Genetic determinants of blood lipids and cerebral small vessel disease: role of high-density lipoprotein cholesterol - PubMed (original) (raw)

Genetic determinants of blood lipids and cerebral small vessel disease: role of high-density lipoprotein cholesterol

Marios K Georgakis et al. Brain. 2020.

Abstract

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.

Keywords: Mendelian randomization; high-density lipoprotein; lacunar stroke; lipids; small vessel disease.

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Figures

Figure 1

Mendelian randomization associations of genetic determinants of blood lipid levels (HDL-C, LDL-C, triglycerides) with risk of small vessel stroke and WMH volume. Shown are the results derived from random-effects IVW (inverse-variance weighted) Mendelian randomization and multivariable Mendelian randomization (MVMR) analyses adjusting for the effects of the genetic variants on all the three blood lipid traits. SD = standard deviation; TG = triglycerides.

Figure 2

Mendelian randomization associations of genetic determinants of cholesterol (C) and triglyceride (TG) concentrations in size-defined lipoprotein particles with risk of small vessel stroke and WMH volume. Shown are the results derived from random-effects inverse-variance weighted (IVW) Mendelian randomization and multivariable Mendelian randomization (MVMR) analyses. MVMR for cholesterol in HDL particles adjusted for LDL-C and triglycerides; for cholesterol in LDL and larger particles adjusted for HDL-C and triglycerides; and for triglycerides in any particles adjusted for HDL-C and LDL-C. IDL = intermediate density lipoprotein; L = large; M = medium; S = small; VLDL = very low density lipoprotein; XL = extra-large.

Figure 3

Mendelian randomization (MR) associations of genetic determinants of HDL-C with risk of small vessel stroke and WMH volume. Shown are the results from random-effects inverse-variance weighted (IVW), weighted median and MR-Egger analyses when (A) using the full set of genetic instruments and (B) restricting the analyses to instruments also associated with cholesterol concentration in medium-sized HDL.

Figure 4

Mendelian randomization associations of HDL-C-raising and LDL-C-lowering genetic variants in the loci of known lipid-modifying drug targets with risk of SVS and WMH volume. Shown are the results derived from random-effects inverse-variance weighted (IVW) Mendelian randomization analyses. The results are scaled per 1 SD increment in circulating HDL-C levels (HDL-C-raising drug targets) and per 1 SD increment in circulating LDL-C levels (LDL-C-lowering drug targets).

Figure 5

Mendelian randomization associations between HDL-C raising genetic variants in the CETP locus and (A) risk of SVS, (B) WMH volume, and (C) risk of ICH. Shown are the results from the random-effects inverse-variance weighted (IVW) Mendelian randomization approach. The results are scaled per 1 SD increment in circulating HDL-C levels.

Figure 6

Mendelian randomization associations of genetic determinants of blood lipid levels (HDL-C, LDL-C, triglycerides) with risk of intracerebral haemorrhage. Shown are the results derived from random-effects inverse-variance weighted (IVW) Mendelian randomization and multivariable Mendelian randomization (MVMR) analyses. MVMR for cholesterol in HDL particles adjusted for LDL-C and triglycerides; for cholesterol in LDL and larger particles adjusted for HDL-C and triglycerides; and for triglycerides in any particles adjusted for HDL-C and LDL-C. TG = triglycerides.

Figure 7

Comparisons of association estimates for genetic determinants of lipid traits (blood lipid levels and concentrations of lipoprotein particle components) between SVS, WMH volume, and ICH. Comparisons of the Mendelian randomization association estimates between genetic determinants of lipid traits and risk of SVS with the Mendelian randomization association estimates for WMH volume and risk of ICH. Shown are the meta-regression slopes for the comparisons of these association estimates for: (A) risk of SVS and WMH volume, (B) risk of SVS and risk of ICH, and (C) WMH volume and risk of ICH. Estimates are scaled per 1 SD increment.

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Genetic determinants of blood lipids and cerebral small vessel disease: role of high-density lipoprotein cholesterol - PubMed (original) (raw)