Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
PLoS One. 2010 Jun 25;5(6):e11296. doi: 10.1371/journal.pone.0011296.
In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.
METHODOLOGY/PRINCIPAL FINDINGS: A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB115:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p < 1 x 10(-78)). To control for the effects of the HLA-DRB115:01 haplotype, case control analysis was performed adjusting for this HLA-DRB115:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB115:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values < or = 1 x 10(-8). The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45 x 10(-13)) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.
A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.
在北欧血统人群中，多个多发性硬化症（MS）的遗传易感性与人类白细胞抗原（HLA）II 类基因 DRB1 的等位基因有关。其他主要组织相容性复合体（MHC）基因是否有助于 MS 易感性存在争议。
方法/主要发现：使用两个独立数据集检测的 MHC 跨度内的 958 个单核苷酸多态性（SNP）进行病例对照分析。发现数据集由 1,018 例病例和 1,795 例对照组成，复制数据集由 1,343 例病例和 1,379 例对照组成。发现数据集中与 MS 关联最显著的 SNP 是 rs3135391，这是一个 II 类 SNP，已知标记 HLA-DRB115:01 等位基因，即 MHC 中的主要 MS 易感性等位基因（OR = 3.04，p < 1 x 10(-78))。为了控制 HLA-DRB115:01 单倍型的影响，对该 HLA-DRB115:01 标记 SNP 进行病例对照分析。经过多次比较校正（假发现率=0.05），两个数据集均采用 Cochran-Armitage 趋势检验，在 I、II 和 III 区的 52 个 SNP 与 MS 易感性显著相关。发现和复制数据集合并，排除携带 HLA-DRB115:01 标记 SNP 的受试者。关联测试显示，52 个经复制的 SNP 中有 48 个与 MS 易感性独立相关，与 HLA-DRB1*15:01 无关，该 SNP 由标记 SNP 定义。20 个 I 类 SNP 与 MS 易感性相关，p 值<或=1 x 10(-8)。最显著相关的 SNP 是 rs4959039，这是一个非经典 HLA-G 基因下游非翻译区的 SNP（优势比 1.59，95%CI 1.40，1.81，p=8.45 x 10(-13))，与附近的几个 SNP 呈连锁不平衡。逻辑回归模型显示，该 SNP 对 MS 易感性的贡献独立于本研究中筛选出的 II 类和 III 类 SNP。
MHC I 类基因座独立于 HLA-DRB1*15:01 单倍型，与 MS 易感性相关。
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