The role of FTO, ENPP1 and TCF7L2 in the pathogenesis of diabetes in an adult population from Bellville South, Cape Town, South Africa

Abstract

Background: The Mixed Ancestry population of South Africa has recently been reported to have a higher prevalence of type 2 diabetes (T2DM). However, the genetic risk factors that may contribute to the development of T2DM are currently unknown. We investigated the association of fat mass and obesity-associated gene (FTO), ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) and transcription factor 7-like 2 gene (TCF7L2) with T2DM risk in a community residing in Bellville South, Cape Town. Methods: Five hundred and sixty six participants (11.7% males) who consented to genetic analyses were genotyped for six single nucleotide polymorphisms (SNPs): ENPP1-rs997509 and -rs1044498, FTO-9941349 and -rs3751812, TCF7L2-rs12255372 and -rs7903146. The SNPs were genotyped using their corresponding Taqman genotyping assays, and validated by automated sequencing. Allele and genotype frequencies were determined and regression analyses was conducted to assess the association of the polymorphisms with T2DM and its related,traits. Results: Overall and in subgroups defined by diabetes and obesity statuses, there were present no significant differences in the distribution of alleles and genotypes, except for the polymorphisms observed in the FTO and ENPP1 genes. In logistic regression models adjusted for age, sex, body mass index (BMI) and insulin resistance, minor alleles of ENPP1-rs997509 and ENPP1-rs1044498 were associated with risk for T2DM respectively, 4.55 (1.06-19.49) (p=0.041) and 1.81 (1.09-2.98) (p=0.021) assuming a recessive genetic model. Furthermore, the FTO rs9941349 minor allele was associated with the prevalent T2DM under the log-additive model: 1.40 (1.00 to 1.96) (0.049). The TCF7L2 polymorphisms showed no evidence of association with T2DM and/or insulin sensitivity/resistance indicators. Conclusion: Our results demonstrate that ENPP1 and FTO polymorphisms may contribute to T2DM susceptibility in this population, confirming previous findings that insulin resistance may mediate the development of the disease in the Mixed Ancestry population group of South Africa.