A second major histocompatibility complex susceptibility locus for multiple sclerosis

Tai Wai Yeo, Philip L. De Jager, Simon G. Gregory, Lisa F. Barcellos, Amie Walton, An Goris, Chiara Fenoglio, Maria Ban, Craig J. Taylor, Reyna S. Goodman, Emily Walsh, Cara S. Wolfish, Roger Horton, James Traherne, Stephan Beck, John Trowsdale, Stacy J. Caillier, Adrian J. Ivinson, Todd Green, Susan PobywajloEric S. Lander, Margaret A. Pericak-Vance, Jonathan L. Haines, Mark J. Daly, Jorge R. Oksenberg, Stephen L. Hauser, Alastair Compston, David A. Hafler, John D. Rioux, Stephen Sawcer

Research output: Contribution to journalArticlepeer-review


Objective: Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRBl gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed. Methods: Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DKB1* 1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects. Results: Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 X 10 -5). Interpretation: Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.

Original languageEnglish
Pages (from-to)228-236
Number of pages9
JournalAnnals of Neurology
Issue number3
Publication statusPublished - Mar 2007

ASJC Scopus subject areas

  • Neuroscience(all)


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