广东汉族人群HLA Ⅰ、Ⅱ基因多态性及单倍型分析

目的 检测广东汉族人群HLA-A、B、Cw、DRB1基因频率，分析该人群HLAⅠ、Ⅱ等位基因多态性及其单倍型特点。方法 骨髓移植供者160人，抗凝血提取DNA，半量全自动聚合酶链反应-单链构象多态分型检测HLA-A、B、Cw、DRB1基因型。结果 在低分辨水平分别检出HLA-A、B、Cw及DRB1等位基因12、23、11、13个。统计分析呈现显著连锁不平衡的HLA-A-B单倍型9个，B-Cw单倍型20个，A-Cw单倍型7个，HLA-A-DRB1单倍型8个，B-DRB1单倍型9个，Cw-DRB1单倍型10个。结论 广东汉族群体HLA-基因具有较为丰富的多态性，其双座位连锁不平衡单倍型具有地区性遗传特征。     

对西北维吾尔族人群HLA五座位单倍型的分析

在HLA研究中往往涉及单倍型。分析HLA单倍型需做家系分析,但家系分析因限于条件,较难实行,所以多用计算来估计。一般只计算二位点单倍型,这是利用HLA位点间等位基因的连锁现象先计算连锁不平衡参数,然后分析最可能出现的单倍型。连锁不平衡参数的计算原理是通过统计两个等位基因(i,j)同时出现的频率,用以下公式完成[1]:Δij=d/N-BD/N　　Δij为二座位某一等位基因或抗原的连锁不平衡参数。这个参数表示了在具体到个人的二座位的表现型中最有可能被连锁在一起的两个等位基因,因此判断最有可能出现的两位点单倍型。但HLA是由复等位基因…     

中国北方汉族寻常型天疱疮与HLA-Ⅱ类基因单倍型的相关性研究

目的：探讨HLA—DR、DQ基因单倍型与中国东北地区汉族人寻常型天疱疮的相关性。方法：应用序列特异性引物-聚合酶链反应（PCR—SSP）技术对27例中国东北汉族PV患者的HLA—DRB1、DQB1等位基因测定，进行单倍型分析，并与99例健康对照者进行比较。结果：与对照组比较，寻常型天疱疮患者组中单倍型DRB1＊140x-DQB1＊0503、DRB1＊140x-DQB1＊0201、DRB1＊120x-DQB1＊0503和DRB1＊140x—DQB1＊0302的频率明显增高，经统计学检验差异有显著意义（P〈0．05）。结论：特异单倍型可能是决定寻常型天疱疮发生的重要因素。     

转化生长因子-β1基因型在移植肾慢性排斥反应中的作用

 目的 探讨供、受者转化生长因子-β1 (TGF-β1)基因型与移植肾慢性排斥反应的关系。方法 用序列特异引物聚合酶链反应（PCR-SSP）方法，对144例肾移植受者和65例部分供者的TGF-β1基因分泌型进行检测。结果 受者TGF-β1为高分泌型时移植肾慢性排斥反应发生率与受者为中低分泌型者相比差异有统计学意义（P<0.01）。供者TGF-β1为高分泌型时移植肾慢性排斥反应发生率与供者为中低分泌型者相比差异无统计学意义（P>0.05）。受者高分泌/供者高分泌TGF-β1基因型组合的受者慢性排斥反应发生率比所有其它基因型组合者高（P<0.01）。而受者中低分泌/供者中低分泌TGF-β1基因型组合的受者慢性排斥反应发生率比所有其它基因型组合者低(P<0.01)。结论 同时检测供、受者TGF-β1基因分泌型对预测移植肾慢性排斥反应发生率有意义。     

