中国胰岛素依赖性糖尿病病人（HLA－DR9）的HLA－DQB1基因顺序分析

用血清学方法研究显示中国人胰岛素依赖性糖尿病（ＩＤＤＭ）与ＨＬＡ－ＤＲ９相关。鉴于白种人中的研究显示ＩＤＤＭ与ＨＬＡ－ＤＱβ链第５７位氨基酸相关，Ａｓｐ－５７对ＩＤＤＭ呈抗性，ｎｏｎ－Ａｓｐ与ＩＤＤＭ易感性相关。我们用ＰＣＲ技术扩增了中国人中血清学ＤＲ９纯合的ＩＤＤＭ患者和正常对照的ＨＬＡ－ＤＱＢ１基因第二外显子并测定了核苷酸顺序，结果未发现ＩＤＤＭ特异ＨＬＡ－ＤＱＢ１等位基因，但发现ＩＤＤＭ病人ＨＬＡ－ＤＱＢ１５７位均为天冬氨酸。表明中国ＩＤＤＭ患者中的ＨＬＡ－ＤＱＢ１５７位天冬氨酸不一定具有保护个体抵抗ＩＤＤＭ的足够能力。ＩＤＤＭ易感性可能涉及多个基因位点的变化，另外还可能与其它遗传因素及环境因素有关。     

中国胰岛素依赖性糖尿病病人（HLA－DR9）的HLA－DQB1基因顺序分析

用血清学方法研究显示中国人胰岛素依赖性糖尿病（ＩＤＤＭ）与ＨＬＡ－ＤＲ９相关。鉴于白种人中的研究显示ＩＤＤＭ与ＨＬＡ－ＤＱβ链第５７位氨基酸相关，Ａｓｐ－５７对ＩＤＤＭ呈抗性，ｎｏｎ－Ａｓｐ与ＩＤＤＭ易感性相关。我们用ＰＣＲ技术扩增了中国人中血清学ＤＲ９纯合的ＩＤＤＭ患者和正常对照的ＨＬＡ－ＤＱＢ１基因第二外显子并测定了核苷酸顺序，结果未发现ＩＤＤＭ特异ＨＬＡ－ＤＱＢ１等位基因，但发现ＩＤＤＭ病人ＨＬＡ－ＤＱＢ１５７位均为天冬氨酸。表明中国ＩＤＤＭ患者中的ＨＬＡ－ＤＱＢ１５７位天冬氨酸不一定具有保护个体抵抗ＩＤＤＭ的足够能力。ＩＤＤＭ易感性可能涉及多个基因位点的变化，另外还可能与其它遗传因素及环境因素有关。     

家族性肥厚型心肌病易感基因与HLA—DQ位点相关性…

本文报道应用ＰＣＲ／ＳＳＯ方法分析了４个无肌凝蛋白重链基因突变的肥厚型心肌病多发家系成员ＨＬＡ－ＤＱ基因多态性，进行患病同胞共享ＨＬＡ ＤＱＡ１／ＤＱＢ１单倍型分析和Ｌｏｄｓ分析，结果表明，本病的易感基因与ＨＬＡ－ＤＱ基因存在连锁关系，提示在ＨＬＡ－ＤＱ座位附近可能存在与家族性肥厚型心肌病易感性有关的致病基因。     

用PCR—SSP方法研究广西壮族HIL—DQA1和B1基因多态性

目的 检测广西壮族ＨＬＡ－ＤＱＡ１，Ｂ１基因的多态性。方法 应用ＰＣＲ－ＳＳＰ方法对１４０名健康、无血缘关系广西壮族人的ＨＬＡ－ＤＱＡ１和ＤＱＢ１进行基因分型。结果 共检出７个ＤＱＡ１等位基因和１６个ＤＱＢ１等位基因。在检出的ＤＱＡ１等位基因中，０３０１的基因频率最高（３５％），０４０１的基因频率最低（１．１％）。在ＤＱＢ１等基因中，０６０１（２２．１％），０３０１（２０．７％），０５０１（１３．     

原发性肥厚型心肌病与HLA0DQ的相关性研究

本文用ＰＣＲ／ＳＳＯ方法对４１例原发性肥厚型心肌病患者和５２例正常人ＨＬＡ－ＤＱＡ１和ＤＱＢ１基因的多态性进行分析。发现，在肥厚型心肌病患者中，ＤＱＡ１＊０２０１，ＤＱＢ１＊０５０４，０５０２等位基因频率明显较低，其相对风险值分别为９．５１、５．８７和１１．６０；而ＤＱＡ１＊０５０１，ＤＱＢ１＊０３０３１的频率明显地高，相对风险值分别为２．９３和６．６５。初步认为，原发性肥厚型心肌病与某些ＨＬＡ－     

