Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, CA 94720-7356, USA.
Hum Mol Genet. 2010 Nov 1;19(21):4286-95. doi: 10.1093/hmg/ddq328. Epub 2010 Aug 10.
The primary genetic risk factor in multiple sclerosis (MS) is the HLA-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has yet to be elucidated. Several lines of evidence support a role for neuroendocrine system involvement in autoimmunity which may, in part, be genetically determined. Here, we comprehensively investigated variation within eight candidate hypothalamic-pituitary-adrenal (HPA) axis genes and susceptibility to MS. A total of 326 SNPs were investigated in a discovery dataset of 1343 MS cases and 1379 healthy controls of European ancestry using a multi-analytical strategy. Random Forests, a supervised machine-learning algorithm, identified eight intronic SNPs within the corticotrophin-releasing hormone receptor 1 or CRHR1 locus on 17q21.31 as important predictors of MS. On the basis of univariate analyses, six CRHR1 variants were associated with decreased risk for disease following a conservative correction for multiple tests. Independent replication was observed for CRHR1 in a large meta-analysis comprising 2624 MS cases and 7220 healthy controls of European ancestry. Results from a combined meta-analysis of all 3967 MS cases and 8599 controls provide strong evidence for the involvement of CRHR1 in MS. The strongest association was observed for rs242936 (OR = 0.82, 95% CI = 0.74-0.90, P = 9.7 × 10(-5)). Replicated CRHR1 variants appear to exist on a single associated haplotype. Further investigation of mechanisms involved in HPA axis regulation and response to stress in MS pathogenesis is warranted.
多发性硬化症（MS）的主要遗传风险因素是 HLA-DRB1*1501 等位基因；然而，MS 遗传贡献的大部分仍有待阐明。有几条证据支持神经内分泌系统参与自身免疫的作用，其中部分可能是由遗传决定的。在这里，我们全面研究了八个候选下丘脑-垂体-肾上腺（HPA）轴基因内的变异与 MS 的易感性。在一项包含欧洲血统的 1343 例 MS 病例和 1379 例健康对照的发现数据集，使用多分析策略，研究了 326 个 SNP。随机森林是一种监督机器学习算法，确定了 17q21.31 上的促肾上腺皮质激素释放激素受体 1 或 CRHR1 基因座内的 8 个内含子 SNP 是 MS 的重要预测因子。基于单变量分析，在对多个测试进行保守校正后，CRHR1 的六个变体与疾病风险降低相关。在一项包含欧洲血统的 2624 例 MS 病例和 7220 例健康对照的大型荟萃分析中观察到 CRHR1 的独立复制。对所有 3967 例 MS 病例和 8599 例对照进行的联合荟萃分析结果为 CRHR1 参与 MS 提供了强有力的证据。观察到最强的关联是 rs242936（OR = 0.82，95%CI = 0.74-0.90，P = 9.7 × 10(-5)）。复制的 CRHR1 变体似乎存在于单个相关单倍型上。进一步研究 HPA 轴调节和对 MS 发病机制中应激反应的机制是值得的。
