Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects.
| Autor: | Nikolaos A Patsopoulos, Lisa F Barcellos, Rogier Q Hintzen, Catherine Schaefer, Cornelia M van Duijn, Janelle A Noble, Towfique Raj, IMSGC, ANZgene, Pierre-Antoine Gourraud, Barbara E Stranger, Jorge Oksenberg, Tomas Olsson, Bruce V Taylor, Stephen Sawcer, David A Hafler, Mary Carrington, Philip L De Jager, Paul I W de Bakker |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | PLoS Genetics, Vol 9, Iss 11, p e1003926 (2013) |
| Druh dokumentu: | article |
| ISSN: | 1553-7390 1553-7404 |
| DOI: | 10.1371/journal.pgen.1003926 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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