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A second major histocompatibility complex susceptibility locus for multiple sclerosis
Author(s) -
Yeo Tai Wai,
De Jager Philip L.,
Gregory Simon G.,
Barcellos Lisa F.,
Walton Amie,
Goris An,
Fenoglio Chiara,
Ban Maria,
Taylor Craig J.,
Goodman Reyna S.,
Walsh Emily,
Wolfish Cara S.,
Horton Roger,
Traherne James,
Beck Stephan,
Trowsdale John,
Caillier Stacy J.,
Ivinson Adrian J.,
Green Todd,
Pobywajlo Susan,
Lander Eric S.,
PericakVance Margaret A.,
Haines Jonathan L.,
Daly Mark J.,
Oksenberg Jorge R.,
Hauser Stephen L.,
Compston Alastair,
Hafler David A.,
Rioux John D.,
Sawcer Stephen
Publication year - 2007
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21063
Subject(s) - genetics , human leukocyte antigen , linkage disequilibrium , locus (genetics) , major histocompatibility complex , allele , biology , genotyping , multiple sclerosis , haplotype , gene , single nucleotide polymorphism , microsatellite , immunology , genotype , antigen
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 ‐ DRB1 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 DRB1 * 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 × 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. Ann Neurol 2007