脂质和降脂药物靶点基因与非酒精性脂肪性肝病的遗传关联。

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

机构信息

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.

Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

出版信息

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

DOI:10.1016/j.ebiom.2023.104543

PMID:37002989

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10070091/

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 (OR = 0.60 [95% CI 0.50-0.72], p = 2.07 × 10; OR = 0.57 [95% CI 0.39-0.82], p = 3.00 × 10). A significant MR association (OR = 0.71 [95% CI, 0.58-0.87], p = 1.20 × 10) and strong colocalisation association (PP.H = 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).

摘要

背景

一些观察性研究发现血脂异常是非酒精性脂肪性肝病（NAFLD）的一个危险因素，降脂药物可能降低 NAFLD 风险。然而，血脂异常是否是 NAFLD 的病因仍不清楚。本孟德尔随机化（MR）研究旨在探讨脂质特征与 NAFLD 的因果关系，并评估降脂药物靶点对 NAFLD 的潜在影响。

方法

从全球脂质遗传学联合会全基因组关联研究（GWAS）中提取与脂质特征相关的遗传变异和编码降脂药物靶点的基因变异。从两个独立的 GWAS 数据集获得 NAFLD 的汇总统计数据。使用相关组织中的表达数量性状基因座数据进一步测试达到显著性的降脂药物靶点。进行共定位和中介分析，以验证结果的稳健性并探索潜在的中介物。

结果

未发现脂质特征和八种降脂药物靶点对 NAFLD 风险有显著影响。脂蛋白脂肪酶（LPL）增强的遗传模拟与两个独立数据集的较低 NAFLD 风险相关（OR=0.60[95%CI 0.50-0.72]，p=2.07×10；OR=0.57[95%CI 0.39-0.82]，p=3.00×10）。LPL 在皮下脂肪组织中的表达与 NAFLD 存在显著的 MR 关联（OR=0.71[95%CI，0.58-0.87]，p=1.20×10）和强烈的共定位关联（PP.H=0.85）。空腹胰岛素和 2 型糖尿病分别介导了 LPL 对 NAFLD 风险的总效应的 7.40%和 9.15%。