A Major Histocompatibility Class I Locus Contributes to Multiple Sclerosis Susceptibility Independently from HLA-DRB1*15:01

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A Major Histocompatibility Class I Locus Contributes to Multiple Sclerosis Susceptibility Independently from HLA-DRB1*15:01

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dc.contributor.author Cree, Bruce A. C.
dc.contributor.author Rioux, John D.
dc.contributor.author McCauley, Jacob L.
dc.contributor.author Gourraud, Pierre-Antoine F. D.
dc.contributor.author Goyette, Philippe
dc.contributor.author Santaniello, Adam
dc.contributor.author Vyse, Timothy J.
dc.contributor.author Gregersen, Peter K.
dc.contributor.author Mirel, Daniel
dc.contributor.author Haines, Jonathan L.
dc.contributor.author Pericak-Vance, Margaret A.
dc.contributor.author Compston, Alastair
dc.contributor.author Sawcer, Stephen J.
dc.contributor.author Oksenberg, Jorge R.
dc.contributor.author Hauser, Stephen L.
dc.contributor.author Kleinschnitz, Christoph
dc.contributor.author McElroy, Joseph
dc.contributor.author De Jager, Philip Lawrence
dc.contributor.author Hafler, David A.
dc.date.accessioned 2010-12-08T19:59:08Z
dc.date.issued 2010
dc.identifier.citation Cree, Bruce A. C., John D. Rioux, Jacob L. McCauley, Pierre-Antoine F. D. Gourraud, Philippe Goyette, Joseph McElroy, Philip De Jager, et al. 2010. A major histocompatibility class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01. PLoS ONE 5(6): e11296 en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4621125
dc.description.abstract Background: In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial. Methodology/Principal Findings: A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p<1×10−78). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values ≤1×10−8. The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45×10−13) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen. Conclusions: A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi://10.1371/journal.pone.0011296 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892470/pdf/ en_US
dash.license LAA
dc.subject neurological disorders en_US
dc.subject multiple sclerosis and related disorders en_US
dc.subject immunology en_US
dc.subject genetics of the immune system en_US
dc.subject genetics and genomics en_US
dc.subject complex traits en_US
dc.title A Major Histocompatibility Class I Locus Contributes to Multiple Sclerosis Susceptibility Independently from HLA-DRB1*15:01 en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author De Jager, Philip Lawrence
dc.date.available 2010-12-08T19:59:08Z
dash.affiliation.other HMS^Neurology-Brigham and Women's Hospital en_US

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