Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, Zhejiang, 310016, P.R. China.
Lipids Health Dis. 2024 Jun 8;23(1):175. doi: 10.1186/s12944-024-02163-4.
BACKGROUND: The causal associations of lipids and the drug target genes with atrial fibrillation (AF) risk remain obscure. We aimed to investigate the causal associations using genetic evidence. METHODS: Mendelian randomization (MR) analyses were conducted using summary-level genome-wide association studies (GWASs) in European and East Asian populations. Lipid profiles (low-density lipoprotein cholesterol, triglyceride, and lipoprotein[a]) and lipid-modifying drug target genes (3-hydroxy-3-methylglutaryl-CoA reductase, proprotein convertase subtilisin/kexin type 9, NPC1-like intracellular cholesterol transporter 1, apolipoprotein C3, angiopoietin-like 3, and lipoprotein[a]) were used as exposures. AF was used as an outcome. The inverse variance weighted method was applied as the primary method. Summary-data-based Mendelian randomization analyses were performed for further validation using expression quantitative trait loci data. Mediation analyses were conducted to explore the indirect effect of coronary heart disease. RESULTS: In the European population, MR analyses demonstrated that elevated levels of lipoprotein(a) increased AF risk. Moreover, analyses focusing on drug targets revealed that the genetically proxied target gene LPA, which simulates the effects of drug intervention by reducing lipoprotein(a), exhibited an association with AF risk. This association was validated in independent datasets. There were no consistent and significant associations observed for other traits when analyzed in different datasets. This finding was also corroborated by Summary-data-based Mendelian randomization analyses between LPA and AF. Mediation analyses revealed that coronary heart disease plays a mediating role in this association. However, in the East Asian population, no statistically significant evidence was observed to support these associations. CONCLUSIONS: This study provided genetic evidence that Lp(a) may be a causal factor for AF and that LPA may represent a promising pharmacological target for preventing AF in the European population.
背景：脂质和药物靶点基因与心房颤动（AF）风险的因果关系仍不清楚。我们旨在利用遗传证据进行研究。
方法：使用欧洲和东亚人群的全基因组关联研究（GWAS）汇总水平数据进行孟德尔随机化（MR）分析。将血脂谱（低密度脂蛋白胆固醇、甘油三酯和脂蛋白[a]）和血脂调节药物靶点基因（3-羟基-3-甲基戊二酰辅酶 A 还原酶、脯氨酸内切酶/丝氨酸蛋白酶 9、NPC1 样细胞内胆固醇转运蛋白 1、载脂蛋白 C3、血管生成素样 3 和脂蛋白[a]）作为暴露因素，将 AF 作为结局。采用逆方差加权法作为主要方法。使用表达数量性状基因座数据进行汇总数据孟德尔随机化分析，以进一步验证。进行中介分析以探讨冠心病的间接作用。
结果：在欧洲人群中，MR 分析表明脂蛋白（a）水平升高会增加 AF 风险。此外，针对药物靶点的分析表明，LPA 这一遗传上接近的靶点基因，通过降低脂蛋白（a）模拟药物干预的效果，与 AF 风险相关。该关联在独立数据集得到验证。在不同数据集进行分析时，对于其他特征没有观察到一致和显著的关联。这一发现也通过 LPA 和 AF 之间的汇总数据孟德尔随机化分析得到证实。中介分析表明冠心病在这种关联中起中介作用。然而，在东亚人群中，没有观察到统计学上显著的证据支持这些关联。
结论：本研究提供了遗传证据，表明 Lp(a)可能是 AF 的一个因果因素，LPA 可能是欧洲人群预防 AF 的一个有前途的药物靶点。
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