Rheumatoid arthritis as a risk factor for iron deficiency anemia: Results from a two-sample Mendelian randomization study

This study aims to investigate the potential causal relationship between rheumatoid arthritis (RA) and iron deficiency anemia (IDA) using a 2-sample Mendelian randomization approach. Additionally, we perform gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses to explore the biological significance of identified target genes. We utilized summary data from genome-wide association studies to conduct a 2-sample Mendelian randomization analysis. Genetic variants significantly associated with RA were employed as instrumental variables to assess the causal impact on the risk of IDA. GO and KEGG enrichment analyses were conducted using the R package cluster Profiler to understand the biological relevance of the single nucleotide polymorphisms target genes. Our findings indicate a significant causal relationship between RA and an elevated risk of IDA (inverse variance weighted, odds ratio = 1.05, 95% confidence interval = 1.012–1.09, P = .006). However, no significant association was observed between RA and anemia overall (inverse variance weighted, P = .342). GO enrichment analysis revealed that the most significant pathways in the biological process category were associated with interferon-gamma signaling. In the cellular component category, target genes were primarily linked to the endoplasmic reticulum and MHC protein complexes. Molecular function analysis showed involvement in binding and receptor activities related to the immune system. KEGG pathway analysis highlighted significant pathways such as Th1 and Th2 cell differentiation, Th17 cell differentiation, and inflammatory bowel disease, all closely related to immune response. This study provides evidence of a potential causal link between RA and IDA, suggesting RA as a risk factor for IDA in individuals of European ancestry. The enrichment analyses underscore the immune-related functional characteristics of the target genes, aligning with the autoimmune nature of RA. Further studies encompassing diverse populations are necessary to validate these findings and explore therapeutic targets.