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Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

Gibson, G., Patsopoulos, Nikolaos A., Barcellos, Lisa F., Hintzen, Rogier Q., Schaefer, Catherine, van Duijn, Cornelia M., Noble, Janelle A., Raj, Towfique, Gourraud, Pierre-Antoine, Stranger, Barbara E., Oksenberg, Jorge, Olsson, Tomas, Taylor, Bruce V., Sawcer, Stephen, Hafler, David A., Carrington, Mary, De Jager, Philip L., de Bakker, Paul I. W. and Kermode, A.G. (2013) Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects. PLoS Genetics, 9 (11). e1003926.

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Abstract

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

Item Type: Journal Article
Publisher: Public Library of Science
Copyright: 2013 The Authors
URI: http://researchrepository.murdoch.edu.au/id/eprint/28313
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