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OBJECTIVE:To 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. METHODS:We 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. RESULTS:A 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 × 10-8). 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 × 10-3) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 × 10-3) when compared with that for CHD. CONCLUSIONS:In 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.

Original publication

DOI

10.1212/wnl.0000000000007091

Type

Journal article

Journal

Neurology

Publication Date

03/2019

Volume

92

Pages

e1176 - e1187

Addresses

From the Clinical Trial Service Unit and Epidemiological Studies Unit (E.V.-M., S.P., R.C., T.S., J.C.H.) and MRC Population Health Research Unit (S.P.), Nuffield Department of Population Health, University of Oxford, UK; and Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia School of Medicine, Charlottesville, VA.

Keywords

METASTROKE Consortium of the ISGC,, Humans, Brain Ischemia, Coronary Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Causality, Cholesterol, LDL, Hyperlipidemias, Stroke, Mendelian Randomization Analysis, Hypolipidemic Agents