Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases

Zhenqiu Liu; Chen Suo; Hong Fan; Tiejun Zhang; Li Jin; Xingdong Chen

doi:10.1016/j.metabol.2022.155270

Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases

Metabolism. 2022 Oct:135:155270. doi: 10.1016/j.metabol.2022.155270. Epub 2022 Jul 29.

Authors

Zhenqiu Liu¹, Chen Suo², Hong Fan², Tiejun Zhang², Li Jin¹, Xingdong Chen³

Affiliations

¹ State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai 200438, China; Fudan University Taizhou Institute of Health Sciences, Taizhou 225316, China.
² Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, Shanghai 200032, China; Department of Epidemiology, School of Public Health, Fudan University, Shanghai 200032, China.
³ State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai 200438, China; Fudan University Taizhou Institute of Health Sciences, Taizhou 225316, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: xingdongchen@fudan.edu.cn.

PMID: 35914620
DOI: 10.1016/j.metabol.2022.155270

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide and is associated with the risk of many extrahepatic diseases. However, whether NAFLD is a risk marker or a common cause of extrahepatic diseases is unclear.

Methods: We searched PubMed to identify NAFLD-related extrahepatic diseases. Genetic instrumental variables (IVs) for NAFLD surrogated by chronically elevated alanine transaminase levels and eligible extrahepatic diseases were retrieved from the corresponding genome-wide association analysis. We proposed a procedure for Mendelian randomization (MR) analysis and performed validation analyses to dissect the association between NAFLD and extrahepatic diseases. The Bonferroni method was used to correct the bias of multiple testing.

Results: In total, 34 extrahepatic diseases were included and 54 SNPs were used as IVs for NAFLD. The MR analysis gave a robust and significant (or suggestive) estimate for the association between NAFLD and 9 extrahepatic diseases: type 2 diabetes (odds ratio [OR] = 1.182, 95 % confidence interval [CI] 1.125-1.243, P = 5.40 × 10^-11), cholelithiasis (OR = 1.171, 95%CI 1.083-1.266, P = 7.47 × 10^-5), diabetic hypoglycemia (OR = 1.170, 95%CI 1.071-1.279, P = 5.14 × 10^-4), myocardial infarction (OR = 1.122, 95%CI 1.057-1.190, P = 1.46 × 10^-4), hypertension (OR = 1.060, 95%CI 1.029-1.093, P = 1.18 × 10^-4), coronary artery disease (OR = 1.052, 95%CI 1.010-1.097, P = 1.58 × 10^-2), heart failure (OR = 1.047, 95%CI 1.006-1.090, P = 2.44 × 10^-2), dementia (OR = 0.881, 95%CI 0.806-0.962, P = 5.01 × 10^-3), and pancreatic cancer (OR = 0.802, 95%CI 0.654-0.983, P = 3.32 × 10^-2). Validation analyses using IVs from biopsy-confirmed and imaging-determined NAFLD reported similar results to the main analysis. For the remaining 25 outcomes, no significant or definitive association was yielded in MR analysis.

Conclusions: Genetic evidence suggests putative causal relationships between NAFLD and a set of extrahepatic diseases, indicating that NAFLD deserves high priority in clinical practice.

Keywords: Causal relationship; Extrahepatic diseases; Mendelian randomization; NAFLD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine Transaminase
Diabetes Mellitus, Type 2* / genetics
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Non-alcoholic Fatty Liver Disease* / genetics

Substances

Alanine Transaminase