降压药物和降脂药物与眼部疾病的因果关联:一项跨种族药物靶点孟德尔随机化分析

Causal associations of antihypertensive and lipid-lowering drugs with ocular diseases: a cross-ancestry drug target Mendelian randomization study

摘要

目的 通过药物靶点孟德尔随机化(Mendelian randomization, MR)分析，探索东亚和欧洲人群中常用降压药及降脂药与常见眼部疾病的因果关联。方法 利用 GWAS Catalog 公开发布的全基因组关联研究(genome-wide association studies, GWAS)汇总数据，开展跨种族药物靶点 MR 分析。将 5 类常用降压药物，包括血管紧张素转换酶抑制剂(angiotensin-converting enzyme inhibitors, ACEIs)、血管紧张素Ⅱ受体拮抗剂(angiotensin II receptor blockers, ARBs)、β-受体阻滞剂(β-blockers, BBs)、钙通道阻滞剂(calcium channel blockers, CCBs)及噻嗪类利尿剂(thiazide diuretics, TDs) 和 3 类常用降脂药物，包括 3-羟基-3-甲基戊二酰辅酶 A 还原酶(3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR)抑制剂、前蛋白转化酶枯草溶菌素 9(proprotein convertase subtilisin/kexin type 9, PCSK9)抑制剂、尼曼-匹克 C1 型类似蛋白 1(Niemann-Pick C1-like 1, NPC1L1) 抑制剂作为暴露因素，6 种常见眼部疾病(老年白内障、青光眼、干眼症、视力障碍、老花眼、近视)作为结局变量。以逆方差加权法(inverse variance weighted, IVW)作为主要分析方法，对关联有统计学意义的结果辅以 7 种 MR 方法进行验证。采用 Cochran's Q 检验、MR-Egger 截距分析和留一法进行敏感性分析。结果 在东亚人群中，ACEIs 与近视(OR=1.024, 95%CI:1.01~1.038, P_FDR=0.002)、老年白内障(OR=1.022, 95%CI:1.019~1.024;P_FDR<0.001)及青光眼(OR=1.017, 95%CI:1.011~1.023, P_FDR<0.001)风险增加存在因果关联，BBs 与老年白内障风险降低存在因果关联(OR=0.994, 95%CI:0.989~0.999, P_FDR=0.034);PCSK9 抑制剂与老花眼(OR=0.992, 95%CI:0.986~0.997, P_FDR=0.003)和视力障碍(OR=0.996, 95%CI:0.993~0.999, P_FDR=0.048)风险降低存在因果关联。在欧洲人群中，ACEIs 与青光眼风险增加存在因果关联(OR=1.088, 95%CI:1.029~1.152, P_FDR=0.016);HMGCR 抑制剂与老年白内障风险增加存在因果关联(OR=1.194, 95%CI:1.049~1.359, P_FDR=0.022);PCSK9 抑制剂与干眼症(OR=1.106, 95%CI:1.039~1.176, P_FDR=0.004)和老花眼(OR=1.082, 95%CI:1.024~1.145, P_FDR=0.017)风险增加存在因果关联，与青光眼风险降低存在因果关联(OR=0.892, 95%CI:0.822~0.968, P_FDR=0.018);NPC1L1 抑制剂与青光眼风险降低存在因果关联(OR=0.706, 95%CI:0.579~0.861, P_FDR=0.002)。结论 ACEIs 在东亚与欧洲人群中均可能增加部分眼部疾病风险;BBs 在东亚人群中可能降低老年白内障风险;HMGCR 抑制剂在欧洲人群中可能增加白内障风险;NPC1L1 抑制剂在欧洲人群中可能降低青光眼风险;PCSK9 抑制剂对眼部疾病的效应呈现种族差异。

Abstract

Objective To investigate the causal associations between commonly used antihypertensive and lipid-lowering drugs and prevalent ocular diseases in East Asian and European populations using drug-target Mendelian randomization (MR). Methods This cross-ancestry drug-target MR study utilized publicly available genome-wide association study (GWAS) summary data from the GWAS Catalog. Five classes of antihypertensive drugs, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β-blockers (BBs), calcium channel blockers (CCBs), and thiazide diuretics (TDs), and three classes of lipid-lowering drugs, including 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and Niemann–Pick C1-like 1 (NPC1L1) inhibitors were selected as exposures. Six common ocular diseases (senile cataract, glaucoma, dry eye syndrome, visual impairment, presbyopia, and myopia) were defined as outcomes. Inverse variance weighted (IVW) was employed as the primary analytical method, supplemented by seven additional MR methods for findings with statistically significant correlation. Sensitivity analyses were conducted using Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis. Results In East Asian populations, ACEIs were causally associated with increased risks of myopia (OR =1.024, 95%CI: 1.010-1.038, P_FDR =0.002), senile cataract (OR=1.022, 95%CI: 1.019-1.024, P_FDR<0.001), and glaucoma (OR=1.017, 95%CI: 1.011-1.023, P_FDR<0.001); BBs were associated with reduced risk of senile cataract (OR =0.994, 95%CI: 0.989-0.999, P_FDR = 0.034); PCSK9 inhibitors were associated with reduced risks of presbyopia (OR=0.993, 95%CI: 0.986-0.997, P_FDR = 0.003) and visual impairment (OR=0.996, 95%CI: 0.992-0.999, P_FDR =0.048). In European populations, ACEIs were associated with increased glaucoma risk (OR=1.088, 95%CI: 1.029-1.152, P_FDR =0.016); HMGCR inhibitors were associated with increased senile cataract risk (OR=1.194, 95%CI: 1.049-1.359, P_FDR =0.022); PCSK9 inhibitors were associated with increased risks of dry eye syndrome ( OR =1.106, 95%CI: 1. 039-1. 176, P_FDR =0. 004) and presbyopia (OR=1.082, 95%CI: 1.024-1.145, P_FDR =0.017), but with reduced glaucoma risk (OR=0.892, 95%CI: 0.822-0.968, P_FDR =0.018); NPC1L1 inhibitors were associated with reduced glaucoma risk ( OR =0.706, 95%CI: 0.579-0.861, P_FDR =0.002). Conclusion ACEIs may increase risks of certain ocular diseases in both East Asian and European populations. BBs may reduce senile cataract risk in East Asians. HMGCR inhibitors may increase cataract risk in Europeans, while NPC1L1 inhibitors may reduce glaucoma risk in Europeans. The effects of PCSK9 inhibitors on ocular diseases exhibit ethnic differences.

关键词

药物靶点孟德尔随机化 / 降压药 / 降脂药 / 眼部疾病

Key words

Drug target Mendelian randomization / Antihypertensive drugs / Lipid-lowering drugs / Ocular diseases

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基金资助

国家自然科学基金(82373686)

中央高校青年教师科研创新能力支持项目(SRICSPYF-ZY2025123)

山东省自然科学基金(ZR2024JQ029)

山东省泰山学者项目(tsqn202211025)