Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease

被引：76

作者：

Li, Ziang ^{[1
]}

Zhang, Bin ^{[1
]}

Liu, Qingrong ^{[2
]}

Tao, Zhihang ^{[3
]}

Ding, Lu ^{[4
]}

Guo, Bo ^{[5
]}

Zhang, Erli ^{[2
]}

Zhang, Haitong ^{[6
]}

Meng, Zhen ^{[7
]}

Guo, Shuai ^{[1
]}

Chen, Yang ^{[1
]}

Peng, Jia ^{[8
]}

Li, Jinyue ^{[9
,10
]}

Wang, Can ^{[1
]}

Huang, Yingbo ^{[11
]}

Xu, Haiyan ^{[2
]}

Wu, Yongjian ^{[2
]}

机构：

[1] Chinese Acad Med Sci & Peking Union Med Coll, Natl Ctr Cardiovasc Dis, State Key Lab Cardiovasc Dis, Dept Cardiol,Fuwai Hosp, Beijing, Peoples R China

[2] Chinese Acad Med Sci & Peking Union Med Coll, Dept Cardiol, Natl Ctr Cardiovasc Dis, Fuwai Hosp, Beijing, Peoples R China

[3] Shanghai Jiao Tong Univ, Shanghai Inst Digest Dis, Div Gastroenterol & Hepatol,Key Lab Gastroenterol, Renji Hosp,Sch Med,Minist Hlth,State Key Lab Onco, Shanghai, Peoples R China

[4] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Endocrinol, Key Lab Endocrinol,Minist Hlth, Beijing, Peoples R China

[5] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Gen Surg, Beijing, Peoples R China

[6] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Cardiol, Guangzhou, Peoples R China

[7] China Japan Friendship Hosp, Dept Cardiol, Beijing, Peoples R China

[8] Cent South Univ, Affiliated Hosp 1, Dept Cardiol, Xiangya Hosp, Changsha, Peoples R China

[9] Chinese Acad Med Sci & Peking Union Med Coll, Fuwai Hosp, Natl Ctr Cardiovasc Dis, Key Lab Cardiovasc Epidemiol, Beijing, Peoples R China

[10] Chinese Acad Med Sci & Peking Union Med Coll, Natl Ctr Cardiovasc Dis, Dept Epidemiol, State Key Lab Cardiovasc Dis,Fuwai Hosp, Beijing, Peoples R China

[11] Chinese Acad Med Sci & Peking Union Med Coll, State Key Lab Cardiovasc Dis, Fuwai Hosp, Natl Ctr Cardiovasc Dis, Beijing, Peoples R China

来源：

EBIOMEDICINE | 2023年 / 90卷

关键词：

Mendelian randomization; Statins; TG; LDL-C; eQTL; HMG-COA REDUCTASE; MENDELIAN RANDOMIZATION; LIPOPROTEIN-LIPASE; INHIBITION; LDL; STEATOHEPATITIS; EPIDEMIOLOGY; PROTEIN-3; EVENTS; PCSK9;

D O I：

10.1016/j.ebiom.2023.104543

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Some observational studies found that dyslipidaemia is a risk factor for non-alcoholic fatty liver disease (NAFLD), and lipid-lowering drugs may lower NAFLD risk. However, it remains unclear whether dyslipidaemia is causative for NAFLD. This Mendelian randomisation (MR) study aimed to explore the causal role of lipid traits in NAFLD and evaluate the potential effect of lipid-lowering drug targets on NAFLD.Methods Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for NAFLD were obtained from two independent GWAS datasets. Lipid-lowering drug targets that reached significance were further tested using expression quantitative trait loci data in relevant tissues. Colocalisation and mediation analyses were performed to validate the robustness of the results and explore potential mediators.Findings No significant effect of lipid traits and eight lipid-lowering drug targets on NAFLD risk was found. Genetic mimicry of lipoprotein lipase (LPL) enhancement was associated with lower NAFLD risks in two independent datasets (OR1 = 0.60 [95% CI 0.50-0.72], p1 = 2.07 x 10-8; OR2 = 0.57 [95% CI 0.39-0.82], p2 = 3.00 x 10-3). A significant MR association (OR = 0.71 [95% CI, 0.58-0.87], p = 1.20 x 10-3) and strong colocalisation association (PP.H4 = 0.85) with NAFLD were observed for LPL expression in subcutaneous adipose tissue. Fasting insulin and type 2 diabetes mediated 7.40% and 9.15%, respectively, of the total effect of LPL on NAFLD risk.Interpretation Our findings do not support dyslipidaemia as a causal factor for NAFLD. Among nine lipid-lowering drug targets, LPL is a promising candidate drug target in NAFLD. The mechanism of action of LPL in NAFLD may be independent of its lipid-lowering effects. Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

引用

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