The TH01 microsatellite and INS VNTR are strongly associated with type 2 diabetes and fasting insulin secretion

AbstractA variable number of tandem repeats (VNTR) located in the insulin gene (INS) control region may be involved in the development of type 2 diabetes (T2D). The TH01 microsatellite is located close to INS and has previously been suggested to be involved its regulation. Therefore, this observational study investigated whether the TH01 microsatellite and INS VNTR, as assessed via the surrogate marker single nucleotide polymorphism (SNP) rs689, are associated with T2D in the Mexican population. Logistic regression models were used to calculate the risk conferred by TH01 and INS VNTR loci for T2D development. TH01 alleles 6, 8, 9 and 9.3 and allele A of rs689 were independently associated with T2D; differences were found between age at T2D diagnosis and sex. Larger alleles of TH01 ([≥]8 repeats) conferred an increased risk for T2D in males when compared with smaller alleles ([≤]7 repeats) (odds ratio, [≥]1.46; 95% confidence interval, 1.1-1.95). In females, larger alleles conferred a 1.5-fold higher risk for T2D when diagnosed at [≥]46 years whereas they conferred protection when diagnosed at [≤]45 years. Both TH01 and SNP rs689 were associated with T2D in the same groups; the association remained significant for both loci in multivariate models. The median fasting plasma insulin concentration was significantly higher in patients with T2D versus controls, and in those diagnosed at [≤]45 versus [≥]46 years. TH01 larger alleles or the A allele of rs689 may potentiate insulin synthesis in males, but not females, without T2D, a process that is disabled in those with T2D.