Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele

Type 1 diabetes (T1D; or insulin-dependent diabetes mellitus, IDDM) is an a utoimmune disease with both genetic and environmental components. In additi on to the human leukocyte antigen (HLA) complex, the single major genetic c ontributor of susceptibility(1), an unknown number of other unidentified ge nes are required to mediate disease. Although many loci conferring suscepti bility to T1D have been mapped(2), their identification has proven problema tic(3) due to the complex nature of this disease. Our strategy for finding T1D susceptibility genes has been to test for human homologues of loci impl icated in diabetes-prone NOD (non-obese diabetic) mice, together with appli cation of biologically relevant stratification methods(4). We report here a new susceptibility locus, IDDM18 located near the interleukin-12 (IL-12)p4 0 gene, IL12B. Significant bias in transmission of IL12B alleles was observ ed in affected sibpairs and was confirmed in an independent cohort of simpl ex families. A single base change in the 3' UTR showed strong linkage diseq uilibrium with the T1D susceptibility locus. The IL12B 3' UTR alleles showe d different levers of expression in cell lines. Variation in IL-12p40 produ ction may influence T-cell responses crucial for either mediating or protec ting against this and other autoimmune diseases.