Abstract 11959: The Impact of Genetic Variants Related to LDL-cholesterol on Risk of Ischemic Stroke and Coronary Heart Disease
Aims: Statin trials suggest that lowering LDL-C by 1 mmol/l lowers the risk of both ischemic stroke and coronary heart disease (CHD) by about 20%, whilst observational studies have found stronger effects on CHD than on ischemic stroke. This Mendelian randomization study explores the impact of LDL-C related genetic variants, reflecting life-long differences in LDL-C, on risk of ischemic stroke, ischemic stroke subtypes and CHD.
Methods: The effects of 12 single nucleotide polymorphisms (SNPs) previously associated with LDL-C (>0.05 mmol/l per allele) on ischemic stroke risk were estimated in 15 METASTROKE studies (12580 cases, 62546 controls) and combined in a fixed-effects meta-analysis. The effects of these SNPs on coronary heart disease (CHD) were estimated in the HPS and PROCARDIS studies (8419 cases, 9275 controls). A gene score was used to combine the effects of the 12 SNPs, weighted by their LDL-C effects, on risk of stroke and CHD.
Results: A gene score corresponding to a 1 mmol/l higher LDL-C was associated with a non-significant 8% higher risk of ischemic stroke (OR:1.08, 95% CI:0.93-1.25). There was no significant heterogeneity in the effects of the gene score by ischemic stroke subtype (large artery atherothrombotic, cardioembolic, small vessel; p=0.88). In contrast, the gene score was associated with a 2-fold greater risk of CHD (OR: 2.14, 95% CI: 1.67-2.73). Thus, the impact of LDL-C on ischemic stroke was 10-fold weaker than that on CHD (p<0.001). In addition, the effect of LDL-C on ischemic stroke in this genetic study was slightly weaker than that implied by the statin trials, whereas the effect on CHD was about 3-fold stronger than that suggested by the trials.
Conclusions: This Mendelian randomization study, which is not materially affected by confounding, indicates that life-long differences in LDL-C have substantially weaker effects on ischemic stroke and ischemic stroke subtypes than on CHD risk. Insight into the mechanisms by which various LDL-C pathways affect different vascular phenotypes will help to elucidate these findings further.
- © 2012 by American Heart Association, Inc.