TNFa Microsatellite Polymorphism Modulates the Risk of IDDM in Caucasians With the High-Risk Genotype HLA DQA1*0501-DQB1*0201/DQA1*0301-DQB1*0302

I DDM is a genetically controlled autoimmune disease.In particular, the loci of the HLA region on chromosome 6p are associated with the genetic risk for developing IDDM.DQAl*0501-DQBl*0201/DQAl*0301-DQB1*O3O2 is the most prevalent susceptibility genotype in Caucasians, carrying a relative risk between 20 and 50 (1).However, the frequency of this high-risk genotype in the population is 10-20 times higher than the prevalence of IDDM associated with this genotype, suggesting that additional protective genes (HLA or non-HLA) and/or environmental factors can influence susceptibility to the disease (1).Recently, it has been shown that DRBl*0403 protects against IDDM in Caucasians with the high-risk heterozygous DR3-DQ2/DR4-DQ8 genotype (2), but it accounts for only -10% of the protection.Thus, DRB alleles alone cannot explain either protection or susceptibility for IDDM.To define additional markers for genetic susceptibility to or protection against IDDM in the HLA-DQ high-risk genotype group, 120 diabetic patients and 83 nondiabetic control subjects, all sharing the DQAl*0501-DQBl*0201/DQAl*0301-DQBl*0302 genotype, were studied with eight microsatellite loci spanning the entire major histocompatibility complex (MHC) region and a region 2 cM telomeric of MHC.All subjects were unrelated European Caucasians and were recruited by the Belgian Diabetes Registry (2,3).HLA-typing and amplification of microsatellite markers were performed as described previously (3-5).Primer sequences for the markers HLA-F, D6S265, TNFa, D6S273, D6S1014, DQCar, TAP1, and D6S291 are available from the Genome Data Bank and were used as described previously (5).