北方汉族HLA-DRB1、DQB1基因多态性的研究

目的从基因水平了解北方汉族ＨＬＡ－ＤＲＢ１、ＤＱＢ１多态性分布,获得更完整、更准确的遗传学数据。方法应用ＰＣＲ－ＳＳＰ方法对１０７名北方汉族健康人进行了ＨＬＡ－ＤＲＢ１、ＤＱＢ１等位基因分型。结果鉴定了１４个ＤＲＢ１等位基因,９个ＤＱＢ１等位基因,包括了ＤＲ、ＤＱ位点的全部血清学特异性。结论提供了一套比较完整准确的ＤＲＢ１、ＤＱＢ１等位基因的基因频率和连锁不平衡参数。对群体遗传和疾病关联的研究具有重要的意义。     

中国广东汉族群体HLAⅡ类基因多态性的研究

为探讨中国广东汉族群体ＨＬＡⅡ类基因多态性，采用ＰＣＲ／ＳＳＯ方法，随机选择１０２名广东籍汉族人进行了ＨＬＡⅡ类基因的ＤＮＡ分型。测定了包括ＨＬＡ－ＤＲＢ１，ＤＲＢ３，ＤＲＢ５，ＤＱＡ１，ＤＱＢ１和ＤＰＢ１等６个基因座位的等位基因。结果：共检出２３种ＤＲＢ１，３种ＤＲＢ３，４种ＤＲＢ５，８种ＤＱＡ１，１２种ＤＱＢ１和１２种ＤＰＢ１基因。该人群的ＨＬＡⅡ类等位基因多态性的典型性表现在ＨＬＡ－ＤＲＢ＊１２０２的不寻常优势和ＤＲＢ１＊０２单倍型的结构的高度复杂性。还发现了很高频率的一个近年才被正式命名的ＤＰ新型：ＨＬＡ－ＤＰＢ１＊２１０１，并且此型具有极不寻常的ＤＲＢ１＊１２０２－ＤＰＢ１＊２１０１的连锁不平衡。为分子流行病学研究提供了资料。     

我国北方地区Ⅰ型糖尿病患者与HLA-DR,DQ的关联研究

目的 研究我国北方胰岛素依赖型糖尿病人与ＨＬＡ－ＤＲ,ＤＱ的关联。方法 对华北地区５３名胰岛素依赖型糖尿病（ＩＤＤＭ）儿童进行了ＨＬＡ－ＤＲＢ１、ＤＱＡ１、ＤＱＢ１、分型,同１８５名进行了同样分型的华北正常对照人群进行关联分析。结果 发现ＤＲＢ１＊０３０１／ＤＲＢ１＊０４杂合子个体具有最高的风险（ＲＲ＝５１．１３）。进上不分析ＤＱ分子,将ＤＱα链第５２位为精氨酸和ＤＱβ链第５７位为非天冬氨酸分别命     

中国湖北汉族HLA—Ⅱ类等痊基因频率的群体调查

调查中国湖北汉族人群ＨＬＡ－Ⅱ类基因频率。方法,用聚合酶链反应／序列特异性引物和聚合酶链反应／限制性片段长度多态性技术,对中国湖北汉族１６８名正常个体进行了ＨＬＡ－ＤＲＢ１（ｎ＝１６８）、ＨＬＡ－ＤＱＢ１（ｎ＝１６０）、ＨＬＡ－ＤＰＢ１（ｎ＝９３）基因的多态性检测。结果共检出３９种ＤＲＢ１、１５种ＤＱＢ１和１７种ＤＰＢ１等位基因型别,等位基因频率较高的分别是：ＤＲＢ１＊０９０１（ｇｅｎｅｆｒｅｑｕ     

沈阳汉族人群HLA－DR、DQ、DP的DNA分型研究

使用ＰＣＲ／ＳＳＯ方法对９４名沈阳汉族健康人群进行了ＨＬＡ第Ⅱ类抗原等位基因的完全分型。共发现６６种等位基因，基中ＤＲＢ１２８种，ＤＲＢ３３种，ＤＲＢ５４种，ＤＱＡ１８种，ＤＱＢ１Ｉ３种，ＤＰＢ１１０种。分析了ＤＲ－ＤＱ连锁的五位点单倍型，共发现３８种，其中２１种是在白人为主的人群中已发现过的。本研究提出了中国东北人群ＨＬＡ第Ⅱ类抗原等位基因的遗传基本情况，可用于疾病研究的对照和其他中国人群资料的比较。     

Two sets of HLA Class II DRB and DQB1 alleles co-segregate among family members in a single maternal haplotype

