Associations between Genetically Proxied Inhibition of Lipid-Lowering Drug Targets and Serum Micronutrients among Individuals of European Descent: A Mendelian Randomization Study

Abstract

Background: Limited and inconclusive data exist concerning the associations between lipid-lowering drugs and serum micronutrient concentrations.

Methods: We conducted Mendelian randomization (MR) analyses to explore the associations between lipid-lowering drug targets and serum micronutrients. Single-nucleotide polymorphisms in genes encoding molecular targets of LDL cholesterol-lowering therapies were selected as instrumental variables for 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR; target of statins), proprotein convertase subtilisin/kexin type 9 (PCSK9; target of PCSK9 inhibitors), and Niemann-Pick C1-Like 1 (NPC1L1; target of ezetimibe). Exposure data were extracted from a published genome-wide association study (GWAS) of lipids in 188,577 European individuals, with outcome data obtained from the Integrative Epidemiology Unit (IEU) GWAS database (https://gwas.mrcieu.ac.uk). Overall, age and sex information were not calculable from the summary-level GWAS data. MR analyses were performed using the inverse-variance weighted method and MR sensitivity analysis methods.

Results: We found genetically proxied inhibition of HMGCR to lower iron (effect, -0.16; 95% CI: -0.27, -0.06; P value = 0.003), zinc (effect, -0.83; 95% CI: -1.36, -0.31; P value = 0.002), magnesium (effect, -0.17; 95% CI: -0.27, -0.06; P value = 0.003), potassium (effect, -0.17; 95% CI: -0.27, -0.06; P value = 0.002), genetically proxied inhibition of NPC1L1 to increase calcium (effect, 0.28; 95% CI: 0.10, 0.46; P value = 0.003), retinol (effect, 0.25; 95% CI: 0.07, 0.44; P value = 0.01), and genetically proxied inhibition of PCSK9 to increase vitamin D (effect, 0.10; 95% CI: 0.07, 0.12; P value = 1.8 × 10-19). These associations were robust in MR sensitivity analyses. However, the associations between genetically proxied inhibition of HMGCR and NPC1L1 and the micronutrients were not consistent in multiple comparisons.

Conclusions: Our results provide evidence that statin use may lower serum concentrations of iron, zinc, magnesium, and potassium, PCSK9 inhibitors may increase serum vitamin D, and ezetimibe may increase serum calcium and retinol concentrations.

Keywords: Mendelian randomization; PSCK9 inhibitor; ezetimibe; micronutrients; statin.