Rubio Justin P, Bahlo Melanie, Butzkueven Helmut, van Der Mei Ingrid A F, Sale Michèle M, Dickinson Joanne L, Groom Patricia, Johnson Laura J, Simmons Rex D, Tait Brian, Varney Mike, Taylor Bruce, Dwyer Terence, Williamson Robert, Gough Nicholas M, Kilpatrick Trevor J, Speed Terence P, Foote Simon J
Walter and Eliza Hall Institute of Medical Research, and Cooperative Research Centre for Discovery of Genes for Common Human Diseases, Melbourne, Victoria, Australia.
Am J Hum Genet. 2002 May;70(5):1125-37. doi: 10.1086/339932. Epub 2002 Mar 29.
Association of multiple sclerosis (MS) with the human leukocyte antigen (HLA) class II haplotype DRB11501-DQB10602 is the most consistently replicated finding of genetic studies of the disease. However, the high level of linkage disequilibrium (LD) in the HLA region has hindered the identification of other loci that single-marker tests for association are unlikely to resolve. In order to address this issue, we generated haplotypes spanning 14.754 Mb (5 cM) across the entire HLA region. The haplotypes, which were inferred by genotyping relatives of 152 patients with MS and 105 unaffected control subjects of Tasmanian ancestry, define a genomic segment from D6S276 to D6S291, including 13 microsatellite markers integrated with allele-typing data for DRB1 and DQB1. Association to the DRB11501-DQB10602 haplotype was replicated. In addition, we found that the class I/extended class I region, defined by a genomic segment of approximately 400 kb between MOGCA and D6S265, harbors genes that independently increase risk of, or provide protection from, MS. Log-linear modeling analysis of constituent haplotypes that represent genomic regions containing class I (MOGCA-D6S265), class III (TNFa-TNFd-D6S273), and class II (DRB1-DQB1) genes indicated that having class I and class II susceptibility variants on the same haplotype provides an additive effect on risk. Moreover, we found no evidence for a disease locus in the class III region defined by a 150-kb genomic segment containing the TNF locus and 14 other genes. A global overview of LD performed using GOLD identified two discrete blocks of LD in the HLA region that correspond well with previous findings. We propose that the analysis of haplotypes, by use of the types of approaches outlined in the present article, should make it possible to more accurately define the contribution of the HLA to MS.
多发性硬化症（MS）与人类白细胞抗原（HLA）II类单倍型DRB11501 - DQB10602的关联是该疾病基因研究中最一致的重复发现。然而，HLA区域的高度连锁不平衡（LD）阻碍了其他位点的识别，单标记关联测试不太可能解决这些位点。为了解决这个问题，我们生成了跨越整个HLA区域14.754 Mb（5 cM）的单倍型。这些单倍型是通过对152例MS患者和105名塔斯马尼亚血统的未受影响对照受试者的亲属进行基因分型推断出来的，定义了一个从D6S276到D6S291的基因组片段，包括13个微卫星标记以及DRB1和DQB1的等位基因分型数据。与DRB11501 - DQB10602单倍型的关联得到了重复验证。此外，我们发现由MOGCA和D6S265之间大约400 kb的基因组片段定义的I类/扩展I类区域包含独立增加MS风险或提供保护的基因。对代表包含I类（MOGCA - D6S265）、III类（TNFa - TNFd - D6S273）和II类（DRB1 - DQB1）基因的基因组区域的组成单倍型进行对数线性建模分析表明，在同一单倍型上具有I类和II类易感变异对风险具有累加效应。此外，我们在由包含TNF基因座和其他14个基因的150 kb基因组片段定义的III类区域中未发现疾病位点的证据。使用GOLD进行的LD全局概述在HLA区域识别出两个离散的LD块，与先前的发现非常吻合。我们建议，通过使用本文所述的方法对单倍型进行分析，应该能够更准确地定义HLA对MS的贡献。
