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

Ziang Li; Bin Zhang; Qingrong Liu; Zhihang Tao; Lu Ding; Bo Guo; Erli Zhang; Haitong Zhang; Zhen Meng; Shuai Guo; Yang Chen; Jia Peng; Jinyue Li; Can Wang; Yingbo Huang; Haiyan Xu; Yongjian Wu

doi:10.1016/j.ebiom.2023.104543

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

EBioMedicine. 2023 Apr:90:104543. doi: 10.1016/j.ebiom.2023.104543. Epub 2023 Mar 30.

Authors

Ziang Li¹, Bin Zhang¹, Qingrong Liu², Zhihang Tao³, Lu Ding⁴, Bo Guo⁵, Erli Zhang², Haitong Zhang⁶, Zhen Meng⁷, Shuai Guo¹, Yang Chen¹, Jia Peng⁸, Jinyue Li⁹, Can Wang¹, Yingbo Huang¹⁰, Haiyan Xu¹¹, Yongjian Wu¹²

Affiliations

¹ State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
² Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
³ State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
⁵ Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁶ Department of Cardiology, the Third-Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
⁷ Department of Cardiology, China-Japan Friendship Hospital, Beijing, China.
⁸ Department of Cardiology, the First-Affiliated Hospital, Xiangya Hospital Central South University, Changsha, China.
⁹ Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹⁰ State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹¹ Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Electronic address: xuhaiyan@fuwaihospital.org.
¹² Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Electronic address: wuyongjian@fuwaihospital.org.

Abstract

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 × 10^-8; OR₂ = 0.57 [95% CI 0.39-0.82], p₂ = 3.00 × 10^-3). A significant MR association (OR = 0.71 [95% CI, 0.58-0.87], p = 1.20 × 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.

Funding: Capital's Funds for Health Improvement and Research (2022-4-4037). CAMS Innovation Fund for Medical Sciences (CIFMS, grant number: 2021-I2M-C&T-A-010).

Keywords: LDL-C; Mendelian randomization; Statins; TG; eQTL.

MeSH terms

Diabetes Mellitus, Type 2* / drug therapy
Diabetes Mellitus, Type 2* / genetics
Genome-Wide Association Study / methods
Humans
Lipids
Mendelian Randomization Analysis / methods
Non-alcoholic Fatty Liver Disease* / etiology
Non-alcoholic Fatty Liver Disease* / genetics
Polymorphism, Single Nucleotide
Risk Factors

Substances

Lipids