Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases
Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases
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DOI：
10.1073/pnas.0909307106
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发表时间：
2009-11-03
影响因子：
11.1
通讯作者：
Hauser, Stephen L.
中科院分区：
文献类型：
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作者：
Rioux, John D.;Goyette, Philippe;Hauser, Stephen L.
人MHC代表自身免疫性疾病的最强易感性位点。然而，鉴定真正的易感基因（S）已被整个地区的强烈连锁不平衡所阻碍。此外，迄今为止，大多数研究仅限于检查HLA和非HLA基因的子集，标记物密度和样本量不足以映射所有独立的关联信号。我们对一组1,472个SNPs进行基因分型，以捕获来自系统性红斑狼疮、克罗恩病、溃疡性结肠炎、类风湿性关节炎、重症肌无力、选择性伊加缺乏症、多发性硬化症患者和适当对照样本的10,576个DNA样本中3.44 Mb经典MHC区域的常见基因组变异。我们确定了每种疾病的主要相关信号，并进行了条件回归以确定独立的次要信号。这些数据表明，MHC与自身免疫性疾病的关联是由于跨越整个区域的复杂的多位点效应。
The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a subset of the HLA and non-HLA genes with a marker density and sample size insufficient for mapping all independent association signals. We genotyped a panel of 1,472 SNPs to capture the common genomic variation across the 3.44 megabase (Mb) classic MHC region in 10,576 DNA samples derived from patients with systemic lupus erythematosus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, myasthenia gravis, selective IgA deficiency, multiple sclerosis, and appropriate control samples. We identified the primary association signals for each disease and performed conditional regression to identify independent secondary signals. The data demonstrate that MHC associations with autoimmune diseases result from complex, multilocus effects that span the entire region.