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

• Published in: BMC medicine Vol. 22; no. 1; pp. 270 - 13
• Main Authors: Liang, Ying, Luo, Shan, Bell, Steven, Mo, Jacky Man Yuen, He, Baoting, Zhou, Yangzhong, Bai, Xiaoyin, Au Yeung, Shiu Lun
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26.06.2024; BioMed Central; BMC
• Subjects: Alanine; Alanine transaminase; Biological markers; Biomarkers; Biomarkers - blood; Blood Glucose - metabolism; Cardiovascular disease; Cirrhosis; Consortia; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Estimates; Fatty liver; Fatty Liver - genetics; Ferritin; Genetic analysis; Genetic aspects; Genome-wide association studies; Genome-Wide Association Study; Genomics; Glucose; Glycemic traits; Health aspects; Homeostasis; Humans; Insulin; Insulin resistance; Iron; Iron - blood; Iron - metabolism; Iron compounds; Liability; Liability (Law); Liver; Liver cirrhosis; Liver Cirrhosis - genetics; Liver diseases; Liver iron; Liver steatosis; Magnetic resonance imaging; Mediation; Medical research; Medicine, Experimental; Mendelian Randomization Analysis; Meta-analysis; Observational studies; Physiological aspects; Proton density (concentration); Randomization; Risk; Sensitivity analysis; Statistical analysis; Steatosis; Type 2 diabetes; Variance analysis; China; Type 2 diabetes; Ferritin; Glycemic traits; Insulin; Liver cirrhosis; Liver iron; Liver steatosis
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-024-03486-w

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. We 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. Genetic liability to T2D and elevated fasting insulin (FI) likely increased risk of liver steatosis (OR : 1.14 per doubling in the prevalence, 95% CI: 1.10, 1.19; OR : 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 (OR : 1.25 per SD, 95% CI 1.07, 1.46; OR : 1.15 per SD, 95% CI: 1.05, 1.26) and liver cirrhosis (OR : 1.31, 95% CI: 1.06, 1.63; OR : 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%). Our 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.