Genetically proxied therapeutic inhibition of kidney function drug targets and type 2 diabetes in Africans: A Mendelian randomization study

Abstract

Background: Despite the growing number of treatments available for diabetics, many people fail to achieve their therapeutic goals. The complexity of diabetes prevention and control exacerbates the situation in low-income countries. These complexities include genetic factors, social, and financial burdens. Strategies for optimizing coverage for new drugs and clinical therapies for type 2 diabetes mellitus (T2DM) have focused on dual-use approaches for new or off-label indications. This study aimed to determine whether inhibition of kidney function drug targets have adverse effect on T2DM. Methods: A two-sample Mendelian randomization (MR) study was conducted based on genetic variants located in or near genes (in 300 kilobyte windows) for encoding significant drug targets. We used summary statistics of eGFR GWAS (n=80,027) of African ancestry individuals and GWAS datasets of T2DM (n=4,347 Africans in South Africa, Nigeria, Ghana and Kenya), to predict the effects of drug exposure on T2DM risk. Results: Genetically predicted inhibition of vascular endothelial growth factor A (VEGFA) and Ras homolog enriched in brain (RHEB) were associated with higher odds of T2DM incidence (OR, 2.66; 95% CI 1.34–3.78, and OR, 2.25; 95% CI, 1.34–3.28, respectively). Genetically predicted inhibition of SLC22A2 and inhibition of CLDN14 were not associated with T2DM occurrence (OR, 0.95; 95% CI, 0.61-1.48 and OR, 1.56; 0.71–2.20, respectively). Interpretation: Our results suggest VEGFA inhibitors and RHEB inhibitors drugs may increase the risk or exacerbate T2DM risk in Africans, hence a need for closely monitoring the safety and efficacy of anti-diabetic drugs in the African population.