TY - JOUR
T1 - A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis
AU - Field, Judith
AU - Browning, Sharon R.
AU - Johnson, Laura J.
AU - Danoy, Patrick
AU - Varney, Michael D.
AU - Tait, Brian D.
AU - Gandhi, Kaushal S.
AU - Charlesworth, Jac C.
AU - Heard, Robert N.
AU - Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene)
AU - Stewart, Graeme J.
AU - Kilpatrick, Trevor J.
AU - Foote, Simon J.
AU - Bahlo, Melanie
AU - Butzkueven, Helmut
AU - Wiley, James
AU - Booth, David R.
AU - Taylor, Bruce V.
AU - Brown, Matthew A.
AU - Rubio, Justin P.
AU - Stankovich, Jim
AU - Broadley, Simon A.
AU - Browning, Brian L.
AU - Carroll, William M.
AU - Griffiths, Lyn R.
AU - Kermode, Allan G.
AU - Lechner-Scott, Jeanette
AU - Moscato, Pablo
AU - Perreau, Victoria M.
AU - Scott, Rodney J.
AU - Slee, Mark
N1 - This is an open-access article distributed under the terms of the Creative Commons Attribution License
PY - 2010/10/26
Y1 - 2010/10/26
N2 - 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≤4×10-6). 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 × 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 × 10-9, replication set P = 7 × 10-4, combined P=2 × 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 genome-wide 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.
AB - 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≤4×10-6). 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 × 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 × 10-9, replication set P = 7 × 10-4, combined P=2 × 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 genome-wide 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.
UR - http://www.scopus.com/inward/record.url?scp=78149463010&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0013454
DO - 10.1371/journal.pone.0013454
M3 - Article
C2 - 21049023
AN - SCOPUS:78149463010
SN - 1932-6203
VL - 5
JO - PLoS One
JF - PLoS One
IS - 10
M1 - e13454
ER -