DR4 and HLA-DR1, which were known to be associated with Caucasian and Japanese schizophrenics, respectively, did not show statistical association with Korean schizophrenics. This association need to be reassured though further studies with families or association study with larger numbers of subjects. KEY WORDS:Schizophrenia·HLA-DRB1·Association study.

옛사람뼈 DNA에서 HLA-DRB1 염기서열의 분석

우지영(Ji-Young Woo),김기정(Kijeong Kim),바좌라그촤 문흐체첵(Bazarragchaa Munkhtsetseg),김재현(Jae-Hyun Kim),가와치멛 르학와수렝(Gavaachimed Lkhagvasuren),손동섭(Dong-Suep Sohn),박애자(Ae-Ja Park),이광호(Kwang-Ho Lee),김대진(Dae-Jin Kim),정 대한체질인류학회 2010 해부·생물인류학 (Anat Biol Anthropol) Vol.23 No.2

옛사람 시료의 DNA 분석은 인류학 및 사람 진화 연구에서 최근 세계적으로 널리 이용되고 있는 추세이다. 인류의 유전자 연구에 있어서 사립체 DNA 및 Y 염색체 DNA와 더불어 널리 이용되고 있으나 옛사람으로부터 HLA 분석은 드문 형편이다. 본 연구에서는 고대 사람 시료로부터 HLA 유전자의 염기서열의 분석을 위해 PCR 증폭할 수 있는 방법을 개발하고자 하였다. 연구자들은 염기서열에 기초한 HLA-DRB1 분석을 위한 방법을 개발하였고, 3000년 전부터 500년 전에 해당하는 한국과 몽골 지역에서 출토된 옛사람뼈로부터 HLA-DRB1의 염기서열을 밝혀 대립유전자의 유형을 분석하였다. 유전자형은 HLA database (http://www.ebi.ac.uk/Tools/blast2/nucleotide.html)에서 염기서열을 비교하여 대립유전자형을 결정하였다. 한국인과 몽골인의 HLA-DRB1의 대립유전자는 유형별로 분리하여 구분하였고, 이외에도 몽골의 지형적 분류를 근거로 서부, 중부, 동부, 그리고 북부로 구분하여 각 대립유전자형의 빈도를 나타내었다. 종합하면 옛사람뼈에서 분리 정제한 DNA로부터 성공적으로 HLA-DRB1을 증폭하여 대립유전자의 유형을 분석할 수 있었다. 이 방법은 앞으로 HLA 염기서열 분석을 통해 개인이나 개체군의 유연관계 분석을 위해 이용될 수 있을 것으로 기대한다. The analysis of ancient human DNA is increasingly used recently in the study of anthropology and human evolution. Although mitochondrial DNA and Y chromosomal DNA has commonly been the target in the field of human DNA study, HLA analysis of ancient human DNA is extremely rare. This study aimed to develop the PCR method of ancient human DNA for analyzing the sequence of HLA. Authors established a new method for HLA-DRB1 analysis by sequence-based typing. Alleles of HLA-DRB1 were analyzed and typed by sequencing with DNA of ancient human skeletons from Korea and Mongolia 3000-500 years ago. The types of HLA-DRB1 were determined by comparing the sequences with those of HLA database (http://www. ebi.ac.uk/Tools/blast2/nucleotide.html). The alleles of HLA-DRB1 of ancient human DNA from Korea and Mongolia were classified by types. The frequencies of HLA-DRB1 types of Mongolia were also presented according to the geography such as West, Central, East, and North. In summary, our method was successful in the analyzing the type of HLA-DRB1 from DNA of ancient human bones. Authors anticipate that many researchers could do their research in a better way to get the genetic information for the kinship analysis between individuals or communities from ancient human bones.

