Appraising the causal effects of circulating micronutrients on liver cirrhosis: Evidence from large‐scale Mendelian randomization analysis

Abstract Aims Observational research has identified links between micronutrient levels and chronic liver disease. However, the lack of randomized controlled experiments has impeded the ability to establish a cause‐and‐effect connection regarding micronutrients and cirrhosis of the liver. This Mendelian randomization (MR) analysis aimed to examine the causal impact of micronutrients on liver cirrhosis. Methods We selected genetic instrumental variables related to 12 micronutrients from genome‐wide studies on individuals of European descent, covering an array of over 9,851,867 single nucleotide polymorphisms and 460,351 participants. Data from patients with cirrhosis in the FinnGen database ( https://www.finngen.fi/fi ) were used. A two‐sample MR approach was employed to establish genetically causal estimates. Primary analyses used random effects and inverse variance weighted (IVW) methods, with additional sensitivity analyses for validation. MR–Egger intercept analysis and Cochran's Q test assessed horizontal pleiotropy and heterogeneity. Furthermore, multivariable Mendelian randomization (MVMR) was conducted to address potential confounding variables. Results IVW and weighted median methods showed that most micronutrients included were not significantly associated with a genetic susceptibility to liver cirrhosis. However, MR analysis demonstrated a significant association between circulating vitamin D levels and a reduced risk of liver cirrhosis (odds ratio IVW = 0.53, p < 0.010). The MR–Egger intercept showed no evidence of horizontal pleiotropy ( p = 0.178), whereas Cochran's Q test found no heterogeneity ( p = 0.799). Furthermore, MVMR analysis confirmed vitamin D was identified as a factor that independently mitigates the risk of liver cirrhosis. Conclusion This research constitutes the most comprehensive MR investigation in this field, providing evidence supporting a protective link between circulating vitamin D levels and cirrhosis incidence. It suggests that maintaining sufficient vitamin D could be a cost‐effective strategy for early intervention in liver cirrhosis.