A Major Histocompatibility Class I Locus Contributes to Multiple Sclerosis Susceptibility Independently from HLA-DRB1*15:01
Year: 2010
Type: article
Study design: Observational Study
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 x 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 < or = 1 x 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 x 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.
Source: PLoS ONE
Authors: Bruce A. C. Cree, John D. Rioux, Jacob L. McCauley, Pierre-Antoine F. D. Gourraud, Philippe Goyette, Joseph McElroy, Philip De Jager, Adam Santaniello, Timothy J. Vyse, Peter K. Gregersen, Daniel Mirel, David A. Hafler, Jonathan L. Haines, Margaret A. Pericak-Vance, Alastair Compston, Stephen J. Sawcer, Jorge R. Oksenberg, Stephen L. Hauser, IMAGEN, IMSGC
Institutions: University of California, San Francisco, Montreal Heart Institute, Dr. John T. Macdonald Foundation, Brigham and Women's Hospital, Harvard University, Hammersmith Hospital, Imperial College London, Feinstein Institute for Medical Research, Broad Institute, Yale University, Vanderbilt University Medical Center, University of Cambridge
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: National Multiple Sclerosis Society, Brigham and Women's Hospital, Massachusetts General Hospital, Vanderbilt University, University of Miami, Massachusetts Institute of Technology, Harvard University, Wellcome Trust, Vanderbilt University Medical Center, Broad Institute, National Institute for Health and Care Research, Multiple Sclerosis Society, National Institutes of Health, University of California, San Francisco, Medical Research Council, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources
Awards: G1137313802, Correlating Multiple Sclerosis Phenotypes with Genotypes, G1567724564, Immunogenetic Studies in Multiple Sclerosis, G2747922546, G3349769430, Molecular Genetics of HLA and Disease, G5502349062, G5568298347, A national DNA control series for genetic case-control studies based on the British 1958 birth cohort, G600947484, An NCRR Center for High Throughput SNP Genotyping and Analysis, A Haplotype Map for Multiple Sclerosis, G8856880592, NIHR Senior Investigator Award
OpenAlex ID: W2132142991