Iron status and non-alcoholic fatty liver disease: A Mendelian randomization study

Here we studied the association of genetically determined iron status with the risk of non-alcoholic fatty liver disease (NAFLD) using two-sample Mendelian Randomisation (MR) analysis. We applied single nucleotide polymorphisms (SNPs) associated at genome-wide significance with iron status proxied by serum iron, ferritin, transferrin and transferrin saturation from the Genetics of Iron status Consortium (n=48,793), in a genome-wide association study of 1,664 NAFLD cases and 400,055 controls from the UK (United Kingdom) Biobank. A SNP associated with multiple markers of iron status was only applied to one marker with the strongest association in the main analysis. Their effects on NAFLD were calculated using inverse variance weighting after excluding SNPs associated with alkaline phosphatase and lipid metabolism. The risk of NAFLD is negatively associated with genetically predicted serum transferrin level with 20% reduction in NAFLD risk per standard deviation (0.65g/L) increase in transferrin [95% confidence interval (CI): 0.66 to 0.97], and trending positive association with transferrin saturation [odds ratio (OR)=0.80=1.50, 95% CI: 0.96 to 2.35] but it was not associated with serum iron (OR=0.90, 95% CI: 0.63 to 1.29) and ferritin (OR=1.33, 95% CI: 0.54 to 3.30). MR analysis provided evidence that genetically predicted higher serum transferrin, indicating lower iron status, may be protective against NAFLD, while higher transferrin saturation, indicating higher iron status, might increase the risk of NAFLD and its pathogenesis.