The HLA-DRB1 Polymorphism is Associated With Atopic Dermatitis, but not Egg Allergy in Korean Children

Hwayoung Park,안강모,박명희,Sang Il Lee 대한천식알레르기학회 2012 Allergy, Asthma & Immunology Research Vol.4 No.3

Purpose: We investigated whether particular HLA-DRB1 polymorphisms contribute to egg allergy development in Korean children with atopic dermatitis (AD). Methods: HLA-DRB1 alleles were determined by PCR-sequence-specific oligonucleotide (SSO) and PCR-single-strand conformation polymorphism (SSCP) methods in 185 patients with AD and 109 normal control (NC) subjects. AD patients were divided into two groups: 1) AD with egg allergy, consisting of 96 patients with egg allergies as determined by egg-specific immunoglobulin E (IgE) reactivity; and 2) AD without egg allergy,consisting of 89 patients without egg allergies. HLA-DRB1 alleles were classified into functional groups (A, De, Dr, E, Q, R, a). HLA-DRB1 phenotype and functional group frequencies in the AD, AD with egg allergy, and AD without egg allergy groups were compared with those in the NC group. Results: The frequency of DRB1*08:02 was decreased in the AD with egg allergy group compared with the AD without egg allergy group (2.1%vs. 10.1%, P=0.021), and DRB1*15:01 was increased in the AD with egg allergy group compared with the AD without egg allergy group (22.9% vs. 11.2%, P=0.036). However, significance was lost after Bonferroni correction. HLA-DRB1*11:01 had a significantly higher frequency in AD patients compared with NCs (12.4% vs. 1.8%, corrected P=0.048) and was regarded as a susceptibility factor associated with AD. DRB1*08:03 was decreased in AD patients compared with NCs (10.8% vs. 19.3%, P=0.043). HLA-DRB1 functional group ‘a’, which includes DRB1*15:01, seemed to be associated with the development of egg allergy in AD (P=0.033), but this result was not significant after Bonferroni correction. Conclusions: HLADRB1polymorphism is not associated with egg allergy, but HLA-DRB1*11:01 is associated with AD in Korean children.

Identification of a New HLA-DRB1*1101 Allele by Sequence-based Typing from a Bronze Aged Mongolian Skeletal Remain

아리오나 턱럼 외 중앙대학교 의과대학 의과학연구소 2008 中央醫大誌 Vol.33 No.3/4

고대 사람 시료의 DNA 분석은 인류학 및 사람 진화 연구에서 최근 세계적으로 널리 이용되고 있는 추세이다. HLA 분석은 조직 및 기관 이식시 조직적합판정을 위한 필수적인 방법으로 이용되며 또한 인류 진화 연구에 있어서 사립체 및 Y 염색체 DNA와 더불어 널리 이용되고 있다. 고대 사람 시료로부터 HLA 분석 성공 보고는 매우 드물다. 본 연구에서는 고대 사람 시료로부터 DNA를 추출하고 고해상도 염기서열에 기초한 HLA-DRB1 염기서열 분석을 위한 방법을 개발하였고, 청동기시대로 추정되는 서부 몽고 지역에서 출토된 사람 뼈로부터 새로운 HLA DRB1 대립유전자를 발견하였다. 이 HLA 대립유전자는 새로운 HLA-DRB1*1101 대립유전자에 속하였다. 이 대립유전자는 49번째 코돈에서 alanine 아미노산이 threonine 아미노산으로 바뀐 (GCG → ACG) 변이를 함유하였으며 74번째 코돈에서 GCG → GCA로 바뀐 침묵변이를 함유하였다. 이는 현재까지 알려진 DRB1*110101, DRB1*110102와 DRB1*110106과 다른 양상을 나타내었다. 본 연구는 고대 사람 시료로부터 처음으로 새로운 HLA 염기서열의 존재를 증명하였다. 이 새로운 HLA DRB1 염기서열은 GenBank에 등록을 하였으며, 앞으로 HLA 염기서열 분석을 통한 사람 유연관계 분석과 잠재적 조직이식 적합성 분석을 위한 데이터베이스의 한 자료로 이용될 수 있을 것으로 기대한다.

