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. 2023 Jul 3;28(1):215.
doi: 10.1186/s40001-023-01147-x.

Association between leptin and NAFLD: a two-sample Mendelian randomization study

Ziwei Guo  1   2 , Hongbo Du  1   3 , Yi Guo  1   3 , Qian Jin  1   2 , Ruijia Liu  1   2 , Zhangjun Yun  1   2 , Jiaxin Zhang  4   5 , Xiaoke Li  6   7 , Yong'an Ye  8   9
Affiliations

Association between leptin and NAFLD: a two-sample Mendelian randomization study

Ziwei Guo et al. Eur J Med Res. .

Abstract

Background: The etiology of nonalcoholic fatty liver disease (NAFLD) involves a complex interaction of genetic and environmental factors. Previous observational studies have revealed that higher leptin levels are related to a lower risk of developing NAFLD, but the causative association remains unknown. We intended to study the causal effect between leptin and NAFLD using the Mendelian randomization (MR) study.

Methods: We performed a two-sample Mendelian randomization (TSMR) analysis using summary GWAS data from leptin (up to 50,321 individuals) and NAFLD (8,434 cases and 770,180 controls) in a European population. Instrumental variables (IVs) that satisfied the three core assumptions of Mendelian randomization were selected. The TSMR analysis was conducted using the inverse variance weighted (IVW) method, MR-Egger regression method, and weighted median (WM) method. To ensure the accuracy and stability of the study results, heterogeneity tests, multiple validity tests, and sensitivity analyses were conducted.

Results: The findings of the TSMR correlation analysis between NAFLD and leptin were as follows: IVW method (odds ratio (OR) 0.6729; 95% confidence interval (95% CI) 0.4907-0.9235; P = 0.0142), WM method (OR 0.6549; 95% CI 0.4373-0.9806; P = 0.0399), and MR-Egger regression method (P = 0.6920). Additionally, the findings of the TSMR correlation analysis between NAFLD and circulating leptin levels adjusted for body mass index (BMI) were as follows: IVW method (OR 0.5876; 95% CI 0.3781-0.9134; P = 0.0181), WM method (OR 0.6074; 95% CI 0.4231-0.8721; P = 0.0069), and MR-Egger regression method (P = 0.8870). It has also been shown that higher levels of leptin are causally linked to a lower risk of developing NAFLD, suggesting that leptin may serve as a protective factor for NAFLD.

Conclusions: Using TSMR analysis and the GWAS database, we investigated the genetic relationship between elevated leptin levels and lowered risk of NAFLD in this study. However, further research is required to understand the underlying mechanisms.

Keywords: Causal effect; Leptin; Nonalcoholic fatty liver disease; Two-sample Mendelian randomization.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Workflow of this Mendelian randomization study. GWAS, genome-wide association study
Fig. 2
Fig. 2
Basic assumptions of Mendelian randomization. IV1: IVs are strongly correlated with exposure. IV2: IVs are independent of outcomes. IV3: IVs are not related to confounding factors
Fig. 3
Fig. 3
TSMR analysis. The intercept estimate can be interpreted as an estimate of the average pleiotropy of all SNPs, and the slope coefficient estimates the causal effect’s bias. a Leptin; b circulating leptin levels adjusted for BMI
Fig. 4
Fig. 4
Forest plots for the TSMR leave-one-out analysis of the significant IVW estimates. Within each panel, the black points represent the causal estimate of the association between a specific metabolite and epilepsy after discarding each SNP in turn. Red points represent the pooled IVW estimates. Horizontal lines denote 95% confidence intervals(CI). a Leptin; b circulating leptin levels adjusted for BMI
See this image and copyright information in PMC

References

    1. Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, Wai-Sun Wong V, Yilmaz Y, George J, Fan J, et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2019;69(6):2672–2682. doi: 10.1002/hep.30251. - DOI - PubMed
    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi: 10.1002/hep.28431. - DOI - PubMed
    1. Yin X, Guo X, Liu Z, Wang J. Advances in the diagnosis and treatment of non-alcoholic fatty liver disease. Int J Mol Sci. 2023;24(3):2844. doi: 10.3390/ijms24032844. - DOI - PMC - PubMed
    1. Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58(11):1538–1544. doi: 10.1136/gut.2008.171280. - DOI - PMC - PubMed
    1. Paternostro R, Trauner M. Current treatment of non-alcoholic fatty liver disease. J Intern Med. 2022;292(2):190–204. doi: 10.1111/joim.13531. - DOI - PMC - PubMed

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