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

Literature - Hindy G, Engström G, Larsson SC, et al. - Stroke. 2018;49:820-827

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 [4]. 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 [5]. Based on the Org 10172 in Acute Stroke Treatment criteria [6], 2,410 cases were large artery atherosclerosis IS, 3,186 were small artery occlusion IS, and 3,427 were cardio-embolic IS cases.

Main results

  • 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.


1. Baigent C, Blackwell L, Emberson J, et al; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681.

2. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–559.

3. Hosomi N, Nagai Y, Kohriyama T, et al; J-STARS Collaborators. The Japan Statin Treatment Against Recurrent Stroke (J-STARS): a multicenter, randomized, open-label, parallelgroup study. EBioMedicine. 2015;2:1071–1078.

4. Willer CJ, Schmidt EM, Sengupta S, et al; Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–1283.

5. NINDS Stroke Genetics Network (SiGN), International Stroke Genetics Consortium (ISGC). Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. Lancet Neurol. 2016;15:174–184.

6. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41.

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