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

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).TheMR–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.