Work

Evaluating Lipid‐Lowering Drug Targets for Parkinson's Disease Prevention with Mendelian Randomization

Year: 2020

Type: article

Abstract: Objective To examine whether long-term exposure to statins and other lipid-lowering drugs may affect PD risk – either beneficially or adversely – using Mendelian randomization (MR). Methods MR analyses were based on variants in genes encoding the targets of several approved or emerging drug classes that reduce circulating low-density lipoprotein cholesterol (LDL-C) or triglycerides. Variants were weighted by their associations with differences in circulating LDL-C, triglycerides or apolipoprotein B (ApoB) using data from genome-wide association studies of lipids (N = 14,004 to 295,826). MR models indexing the effects of modulating each drug target on PD risk were then estimated from genetic associations with PD case-control status (N = 37,688 cases and 981,372 controls). Results Estimates for statin exposure were incompatible with drug use increasing PD risk, but were not precise enough to confirm a protective effect: odds ratio for PD per standard deviation (SD) reduction in low-density lipoprotein cholesterol = 0.83; 95% confidence interval (CI): 0.65, 1.07. Findings for other LDL-lowering targets were also close to the null. Among triglyceride-lowering targets, variants indexing Apolipoprotein-A5 / Apolipoprotein-C3 modulation suggested a protective effect (OR per SD lower triglycerides = 0.84; 95% CI = 0.80, 0.89), whereas others were null. Interpretation This genetic evidence does not support findings from large observational studies which suggest that statin exposure could alter risk of PD. Our overall pattern of results suggest peripheral lipid transport may not influence PD etiology, but this does not necessarily exclude effects of statins or the modulation of apolipoproteins A5/C3 via other mechanisms.

Source: Annals of Neurology

DOI: 10.1002/ana.25880

Authors: Dylan M. Williams, Sara Bandres‐Ciga, Karl Heilbron, David Hinds, Alastair J. Noyce