Associations of genetic variants in TCF7L2, MC4R, AGT and ACE genes with cardiometabolic diseases in Black South Africans

Our study investigated the association between transcription factor 7-like 2 (TCF7L2-rs7903146), angiotensin convertase enzyme (ACE-rs4646994), angiotensinogen (AGT-rs699), angiotensin II type 1 receptor (AGT1R-rs5186), fat mass and obesity-associated (FTO-rs17817499) and melanocortin 4 receptor (MC4R-rs17782313, rs12970134 and rs229616) single nucleotide polymorphisms (SNPs) with type 2 diabetes (T2D), obesity and hypertension in a Black South African population.

This cross-sectional study involved 560 Black South Africans aged 25 to 74 years. Participant demographic and lifestyle characteristics were self-reported; anthropometry and blood pressures (BP) measured; oral glucose tolerance tests used to diagnose T2D; and SNPs genotyped by polymerase chain reaction. The Benjamini-Hochberg method was used to control for multiple hypothesis testing, using a significance threshold of 0.12.

Using the median test, systolic BP was significantly higher in carriers of the G/G genotype of rs229616 within the MC4R gene compared to carriers of the G/A genotype (p = 0.006, p-FDR = 0.030). In the same gene, logistic regression analysis showed that carriers of the minor C/C genotype of the rs17782313 SNP had a significantly higher risk of hypertension (OR = 1.37, p = 0.023, p-FDR = 0.115) in the unadjusted model. However, the significance was attenuated after adjusting for age, gender and BMI (OR = 1.32, p = 0.084, p-FDR = 0.140). Moreover, carriers of the minor T/T genotype of the TCF7L2 rs7903146 SNP had a lower risk of T2D in the crude model (OR = 0.66, p = 0.043, p-FDR = 0.108) and after adjustment for age, gender and BMI (OR = 0.63, p = 0.041, p-FDR = 0.108). These findings remained significant after correction for multiple comparisons.

TCF7L2-rs7903146 (C/C genotype) and MC4R-17,782,313 (C/C genotype) SNPs are potential genetic risk factors for T2D and hypertension, respectively, in the Black South African population. Replicating these findings and exploring the role played by these genetic variants in downstream molecular pathways could aid in risk stratification and facilitate personalized approaches to healthcare delivery.