A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB115:01

• Published in: PloS one 2010-06, Vol.5 (6), p.e11296-e11296
• Main Authors: Cree, Bruce A C, Rioux, John D, McCauley, Jacob L, Gourraud, Pierre-Antoine F D, Goyette, Philippe, McElroy, Joseph, De Jager, Philip, Santaniello, Adam, Vyse, Timothy J, Gregersen, Peter K, Mirel, Daniel, Hafler, David A, Haines, Jonathan L, Pericak-Vance, Margaret A, Compston, Alastair, Sawcer, Stephen J, Oksenberg, Jorge R, Hauser, Stephen L
• Format: Article
• Language: English
• Subjects: Alleles; Analysis; Antigens; Biophysics; Cancer; Case-Control Studies; Chromosomes; Datasets; Disease susceptibility; Drb1 protein; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genetics and Genomics/Complex Traits; Genetics and Genomics/Genetics of the Immune System; Genomes; Genomics; Haplotypes; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - genetics; HLA antigens; HLA-DR Antigens - genetics; HLA-DRB1 Chains; Humans; Immunology/Genetics of the Immune System; Leukocytes; Linkage Disequilibrium; Loci; Logistic Models; Major histocompatibility complex; Marking; Medicin och hälsovetenskap; Meta-analysis; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; Nervous system; Neurological Disorders/Multiple Sclerosis and Related Disorders; Neurology; Neurosciences; Physiology; Polymorphism, Single Nucleotide; Population genetics; Recruitment; Regression analysis; Replication; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Standard deviation; Studies; Trends
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0011296

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. 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. A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.