上海人群中HLA-DR7单倍型同时表达两种纯合分型细胞检出的特异性Dw7c及Dw3

采用国际组织相容性会议提供的纯合分型细胞(HTC)和血清对上海地区56例无亲缘关系个体作HLA-A、B、C、D、DR、DQ分型并研究中国人DR-Dw关系后,发现11例Dw3阳性个体中仅5例表达命名相当的DR3特异性,另外6例Dw3阳性者却与DR7及Dw7c(Dw7+Dw17)共同表达于一条单倍型,使同一个体呈现HLA-D“三联体”这样一种未曾报导过的格局。中国人Dw3因而分成两类:一类见于传统的单倍型HLA-DR3-Dw3;另一类组成新单倍型HLA-DR7-Dw7c-Dw30。间接证据表明,后者的出现可能是中国人中一个新的HLA-DQw2分裂体同时参与Dw7c及Dw3功能表达并被HTC所识别的结果。     

643例中国北方汉族急性淋巴细胞白血病患者人类白细胞抗原连锁不平衡分析

目的 分析643例中国北方汉族急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)患者组和20359名健康对照组的人类白细胞抗原(human leukocyte antigen,HLA)HLA-A-B、B-DR和AB-DR单倍型频率及连锁不平衡分布差异.方法 应用最大似然性算法(expectation-maximization,EM)计算患者组和对照组的HLA-A-B、B-DRB1和A-B-DRB1单倍型频率及连锁不平衡参数,采用X2检验比较其分布差异.结果 HLA-A30-B13、A2-B46、A33-B58,B13-DR7、B46-DR9、B52-DR15、B58-DR17,A30-B13-DR7、A33-B58-DR17和A1-B37-DR10单倍型是两组常见、共有呈强连锁不平衡单倍型.A30-B13、A2-B46、A33-B44、B13-DR7、A30-B13-DR7和A2-1346-DR9的单倍型频率和连锁不平衡水平,患者组低于对照组,差异有统计学意义(X2＞3.84,P＜0.05).A2-B52、A2-B27、A24-B8,B60-DR9、B27-DR4、B52-DR14、B44-DR17、B27-DR12、和A11-B27-DR12的单倍型频率和连锁不平衡水平,患者组高于对照组,差异有统计学意义(X2＞3.84,P＜0.05).结论 643例北方汉族ALL患者组HLA-A-B、B-DRB1、A-B-DRB1单倍型频率分布及连锁不平衡遗传特征和对照组具有高度的同源性.患者组与对照组之间的部分HLA单倍型频率及连锁不平衡分布存在统计学差异.本研究结果 为ALL与HLA疾病相关性及HLA相合供者的寻找提供了基础数据.     

上海人群抗原处理相关基因的分布及其与原发性IgA肾炎关联研究

采用PCR SSO和PCR RFLP技术对 6 0例经临床及肾穿刺证实的IgA肾炎 (IgAN )患者和 80例正常人的TAP、LMP2和DM等位基因频率进行了检测。结果显示在患者和正常人中各等位基因频率均无显著性差异 ,表明IgAN与抗原处理相关基因无关联。同时分析了经典Ⅱ类基因 (DR/DQ/DP )和抗原处理相关基因 (TAP/LMP2 /DM )之间可能存在的连锁不平衡 ,获得了扩展的HLAⅡ类单倍型 ,为HLAⅡ类基因与某些自身免疫病的关联性研究提供了有价值的数据     

HLA-DRB1、DQB1基因与汉族人群寻常型天疱疮的相关性研究

目的　探讨 HL A- DRB1、DQB1位点基因在汉族人群寻常型天疱疮易感性中的作用。方法用序列特异性引物 -聚合酶链反应方法 ,对 6 1例寻常型天疱疮 (pemphigus vulgaris,PV)患者和 5 7名正常对照进行了 HL A- DRB1、DQB1等位基因的分型 ,并分析了 DRB1、DQB1基因在两组中的分布。结果　与正常对照组比较 ,PV组 DR4、DRB1* 14 (* 14 0 1、* 14 0 4、* 14 0 5 )基因频率明显增高 (Pc分别 <0 .0 5及P<0 .0 1) ,差异有显著性 ;PV组 DQB1* 0 5 0 3、DQB1* 0 30 2基因频率明显增高 (Pc均 <0 .0 5 ) ,差异有显著性。对 DR4阳性样本的组内基因亚型分型结果发现 ,PV组中 DRB1* 0 4 0 3、DRB1* 0 4 0 6频率显著增高(Pc<0 .0 5 ) ,差异有显著性。 PV患者组单倍型 HL A- DRB1* 0 4 ,DQB1* 0 30 2和 HL A- DRB1* 14 ,DQB1* 0 5 0 3频率明显增高 (P<0 .0 5 )。结论　HL A- DRB1* 0 4 ,DQB1* 0 30 2和 HL A- DRB1* 14 ,DQB1* 0 5 0 3可能是汉族人 PV推测的易感单倍型。     