HLA class II typing by sequence specific oligonucleotide probes (SSOP) on the family of a Burkit's Lymphoma patient produced hybridization patterns indicating the presence of two DRB1, and two linked DQB1 genes on the same maternal chromosome. DRB and DQB1 exon 2 amplification products associated with the novel maternal haplotype were identified by DNA typing techniques: These products corresponded to DRB1*0101, DRB1*1501, DRB5*01, DQB1*0501 and DQB1*0602 alleles. These alleles were seen to co-segregate among siblings sharing the same maternal haplotype. The patient, his mother and two of his siblings each appeared to possess elements of three DRB1, DQA1 and DQB1 genes. HLA DNA typing results indicated that a DNA sequence of approximately 100 Kb, spanning the region between, and including, DRB1 and DQB1 genes was inserted into the maternal haplotype. Serological typing on EBV transformed B lymphocytes obtained from the patient's mother showed three expressed DRB1 antigens. Serology on EBV transformed patient's cells also indicated multiple DRB1 antigen expression. The expression of three DRB1 and DQB1 genes on the cells of this patient would make it virtually impossible to obtain a suitably matched unrelated stem cell donor.     

中国汉族白血病患者及其相关人群罕见的HLA-DR/DQ连锁不平衡研究

 目的 研究中国汉族白血病患者及其相关人群罕见的HLA-DR/DQ连锁不平衡单倍型。方法 对2000－2005年在我院进行异基因造血干细胞移植前HLA配型的白血病患者及与患者有血缘关系的家系供者共1500例的血液标本，采用低分辨序列特异性引物聚合酶链反应（PCR-SSP）方法进行HLA-DR/DQ基因分型，并对两位点间连锁不平衡参数进行统计学分析。1500例中患者650例，平均年龄25岁；家系供者850例，平均年龄42岁。结果 在41例的血液标本中发现13种罕见的连锁不平衡单倍型，主要为HLA-DQ8 或HLA-DQ9与不同DR位点的连锁。其中DR14/DQ4、DR4/DQ5、DR9/DQ6、DR9/DQ7、DR8/DQ8、DR9/DQ8、DR12/DQ8、DR13/DQ8和DR14/DQ9共9种单倍型尚未见报道。650例白血病患者中有20例存在12种罕见的连锁不平衡单倍型，850例家系供者中有21例存在8种罕见的连锁不平衡单倍型。DR8/DQ8单倍型只见于家系供者，而DR14/DQ4、DR12/DQ6、DR11/DQ8、DR13/DQ8和DR14/DQ9单倍型则只见于白血病患者。41例HLA-DR/DQ基因分型结果显示，连锁不平衡单倍型与DR52（DRB3）宽抗原相关联者占58.5%（24/41），与DR53（DRB4）宽抗原相关联者占36.6%（15/41），而与DR51（DRB4）宽抗原相关联者仅占4.9%（2/41）。所发现单倍型频率最高的为DR12/DQ8（0.0023）和DR9/DQ8（0.0023），其次为DR11/DQ9（0.0020）和DR12/DQ9（0.0017）。13种连锁不平衡单倍型的绝对及相对连锁不平衡参数均为负值，说明它们在中国汉族人群中较为罕见，并处于连锁不稳定状态。结论 发现了罕见的DR/DQ连锁不平衡单倍型，对补充中国汉族人群HLA-DR/DQ基因的连锁不平衡类型，提高HLA分型结果的准确性具有一定意义；同时，DR/DQ连锁不平衡单倍型在不同人群中的差异为疾病关联研究提供了思路。     

Celiac disease prevalence and predisposing-HLA in a cohort of 93 Williams-Beuren syndrome patients

Williams-Beuren syndrome is considered to be at increased risk for celiac disease, as for recent literature data and celiac disease guidelines, despite pathogenic mechanisms are still unclear. Our study analyzed the prevalence of autoimmune disorders, HLA DQ2 and/or DQ8 haplotypes, of transglutaminase antibodies and of diagnosis of celiac disease in a cohort of 93 Williams-Beuren syndrome's patients (mean age 21.26 years). Our study showed an increased prevalence of celiac disease equal to 10.8% (10/93 patients). We did not find a significant different frequency of predisposing HLA in subjects with Williams-Beuren syndrome compared to literature data in the general population (49.5% vs. 42.9%, with p > .1), nor a susceptibility to autoimmunity. This suggests that the increased prevalence of celiac disease in Williams-Beuren syndrome cannot be ascribed to HLA haplotype and may be related to other factors that still need to be identified in these patients.     

