Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
Barcellos, Lisa F.
Hintzen, Rogier Q.
van Duijn, Cornelia M.
Noble, Janelle A.
Stranger, Barbara E.
Taylor, Bruce V.
de Bakker, Paul I. W.Note: Order does not necessarily reflect citation order of authors.
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CitationPatsopoulos, N. A., L. F. Barcellos, R. Q. Hintzen, C. Schaefer, C. M. van Duijn, J. A. Noble, T. Raj, et al. 2013. “Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects.” PLoS Genetics 9 (11): e1003926. doi:10.1371/journal.pgen.1003926. http://dx.doi.org/10.1371/journal.pgen.1003926.
AbstractThe 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11879129
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