一寻常型银屑病家系的HLA等位基因分析

目的分析北方一寻常型银屑病家系的发病与HLA-A、B、DRB1等位基因的相关性。方法采用序列特异性寡核苷酸探针-聚合酶链反应(PCR-SSO)方法检测一北方家系16人的HLA-A、B、DRB1等位基因。结果家系中共有6人患寻常型银屑病,其中4个早发寻常型银屑病患者(Ⅱ-2、Ⅱ-4、Ⅲ-1、Ⅲ-5)发病均在30岁以前,B位点均为B*13、DRB1位点均为DRB1*07;家系中有6人携带单倍型11-15-15,其中4人发病(Ⅰ-2、Ⅱ-2、Ⅱ-4、Ⅲ-1),年龄稍小的2人未发病(Ⅲ-3、Ⅲ-4)。结论此家系中寻常型银屑病的发病涉及多个易感位点,携带B*13-DRB1*07基因的早发病者可能与对遗传因素和/或环境因素敏感性增加有关;易感单倍型携带者的发病受环境因素和/或其他易感因素的影响。     

瘢痕疙瘩与HLA-II类基因相关性研究

目的 :探讨免疫遗传学因素在瘢痕疙瘩发病机制中的作用。方法 :用聚合酶链反应 序列特异性引物 (PCR SSP)技术对 5 0例瘢痕疙瘩患者进行HLA Ⅱ类基因分型 ,并以 1 0 0例正常人的HLA Ⅱ类基因为对照。结果 :瘢痕疙瘩组HLA DQ5抗原频率 ( 3 0 % )明显高于对照组 ( 1 4% ) ,相对危险率 (RR) =2 .63 ;HLA DR1 7和HLA DQ8抗原频率 ( 2 % )明显低于对照组 ( 1 4% ,1 5 % ) ,RR =0 .1 3 ,0 .1 2。结论 :瘢痕疙瘩与HLA DQ5基因呈正相关 ,与HLA DR1 7和HLA DQ8基因呈负相关。HLA DQ5、HLA DR1 7和HLA DQ8基因可能是瘢痕疙瘩患者易感的单倍型     

The HLA-DRB1*0405 haplotype is most strongly associated with IDDM in Algerians.

Insulin-dependent diabetes mellitus (IDDM) in Caucasians is strongly associated with HLA-DR3-DQ2 and DR4-DQ8. In order to investigate the HLA class II associations with IDDM in Algerians, we have used polymerase chain reaction (PCR) and sequence specific oligonucleotide analysis (SSO) to identify DQA1, DQB1, and DRB1 alleles, haplotypes and genotypes in 50 unrelated IDDM patients and 46 controls from a homogeneous population in Western Algeria. Both DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) haplotypes were found at increased frequencies among the patients compared to controls (45% vs. 13%, RR = 5.5, Pc < 10(-5) and 37% vs. 4%, RR = 12.9, Pc < 10(-4), respectively). Among the latter, in contrast to other Caucasian populations, only DRB1*0405-DQA1*0301-DQB1*0302 was significantly increased in the Algerian patients (25% vs. 1% in controls, RR = 30.3, Pc < 10(-3). Accordingly, the highest risk of disease was observed in DRB1*0301-DQA1*0501-DQB1*0201/DRB1*0405-DQA1+ ++*0301-DQB1*0302 heterozygotes (34% in patients vs. 0% in controls; RR = 49; Pc < 10(-3). This observation and its comparison with DR-DQ haplotypes in other ethnic groups suggest that the DRB1*0405 allele which encodes an Asp57-negative beta chain may contribute to IDDM susceptibility in a similar way as Asp57-negative DQ beta chains.     

