A Polymorphism in the HLA-DPB1 Gene Is Associated with Susceptibility to Multiple Sclerosis

被引：45

作者：

Field, Judith ^{[1
,2
]}

Browning, Sharon R. ^{[3
]}

Johnson, Laura J. ^{[1
,2
]}

Danoy, Patrick ^{[4
]}

Varney, Michael D. ^{[5
]}

Tait, Brian D. ^{[5
]}

Gandhi, Kaushal S. ^{[6
]}

Charlesworth, Jac C. ^{[7
]}

Heard, Robert N. ^{[6
]}

Stewart, Graeme J. ^{[6
]}

Kilpatrick, Trevor J. ^{[1
,2
,8
]}

Foote, Simon J. ^{[9
]}

Bahlo, Melanie ^{[10
]}

Butzkueven, Helmut ^{[1
,11
,12
]}

Wiley, James ^{[1
]}

Booth, David R. ^{[6
]}

Taylor, Bruce V. ^{[9
]}

Brown, Matthew A. ^{[4
,13
]}

Rubio, Justin P. ^{[1
,14
]}

Stankovich, Jim ^{[9
]}

机构：

[1] Univ Melbourne, Florey Neurosci Inst, Melbourne, Vic, Australia

[2] Univ Melbourne, Ctr Neurosci, Melbourne, Vic, Australia

[3] Univ Auckland, Dept Stat, Auckland 1, New Zealand

[4] Univ Queensland, Princess Alexandra Hosp, Univ Queensland Diamantina Inst, Brisbane, Qld, Australia

[5] Australian Red Cross Blood Serv, Melbourne, Vic, Australia

[6] Univ Sydney, Westmead Millenium Inst, Sydney, NSW 2006, Australia

[7] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA

[8] Royal Melbourne Hosp, Melbourne, Vic, Australia

[9] Univ Tasmania, Menzies Res Inst, Hobart, Tas, Australia

[10] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia

[11] Univ Melbourne, Dept Med, Melbourne, Vic, Australia

[12] Box Hill Hosp, Dept Neurol, Box Hill, Vic, Australia

[13] Univ Oxford, Botnar Res Ctr, Nuffield Dept Orthopaed Surg, Oxford, England

[14] GlaxoSmithKline, Harlow, Essex, England

来源：

PLOS ONE | 2010年 / 5卷 / 10期

基金：

澳大利亚研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

CLASS-I REGION; CLINICAL-COURSE; RISK; MHC; HLA-DRB1; ALLELES; LOCI; COMPLEX; HETEROGENEITY; REPLICATION;

D O I：

10.1371/journal.pone.0013454

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：

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P <= 4 x 10(-6)). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P <= 0.001) and were highly significant in the combined dataset (P <= 6 x 10(-8)). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9), replication set P = 7 x 10(-4), combined P = 2 x 10(-10)). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genomewide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

引用

页数：7

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