Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases

Abstract

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.autoimmunity ͉ genes ͉ genetics

Multiple sclerosis genetics

“…Many of these genes are highly polymorphic, adding additional complexity to this locus. Multiple autoimmune diseases have risk alleles that map to this region, thereby underscoring its importance in the regulation of immune function (Rioux et al, 2009).…”

Heterogeneity in juvenile idiopathic arthritis: Impact of molecular profiling based on DNA polymorphism and gene expression patterns

“…In addition, this robust experimental design confirms the presence of a protective haplotype (DRB1*1501; DQA1*0602;DQB1*0102) that is shared by both the oligoarticular and the polyarticular JIA subtypes tested. Interestingly, DRB1*1501 is strongly associated with disease risk in both systemic lupus erythematosus and multiple sclerosis, and as in JIA, this allele is protective against IgA immunodeficiency disease; thus, the importance of DRB1*1501 has been consistently noted across multiple forms of autoimmunity (8).…”

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study

“…3 Within the MHC, the human leukocyte antigen (HLA) DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 haplotype has a pre-eminent role, especially for populations of Northern European descent. [4][5][6][7] However, there is now robust, validated evidence that other variants within the MHC have independent roles in rendering individuals susceptible to MS, 8 and there is evidence for a role of the MHC in age at onset 9 and disease course. 10,11 Many studies have used clinical measures of severity to explore this aspect, but MRI-derived measures (such as brain atrophy and T 2 -weighted lesion volume or T2LV) appear to be more sensitive in capturing the course of disease, particularly in the early years after symptom onset.…”