Do iron homeostasis biomarkers mediate the associations of liability to type 2 diabetes and glycemic traits in liver steatosis and cirrhosis: a two-step Mendelian randomization study

Background Previous studies, including Mendelian randomization (MR), have demonstrated type 2 diabetes (T2D) and glycemic traits are associated with increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD). However, few studies have explored the underlying pathway, such as the role of iron homeostasis.MethodsWe used a two-step MR approach to investigate the associations of genetic liability to T2D, glycemic traits, iron biomarkers, and liver diseases. We analyzed summary statistics from various genome-wide association studies of T2D (n = 933,970), glycemic traits (n <= 209,605), iron biomarkers (n <= 246,139), MASLD (n <= 972,707), and related biomarkers (alanine aminotransferase (ALT) and proton density fat fraction (PDFF)). Our primary analysis was based on inverse-variance weighting, followed by several sensitivity analyses. We also conducted mediation analyses and explored the role of liver iron in post hoc analysis.ResultsGenetic liability to T2D and elevated fasting insulin (FI) likely increased risk of liver steatosis (ORliability to T2D: 1.14 per doubling in the prevalence, 95% CI: 1.10, 1.19; ORFI: 3.31 per log pmol/l, 95% CI: 1.92, 5.72) and related biomarkers. Liability to T2D also likely increased the risk of developing liver cirrhosis. Genetically elevated ferritin, serum iron, and liver iron were associated with higher risk of liver steatosis (ORferritin: 1.25 per SD, 95% CI 1.07, 1.46; ORliver iron: 1.15 per SD, 95% CI: 1.05, 1.26) and liver cirrhosis (ORserum iron: 1.31, 95% CI: 1.06, 1.63; ORliver iron: 1.34, 95% CI: 1.07, 1.68). Ferritin partially mediated the association between FI and liver steatosis (proportion mediated: 7%, 95% CI: 2-12%).ConclusionsOur study provides credible evidence on the causal role of T2D and elevated insulin in liver steatosis and cirrhosis risk and indicates ferritin may play a mediating role in this association. center dot Ferritin possibly mediates the association of insulin resistance in liver steatosis. Targeting the reduction of ferritin may mitigate the risk of liver steatosis arising from elevated insulin.center dot Liver iron is likely to be positively associated with liver steatosis and the irreversible stage, liver cirrhosis, and mediates the association of ferritin and liver steatosis.center dot Genetically elevated HbA1c is shown to decrease the risk of liver steatosis due to its erythrocytic property. Caution should be applied when using HbA1c values for MASLD management.