HLA-DR-DQ haplotypes defined by restriction fragment analysis. Correlation to serology

Through the analysis of RFLP (restriction fragment length polymorphism) of the HLA-DR beta, -DQ alpha, and -DQ beta genes from 70 serologically well-characterized individuals, we have established unique HLA-DR-DQ RFLP haplotypes correlating to all of the DR1-w14 specificities. The RFLP of DR beta, DQ alpha, and DQ beta genes is very high using the restriction enzyme TaqI and 21 DR-DQ RFLP haplotypes were defined with this restriction enzyme. Our analysis confirms the strong linkage disequilibrium between alleles in the DR and DQ loci. DR beta RFLP indicates a common ancestor for the DR alleles within either of the supertypic DRw52 and DRw53 specificities. The DQ beta gene shows a high degree of RFLP, and the RFLP alleles partly reflect the serologic DQw1-w3 specificities. The results presented here also demonstrate the heterogeneity of DRw6 (DRw13 and DRw14) associated haplotypes, and the DRw13 related Dw18 and Dw19 specificities were found to have distinct DR-DQ haplotypes. The DQw1 positive haplotypes DR1, 2, w10, w13, and w14 are related with regard to DQ alpha and DQ beta RFLPs and the DRw52 positive haplotypes DR3, w11, and w12, as well as the DRw53 positive haplotypes DR4, 7, and w9, are related with regard to DR beta and DQ alpha RFLPs. These findings indicate that polymorphic sequences around the DQ alpha gene are associated with DR beta and DQ beta polymorphism, which suggests a location of the DQ alpha gene between DR beta and DQ beta.     

Role of HLA class II genes in susceptibility and resistance to multiple sclerosis: studies using HLA transgenic mice

Multiple sclerosis (MS), an inflammatory and demyelinating autoimmune disease of CNS has both, a genetic and an environmental predisposition. Among all the genetic factors associated with MS susceptibility, HLA class II haplotypes such as DR2/DQ6, DR3/DQ2, and DR4/DQ8 show the strongest association. Although a direct role of HLA-DR alleles in MS have been confirmed, it has been difficult to understand the contribution of HLA-DQ alleles in disease pathogenesis, due to strong linkage disequilibrium. Population studies have indicated that DQ alleles may play a modulatory role in the progression of MS. To better understand the mechanism by which HLA-DR and -DQ genes contribute to susceptibility and resistance to MS, we utilized single and double transgenic mice expressing HLA class II gene(s) lacking endogenous mouse class II genes. HLA class II transgenic mice have helped us in identifying immunodominant epitopes of PLP in context of various HLA-DR and -DQ molecules. We have shown that HLA-DR3 transgenic mice were susceptible to PLP_91–110 induced experimental autoimmune encephalomyelitis (EAE), while DQ6 (DQB1*0601) and DQ8 (DQB1*0302) transgenic mice were resistant. Surprisingly DQ6/DR3 double transgenic mice were resistant while DQ8/DR3 mice showed higher disease incidence and severity than DR3 mice. The protective effect of DQ6 in DQ6/DR3 mice was mediated by IFNγ, while the disease exacerbating effect of DQ8 molecule was mediated by IL-17. Further, we have observed that myelin-specific antibodies play an important role in PLP_91–110 induced EAE in HLA-DR3DQ8 transgenic mice. Based on these observations, we hypothesize that epistatic interaction between HLA-DR and -DQ genes play an important role in predisposition to MS and our HLA transgenic mouse model provides a novel tool to study the effect of linkage disequilibrium in MS.     

Molecular, serological and population studies of the alleles and products of HLA-B*41.

