Relative effects of LDL-C on ischemic stroke and coronary disease: A Mendelian randomization study

• Published in: Neurology Vol. 92; no. 11; pp. e1176 - e1187
• Main Authors: Valdes-Marquez, Elsa, Parish, Sarah, Clarke, Robert, Stari, Traiani, Worrall, Bradford B, Hopewell, Jemma C
• Format: Journal Article
• Language: English
• Published: United States American Academy of Neurology 12-03-2019; Lippincott Williams & Wilkins
• Subjects: bmi; Brain Ischemia - epidemiology; Causality; Cholesterol, LDL - blood; Coronary Disease - epidemiology; density-lipoprotein-cholesterol; genetic-variants; heart-disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hyperlipidemias - drug therapy; Hyperlipidemias - epidemiology; Hyperlipidemias - genetics; Hypolipidemic Agents - therapeutic use; Medicin och hälsovetenskap; Mendelian Randomization Analysis; metaanalysis; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; pcsk9; reduction; risk-factors; statin therapy; Stroke - epidemiology; subtypes
• ISSN: 0028-3878; 1526-632X; 1526-632X
• DOI: 10.1212/WNL.0000000000007091

OBJECTIVETo examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach.
METHODSWe undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity.
RESULTSA 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32−1.68, p = 1.1 × 10). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96−1.30, p = 0.14; p for heterogeneity = 2.6 × 10) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84−1.33, p = 0.64; p for heterogeneity = 8.6 × 10) when compared with that for CHD.
CONCLUSIONSIn contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.