JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, NIHR Biomedical Research Centre, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Diabet Med. 2013 Jun;30(6):710-6. doi: 10.1111/dme.12148. Epub 2013 Mar 21.
Owing to strong linkage disequilibrium between markers, pinpointing disease associations within genetic regions is difficult in European ancestral populations, most notably the very strong association of the HLA-DRB103-DQA105:01-DQB1*02:01 haplotype with Type 1 diabetes risk, which is assumed to be because of a combination of HLA-DRB1 and HLA-DQB1. In contrast, populations of African ancestry have greater haplotype diversity, offering the possibility of narrowing down regions and strengthening support for a particular gene in a region being causal. We aimed to study the human leukocyte antigen (HLA) region in African American Type 1 diabetes.
Two hundred and twenty-seven African American patients with Type 1 diabetes and 471 African American control subjects were tested for association at the HLA class II genes, HLA-DRB1, HLA-DQA1, HLA-DQB1 and 5147 single nucleotide polymorphisms across the major histocompatibility complex region using logistic regression models. Population admixture was accounted for with principal components analysis.
Single nucleotide polymorphism marker associations were explained by the HLA associations, with the major peak over the class II loci. The HLA association overall was extremely strong, as expected for Type 1 diabetes, even in African Americans in whom diabetes diagnosis is heterogeneous. In addition, there were unique features: the HLA-DRB103 haplotype was split into HLA-DRB103:01, which confers greatest susceptibility in these samples (odds ratio 3.17, 95% CI 1.72-5.83) and HLA-DRB1*03:02, an allele rarely observed in Europeans, which confers the greatest protection in these African American samples (odds ratio 0.22, 95% CI 0.09-0.55).
The unique diversity of the African HLA region we have uncovered supports a specific and major role for HLA-DRB1 in HLA-DRB1*03 haplotype-associated Type 1 diabetes risk.
由于标记之间存在强连锁不平衡，因此在欧洲祖先人群中很难确定遗传区域内的疾病关联，最显著的是 HLA-DRB103-DQA105:01-DQB1*02:01 单倍型与 1 型糖尿病风险的强关联，这被认为是由于 HLA-DRB1 和 HLA-DQB1 的组合。相比之下，非洲祖先人群具有更大的单倍型多样性，这提供了缩小区域范围的可能性，并加强了对区域内特定基因因果关系的支持。我们旨在研究非洲裔美国人 1 型糖尿病中的人类白细胞抗原 (HLA) 区域。
对 227 名非洲裔美国 1 型糖尿病患者和 471 名非洲裔美国对照进行 HLA 类 II 基因、HLA-DRB1、HLA-DQA1、HLA-DQB1 和主要组织相容性复合体区域内的 5147 个单核苷酸多态性的关联测试，采用逻辑回归模型。通过主成分分析考虑群体混合。
单核苷酸多态性标记的关联由 HLA 关联解释，主要峰在 II 类基因座上。HLA 关联总体上非常强，与预期的 1 型糖尿病一致，即使在非洲裔美国人中，糖尿病的诊断也存在异质性。此外，还有一些独特的特征：HLA-DRB103 单倍型分为 HLA-DRB103:01，在这些样本中赋予最大的易感性（比值比 3.17，95%置信区间 1.72-5.83）和 HLA-DRB1*03:02，一种在欧洲人中很少观察到的等位基因，在这些非洲裔美国人样本中赋予最大的保护（比值比 0.22，95%置信区间 0.09-0.55）。
我们发现的非洲 HLA 区域的独特多样性支持 HLA-DRB1 在 HLA-DRB1*03 单倍型相关 1 型糖尿病风险中的特定和主要作用。