The HLA-B41 specificity was first identified over 25 years ago and, although both serological and biochemical studies have suggested its subdivision, it is only recently that two HLA-B*41 alleles (B*4101 and B*4102) have been identified and sequenced. We designed three oligonucleotide primers, combined in two mixtures to define these alleles by PCR using sequence-specific primers (PCR-SSP) in a random normal population of 9,464 HLA-A, B, DR, DQ typed Northern European Caucasoid donors from the Welsh Bone Marrow Donor Registry. The HLA-B41 phenotype frequency was 0.835%, and of the 79 HLA-B41 subjects 22 (27.85%) were B*4101 and 57 (72.15%) were B*4102. The phenotype frequencies of B*4101 and B*4102 were 0.232 and 0.602%, respectively, and the gene frequencies were 0.00116 and 0.00301, respectively. Formal two-locus linkage disequilibrium (LD) analysis demonstrated significant associations between B*4101 and A30 and DR11, and between B*4102 and A66 and DR13. LD analysis of three loci showed significant associations between B*4101, DR7, DQ2 and B*4101, DR11, DQ7 (DQB1*0301/0304) and between HLA-A3, B*4102, DR13; A66, B*4102, DR7; A66, B*4102, DR13; B*4102, DR13, DQ6 and B*4102, DR13, DQ7. Examination of the HLA phenotypes (including HLA-C) of the B*41 subjects, together with the LD analysis findings, suggested four different HLA haplotypes bearing B*4101 and five B*4102 haplotypes. The most frequent B*4101 haplotype was: HLA- A30 or other A allele, Cw*1701, B*4101, DRB1*1102, DQB1*0301 and the most freqent B*4102 haplotype was: A*6601 or A3 or other A allele, Cw*1701, B*4102, DRB1*1303, DQB1*0301. In addition, the well-known association of A66 with B41 was between A*6601 and B*4102, and although both B*41 alleles were commonly in association with Cw*1701, B*4101 was found with Cw*07. One-dimensional isoelectric focusing (1D-IEF) analysis of HLA-B proteins from 2 B*4101 and 2 B*4102 subjects clearly showed that the B41.1 and B41.2 1D-IEF variants, identified in the 10th International Histocompatibility Workshop, corresponded to B*4101 and B*4102 products, respectively. Serological titration studies, with 59 lymphocytotoxic pregnancy antisera, containing an HLA-B41 component and stimulated by up to five different HLA-B specificities, were unable to differentiate the two groups of B*41 subjects. This suggests that partition of the HLA-B41 specificity will not normally be achieved by classical serological methods. It is suggested that the previous alleged serological subdivision of HLA-B41 was founded on the unwitting use of antisera detecting the HLA-Cw*17 products.     

HLA class II associations with Type 1 diabetes mellitus: a multivariate approach

The association of HLA class II phenotype with the development of insulin-dependent (Type 1) diabetes mellitus (IDDM) is well established but the contribution of the various HLA-DR and -DQ alleles and haplotypes to disease predisposition is not fully understood. We have determined haplotype and genotype odds ratios, and further employed multivariate tree analysis to explore the contribution of individual HLA-DRDQ haplotypes to the genetic risk for developing IDDM in the Dutch population. Next to haplotype and genotype odds ratios, multivariate tree analysis techniques provide overall risk calculations for each modeled parameter, and offer insight in the interaction of the model parameters via tree-shaped reports, in which subsequent stratifications on the data can easily be followed. We compared 206 Dutch IDDM patients with 840 serologically typed random healthy unrelated Dutch Caucasoid controls. The multivariate tree analysis showed that the HLA-DR7DQ9 and DR15DQ6 haplotype were strongly associated with disease protection (OR = 0.04, P = 0.0003, and OR = 0.07, P < or = 0.0001, respectively). The highest ORs were found for the DR4DQ8/DR8DQ4 genotype (OR = 21.04, P = 0.001), followed by DR4DQ8/DR17DQ2 (OR = 12.45, P < 0.0001) and DR9DQ9/DR17DQ2 (OR = 10.87, P = 0.02). DR4DQ8 homozygous and DR17DQ2 homozygous individuals have a disease OR of 9.0 and 3.0 (P = 0.01 and 0.03), respectively. In conclusion, the results from haplotype, genotype, and tree analyses provide insight into the disease associations for combinations of HLA-DRDQ haplotypes. We confirm that the DR9DQ9/DR17DQ2 genotype is associated with susceptibility in the Dutch population, which has previously been noticed as a HLA risk genotypes in Asian populations only.     

