Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility

被引：118

作者：

Lincoln, Matthew R. ^{[1
,2
]}

Ramagopalan, Sreeram V. ^{[1
,2
]}

Chao, Michael J. ^{[1
,2
]}

Herrera, Blanca M. ^{[1
,2
]}

DeLuca, Gabriele C. ^{[1
,2
]}

Orton, Sarah-Michelle ^{[1
,2
]}

Dyment, David A. ^{[1
,2
]}

Sadovnick, A. Dessa ^{[3
,4
]}

Ebers, George C. ^{[1
,2
]}

机构：

[1] Univ Oxford, John Radcliffe Hosp, Univ Dept Clin Neurol, Oxford OX3 9DU, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[3] Univ British Columbia, Div Neurol, Fac Med, Vancouver, BC V6T 2B5, Canada

[4] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 2B5, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 18期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

genetics; MHC; linkage disequilibrium; HLA CLASS-I; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; LINKAGE DISEQUILIBRIUM; GENETIC SUSCEPTIBILITY; MHC HAPLOTYPES; RISK; ALLELES; DISEASE; COMPLEX; REGION;

D O I：

10.1073/pnas.0812664106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1* 0602 haplotypes (hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1* 15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.

引用

页码：7542 / 7547

页数：6