The class
Mendelian randomization finds genetically raised HDL via CETP predicted to lower small vessel stroke risk (J Am Heart Assoc 2024)
Original title: Lipids, Apolipoproteins, Lipid-Lowering Drugs, and the Risk of Cerebral Small Vessel Disease: A Mendelian Randomization Study
Using two-sample Mendelian randomization on genetic instruments for lipids and apolipoproteins alongside genome-wide association data on cerebral small vessel disease manifestations, researchers found decreased HDL cholesterol (odds ratio 0.85, P equals 0.007) and apolipoprotein A-I (odds ratio 0.83, P equals 0.005), and increased triglycerides (odds ratio 1.16, P equals 0.025), associated with higher risk of small vessel stroke, while low HDL cholesterol was also linked to larger white matter hyperintensity volume. In drug-target Mendelian randomization, LDL-cholesterol-reducing genetic variants at HMGCR and NPC1L1, as well as HDL-cholesterol-raising genetic variants at CETP, were all predicted to decrease small vessel stroke risk, with hypertension identified as a key mediator of the hyperlipidaemia-to-small-vessel-disease pathway, supporting lipid-lowering (and CETP-targeted HDL-raising) drugs as potential therapies for small vessel stroke prevention.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.