HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: Analysis of the Type 1 Diabetes Genetics Consortium families
HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: Analysis of the Type 1 Diabetes Genetics Consortium families
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DOI：
10.2337/db07-1331
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发表时间：
2008-04-01
期刊：
影响因子：
7.7
通讯作者：
Moonsamy, Priscilla
中科院分区：
文献类型：
--
作者：
Erlich, Henry;Valdes, Ana Maria;Moonsamy, Priscilla
目的：1型糖尿病遗传学联合会收集了世界各地的1型糖尿病家系进行基因分析。1型糖尿病的主要遗传决定因素是HLA-DRB1和DQB1基因座上的等位基因，所有人群中都存在DR-DQ单倍型。研究设计与方法：对607个高加索家系和38个亚洲家系进行了DRB1、DQA1和DQB1基因座的高分辨率分型。关联分析是通过比较传递给患病儿童的染色体中DR-DQ单倍型的频率与未传递给任何患病儿童的染色体的频率来进行的。结果：已确定了一些易感、中性和保护性的DR-DQ单倍型，并建立了具有统计学意义的1型糖尿病风险等级。最易感的单倍型是DRB1*0301-DQA1*0501-DQB1*0201(优势比[OR]3.64)和DRB1*0405-DQA1*0301-DQB1*0302、DRB1*0401-DQA1*0301-DQB*0302和DRB1*0402-DQA1*0301-DQB1*0302单倍型(OR 11.37、8.39和3.63)，其次是DRB1*0404-DQA1*0301-DQB1*0302(OR 1.59)和DRB1*0801-DQB1*0401-DQB1*0402(OR 1.25)。最具保护性的单倍型是DRB1*1501-DQA1*0102-DQB1*0602(OR 0.03)、DRB1*1401-DQA1*0101-DQB1*0503(OR 0.02)和DRB1*0701-DQA1*0201-DQB1*0303(OR 0.02)。结论DRB1、DQA1和DQB1基因座上特异的等位基因组合决定了单倍型风险的程度。通过比较具有不同I型糖尿病风险的密切相关的DR-DQ单倍型对，可以确定在确定疾病易感性方面至关重要的特定氨基酸位置。这些数据还表明，与特定的人类白细胞抗原单倍型相关的风险可以受到基因背景的影响，由DQA1*0501和DQB1*0302编码的反式互补异二聚体具有很高的风险。
OBJECTIVE-The Type 1 Diabetes Genetics Consortium has collected type 1 diabetic families worldwide for genetic analysis. The major genetic determinants of type 1 diabetes are alleles at the HLA-DRB1 and DQB1 loci, with both susceptible and protective DR-DQ haplotypes present in all human populations. The aim of this study is to estimate the risk conferred by specific DR-DQ haplotypes and genotypes.RESEARCH DESIGN AND METHODS:-Six hundred and seven Caucasian families and 38 Asian families were typed at high resolution for the DRB1, DQA1, and DQB1 loci. The association analysis was performed by comparing the frequency of DR-DQ haplotypes among the chromosomes transmitted to an affected child with the frequency of chromosomes not transmitted to any affected child.RESULTS-A number of susceptible, neutral, and protective DR-DQ haplotypes have been identified, and a statistically significant hierarchy of type 1 diabetes risk has been established. The most susceptible haplotypes are the DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [OR] 3.64) and the DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB*0302, and DRB1*0402-DQA1*0301-DQB1*0302 haplotypes (ORs 11.37, 8.39, and 3.63), followed by the DRB1*0404-DQA1*0301-DQB1*0302 (OR 1.59) and the DRB1*0801-DQB1*0401-DQB1*0402 (OR 1.25) haplotypes. The most protective haplotypes are DRB1*1501-DQA1*0102-DQB1*0602 (OR 0.03), DRB1*1401-DQA1*0101-DQB1*0503 (OR 0.02), and DRB1*0701-DQA1*0201-DQB1*0303 (OR 0.02).CONCLUSIONS-Specific combinations of alleles at the DRB1, DQA1, and DQB1 loci determine the extent of haplotypic risk. The comparison of closely related DR-DQ haplotype pairs with different type I diabetes risks allowed identification of specific amino acid positions critical in determining disease susceptibility. These data also indicate that the risk associated with specific HLA haplotypes can be influenced by the genotype context and that the trans-complementing heterodimer encoded by DQA1*0501 and DQB1*0302 confers very high risk.