An interracial Mendelian analysis revealed a link between lipid-lowering drugs and renal failure.

Abstract

Lipid-lowering drugs have been used in clinics widely. It is unclear whether the drugs have an effect on renal failure. We chose high-density lipoprotein cholesterol (ieu-b-109), low-density lipoprotein cholesterol (ieu-a-300), triglyceride (ieu-b-111), and total cholesterol (ebi-a-GCST90038690) as exposures. SNPs near drug genes served as instrumental variables. Acute renal failure (ARF) and chronic renal failure (CRF) in Europeans from the GWAS catalog were selected as outcomes. Datasets on renal failure in East Asians and South Asians were used for validation. Inverse variance weighted (IVW) was the primary method for drug-targeted Mendelian randomization. In the Europeans, people who used PPARG reduced ARF risk by 69.3% (OR: 0.307, 95% CI: 0.171-0.553, p = 0.015). NPC1L1 inhibitors increased ARF risk by 2.684 times (OR: 2.684, 95% CI: 2.027-3.341, p = 0.003). APOE increased ARF risk by 1.987 times (OR: 1.987, 95% CI: 1.062-3.716, p = 0.032) but decreased CRF risk by 49.7% (OR: 0.503, 95% CI: 0.283-0.894, p = 0.019). TNFSF12 increased CRF risk by 3.866 times (OR: 3.866, 95% CI: 1.174-12.729, p = 0.026). In the East Asians, PPARG reduced CRF risk by 85.8% (OR: 0.142, 95% CI: 0.054-0.371, p < 0.001). And in the South Asians, APOE decreased ARF risk by 99.8% (OR: 0.002, 95% CI: 2.12e-05-0.179, p = 0.007). We revealed that PPARG could reduce the risk of renal failure in Europeans and Asians. APOE could cause ARF in the Europeans, but it was protective in the South Asians. Clinicians need to consider the characteristics of the local population before administering drugs to patients of different ethnicities.