Investigating The Causal Link Between Serum Iron Status and Pernicious Anaemia Risk: A Mendelian Randomisation Study

IntroductionPernicious anaemia (PA) is characterised by vitamin B12 deficiency due to autoimmune-mediated destruction of gastric parietal cells and the consequent loss of intrinsic factor. A considerable proportion of PA patients also exhibit iron deficiency (ID), both before or at (20.7-52%) and after (46.4%) PA diagnosis. However, findings from observational studies do not clarify whether ID contributes to PA risk or is a consequence of the PA disease process. Given the high prevalence of ID at PA diagnosis, we hypothesised that reduced iron status may play a causal role in PA risk. MethodologyWe conducted two-sample Mendelian Randomisation (MR) analyses to evaluate the causal effect between systemic iron status and PA risk. Genetic association data for iron status were sourced from the deCODE study. Additionally, PA-relevant associative data with the chosen SNPs were obtained from genome-wide-association-study (GWAS) summary statistics, primarily from R10 FinnGen release and from the GWAS conducted by Laisk et al. (2021) for replication purposes. Participant data consisted of 3,694 cases of PA and 393,684 controls. Inverse-variance weighted analysis was the primary MR method, with sensitivity analyses including Egger, and weighted-median estimates, additionally to testing for horizontal pleiotropy and heterogeneity. ResultsFour SNPs were strongly associated with systemic iron status and were used as genetic instruments. We found that genetically predicted iron status was not significantly associated with PA risk (odds ratio per 1 standard deviation increase in serum iron: 1.13, 95% confidence interval 0.80-1.58, P=0.49). Sensitivity analyses had consistent results, indicating that MR assumptions were not violated and highlighting a null result subjectivity due to the presence of horizontal pleiotropy and heterogeneity. ConclusionThis is the first MR study investigating the potential causal relationship between iron status and PA risk. Our results show that genetically predicted iron status is not associated with a significantly increased PA risk among individuals of European ancestry. Further research is needed to understand the manifestation of ID in PA.