Differential effect of LDL- and HDL-levels on small and large vessel disease and stroke type
Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study
Introduction and methods
LDL-c lowering trials show that statin therapy leads to a risk reduction of first and recurrent ischemic stroke (IS) [1-3]. However, it is unclear whether the same holds true for different IS subtypes, and whether HDL-c and triglycerides (TGs) may be causally involved in the development of IS as well.
This Mendelian Randomization (MR) study investigated the causal relationship of LDL-c, HDL-c, and TGs in the development of IS and its subtypes. The subtypes studied were cardio-embolic, large artery atherosclerosis stroke, and small artery occlusion.
Summary-level data for 185 genome-wide single nucleotide polymorphisms associated with LDL-c, HDL-c, and TGs were obtained from the publicly available genome-wide association study data through the Global Lipids Genetics Consortium, including 188,577 individuals of primarily European ancestry . The summary-level data for IS and its subtypes were obtained from the National Institute of Neurological Disorders and Stroke−Stroke Genetics Network, which includes 16,851 IS cases and 32,473 controls of predominantly European ancestry . Based on the Org 10172 in Acute Stroke Treatment criteria , 2,410 cases were large artery atherosclerosis IS, 3,186 were small artery occlusion IS, and 3,427 were cardio-embolic IS cases.
- Genetically predicted LDL-c was associated with higher risk for IS (OR: 1.12; 95%CI: 1.01–1.24; P=0.024; per 1-SD elevation of LDL-c by conventional MR).
- MR-Egger (developed to detect small-study or unbalanced pleiotropy bias) showed a stronger association (OR: 1.22; 95%CI: 1.05–1.43), and did not indicate a pleiotropic bias (P intercept=0.14).
- MR suggested a direct association between genetically elevated LDL-c and large artery atherosclerosis IS (OR: 1.28; 95%CI: 1.07–1.53; P=0.007).
- Genetically predicted LDL-c did not associate with small artery occlusion (OR: 1.21; P=0.303) nor with cardio-embolic stroke.
- Genetically predicted elevations in HDL-c levels were associated with lower risk of small artery occlusion IS (OR: 0.79; 95%CI: 0.67–0.93; P=0.004; per 1-SD elevation of HDL-c). Multivariable MR analyses did not show a significant association between HDL-c and IS, and the MR-Egger estimate showed a null association (OR: 1.01; 95%CI: 0.87–1.18).
- No associations were observed for HDL-c with IS overall (OR: 0.91; P=0.071) or large artery atherosclerosis (OR: 0.93; P=0.480) or cardio-embolic IS.
- Genetically elevated TGs did not associate with IS or any of its subtypes.
This MR study showed that genetically elevated LDL-c levels increase the risk for IS, and in particular the risk of large artery atherosclerosis IS. Genetically predicted elevated HDL-c levels associated with a reduced risk of small artery occlusion IS. Genetically elevated TGs were not associated with a risk reduction of IS or any of its subtypes.