一项全基因组研究确定的多发性硬化症风险等位基因。

Risk alleles for multiple sclerosis identified by a genomewide study.

作者信息

Hafler David A, Compston Alastair, Sawcer Stephen, Lander Eric S, Daly Mark J, De Jager Philip L, de Bakker Paul I W, Gabriel Stacey B, Mirel Daniel B, Ivinson Adrian J, Pericak-Vance Margaret A, Gregory Simon G, Rioux John D, McCauley Jacob L, Haines Jonathan L, Barcellos Lisa F, Cree Bruce, Oksenberg Jorge R, Hauser Stephen L

机构信息

Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, USA.

出版信息

N Engl J Med. 2007 Aug 30;357(9):851-62. doi: 10.1056/NEJMoa073493. Epub 2007 Jul 29.

DOI:10.1056/NEJMoa073493

PMID:17660530

Abstract

BACKGROUND

Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis.

METHODS

We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis.

RESULTS

A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)).

CONCLUSIONS

Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.

摘要

背景

多发性硬化症具有临床上显著的遗传成分。我们开展了一项全基因组关联研究，以鉴定与多发性硬化症风险相关的等位基因。

方法

我们使用DNA微阵列技术在931个三联体家庭（由一名患病儿童及其双亲组成）中鉴定常见的DNA序列变异，并对其进行关联测试。为进行重复验证，我们对另外609个三联体家庭、2322例病例受试者和789例对照受试者进行基因分型，并使用来自两个外部对照数据集的基因分型数据。对12360名受试者的数据进行联合分析，以估计等位基因与多发性硬化症风险之间关联的总体显著性和效应大小。

结果

对931个三联体家庭中的334923个单核苷酸多态性（SNP）进行传递不平衡检验，发现49个SNP与多发性硬化症相关（P<1×10⁻⁴）；这些SNP中，38个被选用于第二阶段分析。对来自三联体家庭的931例病例受试者与2431例对照受试者进行比较，又发现了32个不重叠的SNP（P<0.001）。另外还选择了40个P值较宽松（<0.01）的SNP，第二阶段分析共110个SNP。这些SNP中，白细胞介素-2受体α基因（IL2RA）内的两个SNP与多发性硬化症密切相关（P=2.96×10⁻⁸），白细胞介素-7受体α基因（IL7RA）中的一个非同义SNP（P=2.94×10⁻⁷）以及HLA-DRA基因座中的多个SNP（P=8.94×10⁻⁸¹）也与多发性硬化症密切相关。