Lipids, Apolipoproteins, Lipid-Lowering Drugs, and the Risk of Cerebral Small Vessel Disease: A Mendelian Randomization Study

Abstract

Background: Serum lipids are causally involved in the occurrence of atherosclerosis, but their roles in cerebral small vessel disease remain unclear. This study aimed to investigate the causal roles of lipid or apolipoprotein traits in cerebral small vessel disease and to determine the effects of lipid-lowering interventions on this disease.

Methods and results: Data on genetic instruments of lipids/apolipoproteins, as well as characteristic cerebral small vessel disease manifestations, including small vessel stroke (SVS) and white matter hyperintensity (WMH), were obtained from publicly genome-wide association studies. Through 2-sample Mendelian randomization analyses, it was found that decreased levels of high-density lipoprotein cholesterol (odds ratio [OR], 0.85, P=0.007) and apolipoprotein A-I (OR, 0.83, P=0.005), as well as increased level of triglycerides (OR, 1.16, P=0.025) were associated with a higher risk of SVS. A low level of high-density lipoprotein cholesterol (OR, 0.93, P=0.032) was associated with larger WMH volume. Specifically, the genetically determined expressions of lipid fractions in various size-defined lipoprotein particles were more closely related to the risk of SVS than WMH. Moreover, it was found that the hypertension trait ranked at the top in mediating the causal effect of hyperlipidemia on SVS and WMH by using Mendelian randomization-based mediation analysis. For drug-target Mendelian randomization, the low-density lipoprotein cholesterol-reducing genetic variation alleles at HMGCR and NL1CL1 genes and the high-density lipoprotein cholesterol-raising genetic variation alleles at the CETP gene were predicted to decrease the risk of SVS.

Conclusions: The present Mendelian randomization study indicates that genetically determined hyperlipidemia is closely associated with a higher risk of cerebral small vessel disease, especially SVS. Lipid-lowering drugs could be potentially considered for the therapies and preventions of SVS rather than WMH.

Keywords: Mendelian randomization; cerebral small vessel disease; mediation analysis; microvascular ischemic disease; serum lipids; small vessel stroke; white matter hyperintensity.

Figure 1. Overview of study design.

In this study, genetic variants associated with various serum lipid levels were identified based on results from their corresponding GWAS. These genetic variants were then used as proxies for the serum lipid levels to test their relationship with different CSVD outcomes (SVS and WMH volume) using data from the MEGASTROKE consortium and UK Biobank (univariable MR analysis). Then, MR‐based mediation analyses were performed for those CSVD risk factors (mediators) that were potentially causally associated with both serum lipid levels and CSVD outcomes. Ultimately, drug‐target MR analyses were conducted to determine the effects of genetic predisposition to LDL‐C lowering, HDL‐C raising, and TG lowering through variants in genes encoding targets of lipid‐modifying drugs on CSVD outcomes. CSVD indicates cerebral small vessel disease; GWAS, genome‐wide association study; kb, kilobyte; LD, linkage disequilibrium; MR, Mendelian randomization; SVS, small vessel stroke; and WMH, white matter hyperintensity.

Figure 2. Associations of lipid‐related traits with risk of SVS and WMH volume in inverse‐variance weighted model.

*P<0.05, ^† P<0.01. ApoA‐I indicates apolipoprotein A‐I; ApoB, apolipoprotein B; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; OR, odds ratio; SNV, single nucleotide variant; TG, triglycerides; and WMH, white matter hyperintensity.

Figure 3. Associations of various lipoprotein particle fractions with risk of CSVD in IVW model presented in the form of heatmaps.

*P<0.05. 3‐Hb indicates 3‐hydroxybutyrate; C, cholesterol; CE, cholesterol ester; CON, concentration; HDL, high‐density lipoprotein; IDL, intermediate density lipoprotein; L, large; LDL, low‐density lipoprotein; M, medium; S, small; SVS, small vessel stroke; TG, triglycerides; TL, total lipids; VLDL, very low‐density lipoprotein; WMH, white matter hyperintensity; X, extra; XL, extra‐large; and XS, extra‐small.

Figure 4. Mediating effect of selected traits on the associations of HDL‐C or TG with risk of CSVD.

A, Mediating effect of selected traits on the associations of HDL‐C with SVS. B, Mediating effect of selected traits on the associations of TG with SVS. C, Mediating effect of selected traits on the associations of HDL‐C with WMH. The indirect effect of serum lipid on SVS or WMH through the mediator was calculated by a×b, and the direct effect of serum lipid on SVS or WMH (c') was calculated by c−a×b. *P<0.05, ^† P<0.01. DBP indicates diastolic blood pressure; HDL‐C, high‐density lipoprotein cholesterol; SBP, systolic blood pressure; SHBG, sex hormone binding globulin; SVS, small vessel stroke; TG, triglycerides; and WMH, white matter hyperintensity.

Figure 5. Mendelian randomization associations of LDL‐C‐lowering, HDL‐C‐raising, and TG‐lowering genetic variants in the loci of known lipid‐modifying drug targets with risk of CSVD.

A, Associations of LDL‐C‐lowering, HDL‐C‐raising, and TG‐lowering genetic variants in the loci of known lipid‐modifying drug targets with risk of small vessel stroke. B, Associations of LDL‐C‐lowering, HDL‐C‐raising, and TG‐lowering genetic variants in the loci of known lipid‐modifying drug targets with WMH volume. *P<0.05, ^† P<0.01. HDL‐C indicates high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; OR, odds ratio; SNV, single nucleotide variant; TG, triglycerides; VLDL‐C, very low‐density lipoprotein cholesterol; and WMH, white matter hyperintensity.