Epistatic effects of genes encoding tumor necrosis factor-alpha, immunoglobulin allotypes, and HLA antigens on susceptibility to non-insulin-dependent (type 2) diabetes mellitus

Non-insulin-dependent diabetes mellitus (NIDDM) is a complex disease with a very high degree of heritability. Linkage and segregation analyses have no t been very productive in identifying genes responsible for polygenic disea ses such as NIDDM, and the majority of the genes determining susceptibility to this disorder remain to be identified. Using a case-control study desig n, we investigated the possible roles of genes coding for HLA class II anti gens, tumor necrosis factor-alpha (TNF-alpha), and immunoglobulin (Ig) allo types (GM and KM) in a group of Caucasians from Belgium (214 NIDDM patients and 200 controls). All genetic markers were determined by polymerase chain reaction-based methods. We demonstrate that particular homozygous genotype s of TNF-alpha and GM and KM allotypes epistatically interact with HLA-DQ a lpha 1(Arg) (52) and contribute to an increased relative risk of NIDDM.