The hepato-ovarian axis: genetic evidence for a causal association between non-alcoholic fatty liver disease and polycystic ovary syndrome

BMC Medicine

Research Article

Jian-Gao Fan¹  Xue Gao²  Xiong-Fei Pan³  Dong Liu⁴  Fei Li⁵  Jian Zhao⁶  Tao Zhou⁷  Giovanni Targher⁸  Cairong Zhu⁹ 

[1] Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China;Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China;Ministry of Education Key Laboratory of Birth Defects and Related Diseases in Women and Children, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China;Shuangliu Institute of Women’s and Children’s Health, Shuangliu Maternal and Child Health Hospital, Chengdu, Sichuan, China;Ministry of Education and Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, 200092, Shanghai, China;Ministry of Education and Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, 200092, Shanghai, China;Department of Developmental and Behavioral Pediatric & Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;Department of Maternal and Child Health, School of Public Health, Shanghai Jiao Tong University, Shanghai, China;Ministry of Education and Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, 200092, Shanghai, China;Department of Maternal and Child Health, School of Public Health, Shanghai Jiao Tong University, Shanghai, China;MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK;School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China;Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy;West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China;

关键词: Non-alcoholic fatty liver disease;    Polycystic ovary syndrome;    Mendelian randomization;    Fasting insulin;    Sex hormones;    Hepato-ovarian axis;   

DOI  :  10.1186/s12916-023-02775-0

 received in 2022-10-08, accepted in 2023-02-09,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundRecent studies found associations between non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS), but the causal nature of this association is still uncertain.MethodsWe performed a bidirectional two-sample Mendelian randomization (MR) analysis to test for the causal association between NAFLD and PCOS using data from a large-scale biopsy-confirmed NAFLD genome-wide association study (GWAS) (1483 cases and 17,781 controls) and PCOS GWAS (10,074 cases and 103,164 controls) in European ancestries. Data from glycemic-related traits GWAS (in up to 200,622 individuals) and sex hormones GWAS (in 189,473 women) in the UK Biobank (UKB) were used in the MR mediation analysis to assess potential mediating roles of these molecules in the causal pathway between NAFLD and PCOS. Replication analysis was conducted using two independent datasets from NAFLD and PCOS GWASs in the UKB and a meta-analysis of data from FinnGen and the Estonian Biobank, respectively. A linkage disequilibrium score regression was conducted to assess genetic correlations between NAFLD, PCOS, glycemic-related traits, and sex hormones using full summary statistics.ResultsIndividuals with higher genetic liability to NAFLD were more likely to develop PCOS (OR per one-unit log odds increase in NAFLD: 1.10, 95% CI: 1.02–1.18; P = 0.013). Indirect causal effects of NAFLD on PCOS via fasting insulin only (OR: 1.02, 95% CI: 1.01–1.03; P = 0.004) and further a suggestive indirect causal effect via fasting insulin in concert with androgen levels were revealed in MR mediation analyses. However, the conditional F statistics of NAFLD and fasting insulin were less than 10, suggesting likely weak instrument bias in the MVMR and MR mediation analyses.ConclusionsOur study suggests that genetically predicted NAFLD was associated with a higher risk of developing PCOS but less evidence for vice versa. Fasting insulin and sex hormones might mediate the link between NAFLD and PCOS.

【 授权许可】

CC BY   
© The Author(s) 2023

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