The relationship between sex hormone‐binding protein and non‐alcoholic fatty liver disease using Mendelian randomisation

Abstract

BackgroundThe incidence of non‐alcohol fatty liver disease (NAFLD) has been increasing annually with the improvement of living standards. Numerous epidemiological observations have linked sex hormone‐binding protein (SHBG) levels to NAFLD. However, evidence of the causal role of SHBG in the development and progression of NAFLD is still absent. Therefore, a systematic assessment of the causal relationship is needed.MethodA two‐sample Mendelian randomisation (MR) analysis was conducted. Genome‐wide association study (GWAS) data for SHBG were obtained online from the IEU database (ebi‐a‐GCST90012111) as exposure. GWAS data from the NAFLD of the Finngen consortium were used for preliminary analysis, while NAFLD data from another GWAS involving 8434 participants were used for replication and meta‐analyses. Causal effects were investigated with inverse variance weighted (IVW), weighted median and MR–Egger regression. Sensitivity analyses including Cochran's Q test, leave‐one‐out analysis and MR–Egger intercept analysis were simultaneously conducted to assess heterogeneity and pleiotropy.ResultsAfter rigorous selection, 179 single‐nucleotide polymorphisms (SNPs) were identified as strongly correlated instrumental variables. Preliminary analysis suggested a significant causal relationship between genetically determined serum SHBG levels and NAFLD [odds ratio (OR) IVW = .54, 95% confidence interval (CI) = .30–.98, p = .043], supported by the results of the replication analysis (ORIVW = .61, 95% CI = .46–.81, p = .0006) and further meta‐analysis (OR = .59, 95% CI = .46–.77, p < .0001).ConclusionThe genetic tendency to high levels of SHBG was causally correlated with a reduced risk of NAFLD, indicating that circulating high levels of SHBG was a protective factor for NAFLD.

Endogenous sex hormones and nonalcoholic fatty liver disease in US adults

“…First, a cross‐sectional design was used, which resulted in limitations in our conclusions regarding the temporal causality. A recent Mendelian randomization analysis showed that the genetic tendency to higher SHBG levels was causally associated with a lower risk of NAFLD, indicating that elevated circulating levels of SHBG provide protection against NAFLD 53 . Future prospective studies are needed to confirm these temporal causalities between sex hormones and NAFLD.…”

“…A recent Mendelian randomization analysis showed that the genetic tendency to higher SHBG levels was causally associated with a lower risk of NAFLD, indicating that elevated circulating levels of SHBG provide protection against NAFLD. 53 Future prospective studies are needed to confirm these temporal causalities between sex hormones and NAFLD. Second, regarding the definition of NAFLD, we employed two noninvasive panels for NAFLD in the absence of known causes of other liver diseases or the absence of steatogenic medications, which may underestimate and misclassify the true prevalence of NAFLD.…”

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

“…Concerning lipid metabolism, the overexpression of SHBG protects against the development of MAFLD, inhibiting hepatic lipogenesis by controlling the main lipogenic enzymes. In this sense, the genetic tendency to high levels of transcription of the hepatokine SHBG was causally correlated with a lower risk of developing MAFLD [138,172]. Therefore, fat accumulation reduces the production of SHBG, increasing hepatic lipogenesis and exacerbating the development of MAFLD [40,43,173].…”