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. 2022 Dec 23;15(1):69.
doi: 10.3390/nu15010069.

Associations of Lipids and Lipid-Lowering Drugs with Risk of Vascular Dementia: A Mendelian Randomization Study

Xiaoyu Zhang  1 , Tao Geng  2 , Ning Li  3 , Lijuan Wu  3 , Youxin Wang  3 , Deqiang Zheng  3 , Bo Guo  4 , Baoguo Wang  1
Affiliations

Associations of Lipids and Lipid-Lowering Drugs with Risk of Vascular Dementia: A Mendelian Randomization Study

Xiaoyu Zhang et al. Nutrients. .

Abstract

Accumulating observational studies suggested that hypercholesterolemia is associated with vascular dementia (VaD); however, the causality between them remains unclear. Hence, the aim of this study is to infer causal associations of circulating lipid-related traits [including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB)] with VaD jointly using univariable MR (uvMR), multivariable MR (mvMR) and bidirectional two-sample MR methods. Then, the summary-data-based MR (SMR) and two-sample MR analysis were conducted to investigate the association of lipid-lowering drugs target genes expression (including HMGCR, PCSK9, NPC1L1, and APOB) and LDL-C level mediated by these target genes with VaD. The results of forward MR analyses found that genetically predicted HDL-C, LDL-C, TG, apoA-I, and apoB concentrations were not significantly associated with the risk of VaD (all p > 0.05). Notably, there was suggestive evidence for a causal effect of genetically predicted VaD on HDL-C via reverse MR analysis [odds ratio (OR), 0.997; 95% confidence interval (CI), 0.994−0.999; p = 0.022]. On the contrary, the MR results showed no significant relationship between VaD with LDL-C, TG, apoA-I, and apoB. The results for the SMR method found that there was no evidence of association for expression of HMGCR, PCSK9, NPC1L1, and APOB gene with risk of VaD. Furthermore, the result of MR analysis provided evidence for the decreased LDL-C level mediated by gene HMGCR reduced the risk of VaD (OR, 18.381; 95% CI, 2.092−161.474; p = 0.009). Oppositely, none of the IVW methods indicated any causal effects for the other three genes. Using genetic data, this study provides evidence that the VaD risk may cause a reduction of HDL-C level. Additionally, the finding supports the hypothesis that lowering LDL-C levels using statins may be an effective prevention strategy for VaD risk, which requires clinical trials to confirm this result in the future.

Keywords: Mendelian randomization; eQTL; lipid-lowering drugs; lipid-related traits; vascular dementia.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Causal effects of VaD on lipid-related traits via reverse MR analyses. IVs: instrumental variables; IVW: inverse-variance weighted; MR: Mendelian randomization; PRESSO: pleiotropy residual sum and outlier; OR: odds ratio; CI: confidence interval; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TG: triglyceride; apoA-I: apolipoprotein A-I; apoB: apolipoprotein B.
Figure 2
Figure 2
Scatter plot showing the association of the SNP effects on VaD against the SNP effects on the HDL-C level. The blue line indicates the estimate of the effect using the IVW method. Circles indicate marginal genetic associations with VaD and risk of HDL-C level for each variant. Error bars indicate 95% CIs. IVW: inverse-variance weighted; VaD: vascular dementia; HDL-C: high-density lipoprotein cholesterol; SNP: single nucleotide polymorphism.
Figure 3
Figure 3
Leave-one-out permutation analysis of the causal association between VaD and HDL-C level. VaD: vascular dementia; HDL-C: high-density lipoprotein cholesterol; MR: Mendelian randomization; SNP: single nucleotide polymorphism.
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