HLA class II gene associations in African American type 1 diabetes reveal a protective HLA-DRB1*03 haplotype.
HLA class II gene associations in African American type 1 diabetes reveal a protective HLA-DRB1*03 haplotype.
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非裔美国人1型糖尿病中的HLA II类基因关联揭示了保护性HLA-DRB1*03单倍型。
DOI：
10.1111/dme.12148
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Todd JA
中科院分区：
文献类型：
--
作者：
Howson JM;Roy MS;Zeitels L;Stevens H;Todd JA
由于标记之间的强烈连锁不平衡，在欧洲祖先人群中很难确定遗传区域内的疾病关联，最值得注意的是HLA-DRB1*03-DQA1*05:01-DQB1*02:01单倍型与1型糖尿病风险的相关性非常强，这被认为是由于HLA-DRB1和HLA-DQB1的结合。相比之下，非洲血统的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。我们的目的是研究人类白细胞抗原（HLA）区域在非裔美国人1型糖尿病。采用logistic回归模型对227名非裔美国1型糖尿病患者和471名非裔美国对照者进行了HLA II类基因、HLA- drb1、HLA- dqa1、HLA- dqb1和5147个主要组织相容性复合体区域单核苷酸多态性的相关性检测。用主成分分析法对种群混杂进行了分析。单核苷酸多态性标记与HLA相关，并以ⅱ类位点为主。HLA与1型糖尿病的相关性总体上非常强，正如预期的那样，即使在糖尿病诊断存在异质性的非裔美国人中也是如此。此外，还有独特的特点：HLA-DRB1*03单倍型分裂为HLA-DRB1*03:01和HLA-DRB1*03:02，这两个等位基因在这些样本中具有最大的易感性（优势比3.17,95% CI 1.72-5.83）和HLA-DRB1*03:02，这两个等位基因在欧洲人中很少观察到，在这些非裔美国人样本中具有最大的保护作用（优势比0.22,95% CI 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单倍型相关的1型糖尿病风险中的特定和主要作用。
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-DRB1*03-DQA1*05:01-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-DRB1*03 haplotype was split into HLA-DRB1*03:01, 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.
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影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
7.7
作者：
Howson, Joanna M. M.;Stevens, Helen;Todd, John A.
通讯作者：
Todd, John A.
DOI：
10.1111/j.1463-1326.2008.01001.x
发表时间：
2009-02
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Howson JM;Walker NM;Clayton D;Todd JA;Type 1 Diabetes Genetics Consortium
通讯作者：
Type 1 Diabetes Genetics Consortium
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
--
作者：
Noble JA;Johnson J;Lane JA;Valdes AM
通讯作者：
Valdes AM