THE HLA-DRB1*0405 HAPLOTYPE IS MOST STRONGLY ASSOCIATED WITH IDDM IN ALGERIANS

Insulin-dependent diabetes mellitus (IDDM) in Caucasians is strongly associated with HLA-DR3-DQ2 and DR4-DQ8. In order to investigate the HLA class II associations with IDDM in Algerians, we have used polymerase chain reaction (PCR) and sequence specific oligonucleotide analysis (SSO) to identify DQA1, DQB1, and DRB1 alleles, haplotypes and genotypes in 50 unrelated IDDM patients and 46 controls from a homogeneous population in Western Algeria. Both DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) haplotypes were found at increased frequencies among the patients compared to controls (45% vs. 13%, RR = 5.5, P_c < 10^-5 and 37% vs. 4%, RR = 12.9, P_c < 10^-4, respectively). Among the latter, in contrast to other Caucasian populations, only DRB1*0405-DQA1*0301-DQB1*0302 was significantly increased in the Algerian patients (25% vs. 1% in controls, RR = 30.3, P_c < 10^-3). Accordingly, the highest risk of disease was observed in DRB1*0301-DQA1*0501-DQB1*0201/DRB¹*0405-DQA1*0301-DQB1*0302 heterozygotes (34% in patients vs. 0% in controls; RR = 49; P_c < 10^-3). This observation and its comparison with DR-DQ haplotypes in other ethnic groups suggest that the DRB1*0405 allele which encodes an Asp57-negative β chain may contribute to IDDM susceptibility in a similar way as Asp57-negative DQβ chains.     

Additional association of intra-MHC genes,MICA and D6S273, with Addison's disease

Intra-MHC sequences including MHC class I chain-related genes (MICAs), D6S273 and D6S2223 are associated with autoimmune diseases in addition to HLA class II. In the current study, we ascertained the haplotypes of 57 Caucasian patients with Addison's disease composed of these genetic markers and compared them either with 72 general population controls or with 105 child controls carrying Addison's disease high-risk DR3-DQ2/DR4-DQ8 genotypes. The MICA-A5.1/A5.1 genotype as well as HLA DR3/4 especially with DRB1*0404 were the main susceptibility markers. The homozygous MICA-A5.1/A5.1 genotype was significantly more frequent in the patients with Addison's disease (61%) than in the healthy controls (6%). The MICA-A5.1 allele was increased on both the DR3 and DR4 haplotypes, independent of DQ and DRB1 subtyping, in the patients with Addison's disease compared with the controls. Furthermore, the D6S273*140 allele on the DR3 haplotype and the D6S273*134 allele on the DR4 haplotype in the DR3/4 heterozygotes influenced susceptibility relative to the DR3/4 controls. The risk for Addison's disease was increased for the DR3-D6S273*140-MICA-A5.1/DRB1*0404-D6S273*134-MICA-A5.1 genotypes compared with that conferred by the DR3/4 controls. Susceptibility to Addison's disease is influenced by the genes around MICA and D6S273 for both the HLA DR3-DQ2 and DR4-DQ8 haplotypes.     

