Evaluating the efficacy of GIPR agonists on non-alcoholic fatty liver disease: A Mediation Mendelian Randomization Study

Siyuan Xie; Delong Chen; Yangke Cai; Liyi Xu; Oulan Liao; Xuan Jia; Xiaowei Ji; Hanwen Chen; Jianshan Mao; Jianting Cai

doi:10.1016/j.dld.2024.04.022

Evaluating the efficacy of GIPR agonists on non-alcoholic fatty liver disease: A Mediation Mendelian Randomization Study

Dig Liver Dis. 2024 May 11:S1590-8658(24)00725-4. doi: 10.1016/j.dld.2024.04.022. Online ahead of print.

Authors

Siyuan Xie¹, Delong Chen², Yangke Cai¹, Liyi Xu¹, Oulan Liao³, Xuan Jia¹, Xiaowei Ji¹, Hanwen Chen¹, Jianshan Mao⁴, Jianting Cai⁵

Affiliations

¹ Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China.
² Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China.
³ Department of Gastroenterology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang Province, PR China.
⁴ Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China. Electronic address: jshmao@zju.edu.cn.
⁵ Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China. Electronic address: jtcai6757@zju.edu.cn.

PMID: 38735797
DOI: 10.1016/j.dld.2024.04.022

Abstract

Objective: Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide while still lacks drugs for treatment or prevention. We aimed to investigate the causal role of glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs) on NAFLD and identify the mediated risk factors by which GIPRAs exert their therapeutic effects.

Methods: Genetic proxies of GIPRAs were identified as cis-SNPs of GIPR associated with both the gene expression level and HbA1c and analyses including colocalization and linkage disequilibrium (LD) were performed for validation. We then performed two-sample two-step mendelian randomization to determine the causal effect of GIPRAs on NAFLD.

Results: The MR analysis suggested genetic proxies of GIPRAs were causally associated with reduced risk of NAFLD (Odds ratio (OR): 0.46, 95 % confidence interval (95 % CI): 0.24-0.88, P = 0.02) and T2DM (OR: 0.10, 95 % CI: 0.07-0.13, P < 0.01). In addition, Mediation analysis showed evidence of indirect effect of GIPRAs on NAFLD via TRIG (0.88, [0.85-0.92], P < 0.01) and HDL-C (0.85, [0.80-0.90], P < 0.01).

Conclusions: Our study provided strong evidence to support the causal role of GIPRAs on reducing the risk of NAFLD probably through improving lipid metabolism, especially TG and HDL-C, providing guidance for future clinical trials.

Keywords: Genetic epidemiology; Glucose-dependent insulinotropic polypeptide receptor; Lipoprotein; Mendelian randomization; Nonalcoholic fatty liver disease.