A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01.
A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01.
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DOI：
10.1371/journal.pone.0011296
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发表时间：
2010-06-25
期刊：
影响因子：
3.7
通讯作者：
IMSGC
中科院分区：
文献类型：
--
作者：
Cree BA;Rioux JD;McCauley JL;Gourraud PA;Goyette P;McElroy J;De Jager P;Santaniello A;Vyse TJ;Gregersen PK;Mirel D;Hafler DA;Haines JL;Pericak-Vance MA;Compston A;Sawcer SJ;Oksenberg JR;Hauser SL;IMAGEN;IMSGC
在北方欧洲后裔人群中，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DRB 1的等位基因相关。是否其他主要组织相容性复合体（MHC）基因有助于MS的易感性是有争议的。病例对照分析使用958个单核苷酸多态性（SNPs）跨越两个独立的数据集测定的MHC。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。发现数据集中最显著的MS相关SNP是rs3135391，这是一种已知标记HLA-DRB 1 *15：01等位基因的II类SNP，HLA-DRB 1 *15：01等位基因是MHC中的主要MS易感性等位基因（O.R.= 3.04，p<1×10−78）。 为了控制HLA-DRB 1 *15：01单倍型的影响，进行病例对照分析，调整该HLA-DRB 1 *15：01标记SNP。校正多重比较后（错误发现率= 0.05），使用Cochran Armitage趋势检验，在两个数据集中，I类、II类和III类区域的52个SNP与MS易感性显著相关。 合并发现和复制数据集，排除携带HLA-DRB 1 *15：01标签SNP的受试者。关联检验显示，52个重复的SNP中有48个保留了与MS易感性的显著关联，独立于由标签SNP定义的HLA-DRB 1 *15：01。20个I类SNP与MS易感性相关，p值≤1×10−8。最显着相关的SNP是rs 4959039，这是非经典HLA-G基因下游非翻译区的SNP（比值比1.59，95%CI 1.40，1.81，p = 8.45×10 - 13），并且与几个邻近的SNP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该筛选中鉴定的II类和III类SNP。MHC I类基因座独立于HLA-DRB 1 *15：01单倍型而对MS易感性有贡献。
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. 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-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p<1×10−78). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 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-DRB1*15:01 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 ≤1×10−8. 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 = 8.45×10−13) 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.
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影响因子：
30.8
作者：
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通讯作者：
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