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

Abstract

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.

Figure 1. Effects of genetic variants on coronary heart disease and ischemic stroke risk vs low-density lipoprotein cholesterol (LDL-C) levels

Figures are shown separately for (A) coronary heart disease and (B) ischemic stroke. Effects of the 62 individual genetic variants in the primary analysis are shown per LDL-C increasing allele.

Figure 2. Effects of genetically determined low-density lipoprotein cholesterol (LDL-C) on vascular disease and ischemic stroke subtypes

Causal estimates are based on 62 variants associated with LDL-C in the primary analysis. Odds ratio and 95% confidence intervals (95% CIs) are provided for vascular disease (coronary heart disease and ischemic stroke) and ischemic stroke subtypes per 1 mmol/L higher genetically determined LDL-C.

Figure 3. Effects of low-density lipoprotein cholesterol (LDL-C) on vascular disease in prospective studies, randomized statin trials, and genetic studies

Genetic effect of LDL-C on disease was estimated based on 62 variants associated with LDL-C (see primary analysis methods). Estimates from prospective studies are shown for usual levels of non-high-density lipoprotein cholesterol. Estimates from randomized statin trial for coronary heart disease are based on major coronary events (coronary death or nonfatal myocardial infarction). Estimates from genetic studies are taken from figure 2. CI = confidence interval.