Multi-biobank Mendelian randomization analyses identify opposing pathways in plasma low-density lipoprotein-cholesterol lowering and gallstone disease

被引：0

作者：

Yang, Guoyi ^{[1
,2
]}

Mason, Amy M. ^{[3
,4
]}

Gill, Dipender ^{[5
]}

Schooling, C. Mary ^{[1
,6
]}

Burgess, Stephen ^{[2
,3
]}

机构：

[1] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Hong Kong, Peoples R China

[2] Univ Cambridge, MRC Biostat Unit, Cambridge, England

[3] Univ Cambridge, British Heart Fdn, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England

[4] Univ Cambridge, Victor Phillip Dahdaleh Heart & Lung Res Inst, Cambridge, England

[5] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[6] CUNY, Grad Sch Publ Hlth & Hlth Policy, New York, NY USA

来源：

EUROPEAN JOURNAL OF EPIDEMIOLOGY | 2024年 / 39卷 / 08期

基金：

英国医学研究理事会; 英国惠康基金; 英国经济与社会研究理事会;

关键词：

LDL-cholesterol; Gallstone disease; Drug-target Mendelian randomization; Clustered Mendelian randomization; GENETIC-VARIANTS; URSODEOXYCHOLIC ACID; WIDE ASSOCIATION; STATIN USE; RISK; INSTRUMENTS; HEART; TRANSPORTER; SIMVASTATIN; INHIBITION;

D O I：

10.1007/s10654-024-01141-5

中图分类号：

R1 [预防医学、卫生学];

学科分类号：

1004 ; 120402 ;

摘要：

Plasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation. Different plasma LDL-cholesterol lowering pathways may have distinct effects on biliary cholesterol and thereby gallstone disease risk. We conducted a Mendelian randomization (MR) study using data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). We first performed drug-target MR analyses substantiated by colocalization to investigate the effects of plasma LDL-cholesterol lowering therapies on gallstone disease risk. We then performed clustered MR analyses and pathway analyses to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease risk. For a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower gallstone disease risk (odds ratio 0.72 [95% confidence interval 0.62, 0.83]), but genetic mimics of PCSK9 inhibitors and targeting apolipoprotein B were associated with higher risk (1.11 [1.03, 1.19] and 1.23 [1.13, 1.35]). The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease risk, with some evidence for ancestry-and sex-specific associations. Among variants lowering plasma LDL-cholesterol, those associated with lower gallstone disease risk were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher risk were mapped to pathways relating to plasma lipoprotein assembly, remodelling, and clearance and ATP-binding cassette transporters. This MR study provides genetic evidence that different plasma LDL-cholesterol lowering pathways have opposing effects on gallstone disease risk.

引用

页码：857 / 867

页数：11