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

The objective of this study was to characterize the peptide-binding motif of the major histocompatibility complex (MHC) class II HLA-DR8 molecule included in the type 1 diabetes-associated haplotype DRB1(*)0801-DQA1(*)0401/DQB1(*)0402 (DR8-DQ4), and compare it with that of other diabetes-associated MHC class II alleles; DR8-bound peptides were eluted from an HLA-DR homozygous lymphoblastoid cell line. The repertoire was characterized by peptide sequencing using a LTQ ion trap mass spectrometer coupled to a multidimensional liquid chromatography system. After validation of the spectra identification, the definition of the HLA-DR8 peptide-binding motif was achieved from the analysis of 486 natural ligands, based on serial alignments of all possible HLA-DR-binding cores. The DR8 motif showed a strong similarity with the peptide-binding motifs of other MHC class II diabetes-associated alleles, HLA-DQ8 and H-2 I-A(g7). Similar to HLA-DQ8 and H-2 I-A(g7), HLA-DR8 preferentially binds peptides with an acidic residue at position P9 of the binding core, indicating that DR8 is the susceptibility component of the DR8-DQ4 haplotype. Indeed, some DR8 peptides were identical to peptides previously identified as DQ8- or I-A(g7) ligands, and several diabetes-specific peptides associated with DQ8 or I-A(g7) could theoretically bind to HLA-DR8. These data further strengthen the association of HLA-DR8 with type I diabetes.     

HLA haplotypes in Koreans based on 107 families

Abstract: There are marked differences in the distribution of HLA haplotypes among different populations, and multilocus HLA haplotypes can best be studied by family analysis. In the present study, 107 Korean families were analyzed for HLA-A, B, C, DR, and DQ antigens and haplotypes. Allele frequencies of more than 10% for class I antigens were A2, A24, A33, B44, B62, Cw1, Cw7, Cw9, Cw10, and C blank (CBL) and those for class II antigens were DR4, DR8, DR13, DR15, DQ1, DQ3, DQ4 and DQ7. In the analysis of HLA haplotypes, 18 kinds of A-B-DR and 11 kinds of A-C-B-DR-DQ haplotypes occurred at frequencies of more than 1%, comprising 34% and 24% of the total theoretical haplotypes, respectively. The five most common A-B-DR haplotypes were exclusively related with the five most common A-C-B-DR-DQ haplotypes (frequency>2%). These remarkably conserved five-locus haplotypes in Koreans were A33-CBL-B44-DR13-DQ1 (5.4%), A24-Cw7-B7-DR1-DQ1 (3.5%), A33-Cw7-B44-DR7-DQ2 (3.0%), A33-Cw10-B58-DR13-DQ1 (2.3%), and A30-Cw6-B13-DR7-DQ2 (2.3%). Comparison of the distribution of A-B-DR haplotypes among East Asian populations revealed that Koreans are closest to Japanese, but show a higher degree of polymorphism in the distribution of HLA haplotypes compared to Japanese. The results obtained in this study will be useful as basic data on Koreans for anthropology and organ transplantation.     

A new predictive model for insulin-dependent diabetes mellitus susceptibility based on combinations of molecular HLA-DRB1 and HLA-DQB1 pockets

With a view to establishing an accurate evaluation of the genetic predisposition to insulin-dependent type I diabetes (IDDM), we have built a model based on the characteristics of the relevant pockets of HLA-DR and -DQ molecules. Three independent populations were investigated. Group I and group II were Caucasoids, while group III was Japanese, including a total of 1,166 IDDM patients and 2,391 healthy controls. We formulate the hypothesis that suceptibility to IDDM is not only explained by the absence of Aspartate 57 (negative charge) from pocket 9 of DQB1 (P9DQ), but also by the presence of an electric charge (+/- vs. neutral), generated by residues 70, 71 and 74 in pockets 4 of DRB1 (P4DR) and DQB1 (P4DQ) molecules. The respective weight of each pocket, was evaluated in a multivariate analysis based on the logistic regression method. The 4 components (2 loci and 2 pockets) were systematically analysed in the computer model. It was clearly shown that the structural characteristics of pockets P9DQ-P4DR and, to a lesser degree that of P4DQ, account for IDDM predisposition. On applying the model to the whole international series, it appears that the highest risk concerns individuals with P9DQ non-Asp 57 and both the charged P4 of DRB1 and P4 of DQB1, conferring a 80% prediction of susceptibility. Conversely, P9DQ Asp and neutral P4DR and P4DQ give the lowest risk with a predictive value of 5%. This model of risk susceptibility prediction fits remarkably well with the observed distribution in a worldwide study. It allows a better evaluation of the respective role of HLA-DR and -DQ molecules as a major component of susceptibility to IDDM.