Meta-analysis of the Association between HLA-DRB1 Allele and Rheumatoid Arthritis Susceptibility in Asian Populations

Jun, Kyung Ran,Choi, Sung-Eun,Cha, Choong-Hwan,Oh, Heung-Bum,Heo, Yong-Seok,Ahn, Hong-Yup,Lee, Kwan-Jeh KOREAN ACADEMY OF MEDICAL SCIENCE 2007 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.22 No.6

<P>The aims of this study were to summarize results on the association of HLA-DRB1 with rheumatoid arthritis (RA) in Asians and to determine if the shared epitope (SE) hypothesis could explain the meta-analysis results. Among the papers published between January 1987 and July 2006 on RA susceptibility in Asian-Mongoloid populations (Korean, Japanese, Chinese, and Thai), 12 were selected for the meta-analysis. Mongoloid-Asian patients with RA had significantly higher frequencies of HLA-DRB1*0101, *0401, *0410, and *1001 than controls (OR 1.5-2.1, <I>p</I><0.05 for association). When analyses were restricted to more ethnically homogeneous populations, HLA-DRB1*0405 showed a significant susceptibility to RA in Koreans (OR 5.65, 95% CI 4.32-7.39), whereas the HLA-DRB1*0301, *0403, *0406, *0701, *1301, and *1405 alleles showed protective association with RA (OR 0.32-0.70, <I>p</I><0.05 for association). In conclusion, it was found that HLA-DRB1 *0101, *0401, *0405, *0410, and *1001 are susceptible, while HLA-DRB1*0301, *0403, *0406, *0701, *1301, and *1405 are protective in Asian-Mongoloids. All the RA-associated alleles except DRB1*0301 could be explained by the structural model supporting the SE hypothesis that RA susceptibility is determined by the combination of amino acid residues at HLA-DR β71 and β74, not by β71 alone.</P>

Negative Association of the HLA-DQB1^*02 Allele with Breast Cancer Development among Jordanians

Atoum, Manar Fayiz,Tanashat, Reem Qasem,Mahmoud, Sameer Al Haj Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.11

Background: In the literature, data concerning the relationship between breast cancer and HLA class II gene polymorphisms are limited, so the aim of this study was to determine if HLA-DQB1 and HLA-DRB1 MHC class-II alleles may confer susceptibility or resistance to the disease among Jordanian females. Materials and Methods: This case control study enrolled 56 Royal Hospital breast cancer patients and 60 age matched healthy controls, all of whom provided blood samples (2011-2013). A questionnaire was filled after signing a consent form and DNA was extracted, nucleic acids being amplified for assessment of HLA-DQB1 and HLA-DRB1 alleles by muliplex INNO-LiPA and allele typing carried out by reverse hybridization. Comparison of HLA-DQB1 and HLA-DRB1 allele distributions was carried out with paired t-test and chi-square statistics. Risk factors were assessed by odd ratios with 95% confidence intervals. Results: A significant negative correlation was observed between $HLADQB1^*$ 02 alleles and breast cancers (p=0.013). No significant associations were observed among $HLADQB1^*$ 03, 04, 05 and 06 or among $HLA-DRB1^*$ 01, 03, 04, 07, 08, 10, 11, 13, 14 and 15. Conclusions: $HLADQB1^*$ 02 alleles may provide positive protection against breast tumor risk among Jordanians, but not $HLADQB1^*$ 03, 04, 05 and 06 or $HLA-DRB1^*$ 01, 03, 04, 07, 08, 10, 11, 13, 14 and 15 alleles.

한국인 천포창 환자에서의 HLA - DRB1 대립유전자의 빈도에 관한 연구

양홍윤 ( Hong Yoon Yang ),이창우 ( Chang Woo Lee ),김수찬 ( Soo Chan Kim ),정진호 ( Jin Ho Chung ),유희준 ( Hee Joon Yu ),황적준 ( Juck Joon Hwang ) 대한피부과학회 1998 대한피부과학회지 Vol.36 No.2

