孟德尔随机化
肌萎缩侧索硬化
医学
内科学
载脂蛋白B
内分泌学
调解
脂质代谢
载脂蛋白A1
全基因组关联研究
脂蛋白
胆固醇
遗传学
疾病
生物
基因
单核苷酸多态性
遗传变异
基因型
政治学
法学
作者
Kailun Xia,Veronika Klose,Josef Högel,Tao Huang,Linjing Zhang,Johannes Dorst,Dongsheng Fan,Albert C. Ludolph
摘要
Abstract Objective Previous observational studies revealed a potential but partially controversial relation between lipid metabolism and the risk of amyotrophic lateral sclerosis (ALS), potentially prone to bias. Therefore, we aimed to study whether lipid metabolism involves genetically determined risk factors for ALS through Mendelian randomization (MR) analysis. Methods Using genome‐wide association study summary‐level data for total cholesterol (TC) ( n = 188,578), high‐density lipoprotein cholesterol (HDL‐C) ( n = 403,943), low‐density lipoprotein cholesterol (LDL‐C) ( n = 440,546), apolipoprotein A1 (ApoA1) ( n = 391,193), apolipoprotein B (ApoB) ( n = 439,214), and ALS (12,577 cases and 23,475 controls), we implemented a bidirectional MR study to evaluate a genetic relation between lipids and ALS risk. We performed a mediation analysis to assess whether LDL‐C is a potential mediator on the pathway from traits of LDL‐C‐related polyunsaturated fatty acids (PUFAs) to ALS risk. Results We identified genetically predicted increased lipid levels to be associated with the risk of ALS, whereby elevated LDL‐C had the most potent effect (OR 1.028, 95% CI 1.008–1.049, p = 0.006). The effect of increased levels of apolipoproteins on ALS was similar to their corresponding lipoproteins. ALS did not cause any changes in lipid levels. We found no relation between LDL‐C‐modifying lifestyles and ALS. The mediation analysis revealed that LDL‐C could act as an active mediator for linoleic acid, with the mediation effect estimated to be 0.009. Conclusions We provided high‐level genetic evidence verifying the positive link between preclinically elevated lipid and ALS risk that had been described in previous genetic and observational studies. We also demonstrated the mediating role of LDL‐C in the pathway from PUFAs to ALS.
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