Binding of peptides to HLA-DQ molecules: peptide binding properties of the disease-associated HLA-DQ({alpha}1*0501, {beta}1*0201) molecule

Peptide binding to DQ molecules has not previously been described.Here we report a biochemical peptlde-blndlng assay specificfor the BQ2 [I.e. DQ(1^*0501, ß1^*0201)] molecule. Thismolecule was chosen since It shows a strong association to diseasessuch as celiac disease and insulin-dependent diabetes mellitus.Initially we radlolabelled some selected peptides and testedthem for binding to affinity-purified DQ2 molecules. One ofthe peptides, a Mycobacterium bovis (MB) 65 kDa 243–255Ypeptide, displayed a good slgnal-to-noise ratio and was thuschosen as an indicator peptide in the DQ2 binding assay. TheMB 65 kDa 243–255Y peptide bound to DQ2 In a strictlypH-dependent fashion, with optimal binding around pH 5 and onlyweak binding at pH 7.4. The association of the MB 65 kDa 243–255Ypeptide to DQ2 was slow, but once formed, the peptide-HLA complexeswere very stable. The binding of peptides to DQ2 was specific,as shown in Inhibition experiments with a panel of 47 peptides,differing in length, sequence, and origin. The binding of peptidesto DR3 was tested in a similar assay with a Mycobacterium tuberculosis65 kDa 3–13 peptide as the binding indicator. DQ2 andDR3 molecules bound to different sets of peptides. However,the peptide binding to DQ2 and DR3 showed, In general, similarcharacteristics with respect to pH dependence and kinetic parameters,Indicating that the overall rules for peptide binding to DQmolecules are the same as those previously shown for human DRand murlne I-A and I-E molecules.     

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.     

人类白细胞Ⅱ类抗原DR、DQ基因型与妊娠期糖尿病的相关性研究

目的探讨人类白细胞II类抗原DR、DQ基因型与妊娠期糖尿病的相关性。方法对26例GDM孕妇及同期入院的42例正常健康孕妇,采用序列特异性引物聚合酶链反应技术(PCR-SSP)检测HLA-II类抗原DR和DQ的等位基因。结果研究中发现,DQA1*0101、DQA1*0201、DQB1*0609、DRB l*07-DQA1*0201-DQB1*0201基因频率在GDM中显著高于正常对照组,两组比较,统计学有差异(Ρ<0.05)。DQB1*0301基因频率在GDM中显著低于正常对照组,两组比较,有统计学差异(Ρ<0.05)。结论人类白细胞II类抗原DR、DQ基因型与GDM的易感性和保护性存在关联。DQA1*0101、DQA1*0201、DQB1*0609、DRB l*07-DQA1*0201-DQB1*0201基因是GDM的易感基因。DQB1*0301基因是GDM的保护基因。     

关于我国HLA－DR、DQ位点抗原多态性血清学研究的分析

就国内外１４家实验室的１５组（包括作者自己）ＨＬＡ－ＤＲ、ＤＱ位点多态性的血清学研究，进行了评析，旨在对今后的发展提出其自己的建议。我国ＨＬＡ研究界的当务之急是团结合作，筛选研制出中国自己成套的Ⅱ类抗原分型血清。     

A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan

To investigate the correlation between clinical features and HLA DR/DQ genetic variability in myasthenia gravis (MG), we evaluated HLA DR/DQ allele frequencies in 87 Japanese patients with childhood-onset disease. HLA genotypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303 were significantly higher in patients than in healthy controls (P(c) < 0.0001, RR = 5.5; P(c) < 0.0001, RR = 8.5, for two genotypes, respectively). Patients who had a significantly higher likelihood of the HLA types DRB1*1302/DQA1*0102/DQB1*0604 or DRB1*0901/DQA1*0301/DQB1*0303 belonged to the latent general type (LG) of MG; this is clinically ocular type, but shows myasthenic electromyographic findings in extremity muscles. The LG type of MG was observed in 78% of patients exhibiting the clinically ocular type; this group comprised approximately 75% of patients with childhood-onset MG. These date suggest that LG type of MG may present a particular subset of childhood-onset MG, which is associated with the specific HLA subtypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303.     

Binding of gluten-derived peptides to the HLA-DQ2 (α1*0501, β1*0201) molecule,assessed in a cellular assay

The nature of the immunopathogenic relationship underlying the very strong association of coeliac disease (CD) to the HLA-DQ (A1*0501, B1*0201) genotype is not known, but probably relates to binding of gluten-derived epitopes to the HLA-DQ (α1*0501, β1*0201) heterodimer (DQ2). These epitopes have not yet been defined. In this study we have tested the binding of various gluten-derived peptides to DQ2 in a cellular assay using Epstein–Barr virus (EBV)-transformed B lymphocytes and murine fibroblast transfectants. One of these peptides (peptide A), which has previously been shown to exacerbate the CD lesion in vitro and in vivo, was found to bind to DQ2, albeit only moderately, lending further credence to its possible role in the pathogenesis of CD. The nature of peptide A's binding to DQ2 was explored with truncated and conservative point substituted analogues and compared with the published DQ2 binding motif, the results of which explain the observed level of binding.