Background & Objectives : Pemphigus is an autoimmune bullous disease of the skin and mucous membranes. There are two major types of pemphigus, namely pemphigus vulgaris(PV) and pemphigus foliaceus(PF) which can be classified by the specificity of the autoantibodies against the epidermal desmosomal antigens in this disease. Like many other autoimmune diseases, pemphigus is also considered to be strongly associated with certain HLA alleles; some alleles can be detected with higher frequencies as compared with those found in ethnically matched populations. At this time, we tried to find out if there were certain HLA class II allele(s) associated significantly with Korean patients of pemphigus. Patients & Methods : Thirty patients with pemphigus (fifteen of PV and fifteen of PF), and one hundred healthy Korean controls were enrolled in this study. For the genotyping of HLA class II alleles in DRB1 loci, genomic DNAs prepared from buccal epithelia were amplified by polymerase chain reactions with nucleotide sequence-specific primers. Each allele of thirteen different generic types belonging to the DRB1 loci were used to identify the existence of each allele in both patient and control groups on gel electrophoreses. Results : In PV, there was a significantly increased frequency of HLA-DRB1*01 alleles than from the findings observed in the controls(pc=0.0013, RR:5). In patients with PF, there was a significant degree of association with HLA-DRB1*01(pc=0.00013, RR:5.5) when compared with that in normal controls. However, no allele of negative association with a significantly low frequency in the patient group was detected in both types of the disease. Conclusion : It can be suggested that DRB1*01 alleles may be susceptibility genes in Korean patients with PV, and DRB1*01 alleles could contribute to the autoimmune reactivity in patients with PF. This data shows different patterns in the frequency of each DRB1 allele in patient groups compared with those found in patients of other ethnic backgrounds. (Korean J Dermatol 1998;36(2): 252-260)

The human leucocyte antigen-DRB1^*1302-DQB1^*0609-DPB1^*0201 haplotype may be a strong genetic marker for aspirin-induced urticaria

Kim, SH.,Choi, JH.,Lee, KW.,Kim, SH.,Shin, ES.,Oh, HB.,Suh, CH.,Nahm, DH.,Park, HS. Blackwell Scientific Publications 2005 Clinical and experimental allergy Vol.35 No.3

<P>Summary</P><P>Background</P><P>Urticaria/angioedema is a common aspirin-induced allergy; however, its pathogenic mechanism is not understood.</P><P>Objective</P><P>In order to uncover the genetic mechanism, we studied the associations of the human leucocyte antigen (HLA) genotypes in patients with aspirin-induced urticaria compared with aspirin-intolerant asthma and normal control in a Korean population.</P><P>Methods</P><P>Ninety-four aspirin-induced urticaria patients presenting urticaria/angioedema-induced by both ASA and NSAID (50 had underlying chronic urticaria) and showing positive responses on oral aspirin challenge test, 76 aspirin-intolerant asthmatics with positive responses on lysine–aspirin bronchoprovocation test, and 185 normal healthy controls were enrolled. HLA-DRB1, DQB1, and DPB1 genotypings were performed by direct DNA sequencing analysis.</P><P>Results</P><P>The allele frequencies of HLA-DRB1<SUP>*</SUP>1302 (18.1%) and HLA-DQB1<SUP>*</SUP>0609 (10.1%) in aspirin-induced urticaria were significantly higher than in aspirin-intolerant asthma (5.3%, <I>P</I>=0.0004; 2.0%, <I>P</I>=0.0024) and in normal controls (8.1%, <I>P</I>=0.0005; 3.2%, <I>P=</I>0.0008), and they remained significant after correcting for multiple comparisons. The patients with these two HLA markers had a significantly younger age than patients without, while no associations were found in with respect to atopic status, a history of previous allergic diseases, total IgE level, or presence of underlying chronic urticaria (<I>P</I>>0.05, respectively). In haplotype analysis, the HLA-DRB1<SUP>*</SUP>1302-DQB1<SUP>*</SUP>0609-DPB1<SUP>*</SUP>0201 was significantly higher in the aspirin-induced urticaria (8.0%) than in the aspirin-intolerant asthma (0.7%, <I>P</I>=0.0014) and normal controls (2.0%, <I>P</I>=0.0006).</P><P>Conclusion</P><P>These findings suggest that the HLA-DRB1<SUP>*</SUP>1302-DQB1<SUP>*</SUP>0609-DPB1<SUP>*</SUP>0201 may be a strong genetic marker to determine the aspirin-induced urticaria phenotype.</P>