Genome-wide implicated risk variants of TCF7L2 gene contribute to type 2 diabetes susceptibility by modulating serum lipids in Pakistani population

Diabetes is a socioeconomic burden worldwide as well as in Pakistan. International Diabetes Federation reported 7 million cases of diabetes and 86,384 deaths due to diabetes in Pakistan in 2015. Transcription factor 7 like 2 is a transcription factor encoded by TCF7L2 gene and regulates several physiological processes in the cell. The aim of the current study was to determine the prevalence of two TCF7L2 gene polymorphisms and analyze its effect on various anthropometric and biochemical parameters in a Pakistani cohort. We collected 926 samples, 500 healthy controls (fasting blood sugar < 99 mg/dL, random blood sugar < 126 mg/dL) and 426 cases with diabetes (fasting blood sugar > 99 mg/dL, random blood sugar > 126 mg/dL). The genotyping was done by RFLP-PCR and serum biochemical parameters were determined. The genotyping results of rs7903146 by RLFP-PCR showed the allelic frequency of C = 0.64 and T = 0.36 in controls while C = 0.59 and T = 0.41 in cases and genotypic frequency CC = 43.2%, CT = 41.6%, and TT = 15.2% in controls while CC = 34.03%, CT = 49.06%, and TT = 16.91% in cases. The minor T allele appeared to be a risk allele (OR = 1.25, CI = 1.03–1.51, p = 0.016), i.e., it increased the risk of diabetes in the selected study subjects. The genotyping results of rs12255372 showed allelic frequency G = 0.75 and T = 0.25 in controls while G = 0.63 and T = 0.37 in cases and genotypic frequency GG = 54.2%, GT = 42.2%, and TT = 3.6% in controls, while GG = 40.14%, GT = 46.24%, and TT = 13.62% in cases. The minor T allele appeared to be a risk allele for this SNP as well (OR = 1.77, CI = 1.44–2.16, p = 1.9 × 10 −8 ). The biochemical parameters and general characteristics were checked for association with the TCF7L2 variant rs7903146, showed no association with all tested parameters. While rs12255372 had significant association with fasting plasma glucose, triglycerides, HDLC, LDLC, and leptin, but no association with total cholesterol, age, height, weight, and BMI. However, the multivariate analysis showed significant association of lipid parameters only when homozygous risk genotype of rs12255372 co-existed with all genotypes of rs7903146. In conclusion, the polymorphisms in TCF7L2 gene can increase the susceptibility to diabetes and the effect may involve modulating certain serum traits.