Associations between body circumference and testosterone levels and risk of metabolic dysfunction-associated fatty liver disease: a mendelian randomization study

Abstract

Backgroud: Body circumference and testosterone levels have been reported as associated with metabolic dysfunction-associated fatty liver disease (MAFLD) risk. However, whether body circumference and testosterone levels play a role in the development of MAFLD remains inconclusive.

Methods: Using a large database of genome-wide association studies, genetic loci that are independent of each other and strongly associated with body circumference and testosterone levels were selected as instrumental variables, the causal relationship between body circumference and testosterone and risk of MAFLD was investigated by two-sample Mendelian randomization methods such as inverse variance weighted (IVW), MR-Egger regression, and weighted median estimator (WME), using the odds ratios (ORs) as evaluation indicators.

Results: A total of 344 SNPs were included as instrumental variables in this study, including 180 for waist circumference, 29 for waist-to-hip ratio, and 135 for testosterone levels. Using the above two-sample Mendelian Randomization method to derive the causal association between exposure and outcome. The results of this study showed that three exposure factors were causally associated with the risk of MAFLD. Waist circumference obtained three statistically significant results for IVW, WME and Weighted mode (IVW: OR = 3.53, 95%CI: 2.23-5.57, P < 0.001; WME: OR = 3.88, 95%CI: 1.81-8.29, P < 0.001; Weighted mode: OR = 3.58, 95%CI: 1.05-12.16, P = 0.043). Waist-to-hip ratio obtained one statistically significant result for IVW (OR = 2.29, 95%CI: 1.12-4.66, P = 0.022). Testosterone levels obtained one statistically significant result for IVW (OR = 1.93, 95%CI: 1.30-2.87, P = 0.001). Waist circumference, waist-to-hip ratio and testosterone level were considered as risk factors for MAFLD. The Cochran Q test for IVW and MR-Egger method indicated that there was no intergenic heterogeneity in SNPs. The test for pleiotropy indicated that the possibility of pleiotropy in the causal analysis was weak.

Conclusion: The results of the two-sample Mendelian randomization analysis showed that waist circumference was the exact risk factor for MAFLD, waist-to-hip ratio and testosterone levels were potential risk factors for MAFLD, the risk of developing MAFLD increases with these three exposure factors.

Keywords: Causal Inference6; Hip circumference2; Metabolic dysfunction-associated fatty liver disease4; Testosterone3; Two-sample mendelian randomization analysis5; Waist circumference1.