TNFA-TNFB haplotypes modify susceptibility to type I diabetes mellitus independently of HLA class II in a Moroccan population

The contribution of single nucleotide polymorphisms in tumor necrosis factors (TNF) alpha and beta to autoimmune diseases, and to type 1 diabetes mellitus (T1DM) in particular, is not well established, and may be confounded by linkage disequilibrium to class II HLA genes. At least two polymorphisms seem to have functional relevance in the respective genes: TNFA-307 and TNFB+252. We have typed these two polymporphisms in samples of Moroccan T1DM patients and controls for which class II HLA genes had already been typed. Tumor necrosis factors and compound TNF-class II HLA haplotypes were inferred; it was the first time that such a design had been implemented. Independent of linkage disequilibrium with class II HLA, TNF haplotype TNFA-307*2 - TNFB+252*2 showed a significant protective effect (OR = 0.031), partly exacerbated by partial linkage to protective class II haplotypes. Such effect could be detected because Morocco shows the highest frequency of the TNFA-307*2 allele yet reported. This highlights the possible population differences in alleles contributing to autoimmune diseases.