Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases.
International MHC and Autoimmunity Genetics Network None., Rioux JD., Goyette P., Vyse TJ., Hammarström L., Fernando MM., Green T., De Jager PL., Foisy S., Wang J., de Bakker PI., Leslie S., McVean G., Padyukov L., Alfredsson L., Annese V., Hafler DA., Pan-Hammarström Q., Matell R., Sawcer SJ., Compston AD., Cree BA., Mirel DB., Daly MJ., Behrens TW., Klareskog L., Gregersen PK., Oksenberg JR., Hauser SL.
The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a subset of the HLA and non-HLA genes with a marker density and sample size insufficient for mapping all independent association signals. We genotyped a panel of 1,472 SNPs to capture the common genomic variation across the 3.44 megabase (Mb) classic MHC region in 10,576 DNA samples derived from patients with systemic lupus erythematosus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, myasthenia gravis, selective IgA deficiency, multiple sclerosis, and appropriate control samples. We identified the primary association signals for each disease and performed conditional regression to identify independent secondary signals. The data demonstrate that MHC associations with autoimmune diseases result from complex, multilocus effects that span the entire region.