Linkage disequilibrium with HLA-DRB1-DQB1 haplotypes explains the association of TNF-308G>A variant with type 1 diabetes in a Brazilian cohort

• We studied the -308 G/A polymorphism in a T1D cohort;
• We analyzed its linkage disequilibrium with HLA-DQB1 and HLA-DRB1 alleles;
• We report an association of the -308 G/A polymorphism with T1D;
• This association is accounted for by linkage disequilibrium with HLA risk alleles.

BackgroundA functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association.Methods659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HLA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects.ResultsAssociations with T1D were observed for the A-allele of rs1800629 (OR 1.69, 95% CI 1.33–2.15, p < 0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% CI 3.23–8.59, p < 0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% CI 1.21–7.21, p = 0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14, 95% CI 1.02–4.50, p = 0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D.ConclusionOur results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D.