T.W.Y. and P.L.D. contributed equally to this work.
A second major histocompatibility complex susceptibility locus for multiple sclerosis
Article first published online: 24 JAN 2007
Copyright © 2007 American Neurological Association
Annals of Neurology
Volume 61, Issue 3, pages 228–236, March 2007
How to Cite
Yeo, T. W., De Jager, P. L., Gregory, S. G., Barcellos, L. F., Walton, A., Goris, A., Fenoglio, C., Ban, M., Taylor, C. J., Goodman, R. S., Walsh, E., Wolfish, C. S., Horton, R., Traherne, J., Beck, S., Trowsdale, J., Caillier, S. J., Ivinson, A. J., Green, T., Pobywajlo, S., Lander, E. S., Pericak-Vance, M. A., Haines, J. L., Daly, M. J., Oksenberg, J. R., Hauser, S. L., Compston, A., Hafler, D. A., Rioux, J. D. and Sawcer, S. (2007), A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol., 61: 228–236. doi: 10.1002/ana.21063
- Issue published online: 23 MAR 2007
- Article first published online: 24 JAN 2007
- Manuscript Accepted: 20 NOV 2006
- Manuscript Revised: 13 NOV 2006
- Manuscript Received: 14 SEP 2006
- Wellcome Trust Prize Studentship
- St. Edmund's College
- Cambridge Commonwealth Trust and Cambridge Philosophical Society
- William C. Fowler scholarship in Multiple Sclerosis
- National Institutes of Health. Grant Numbers: K08 NS46341, NS049477, NS026799, NS032830
- GlaxoSmithKline Clinical Fellowship
- Postdoctoral Fellowship of the Research Foundation–Flanders (FWO–Vlaanderen)
- European Neurological Society fellowship
- Cancer Research Institute fellowship
- Medical Research Council (United Kingdom). Grant Number: G0000648
- Wellcome Trust. Grant Numbers: 048880, 057097
- National Multiple Sclerosis Society Center Grant. Grant Number: AP 3758-A-16
- The Penates Foundation
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.
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.
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).
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