Novel mechanistic insights into the comorbidity of anemia and rheumatoid arthritis: Identification of therapeutic targets

Abstract

Objectives

To investigate the mechanisms underlying the comorbidity of anemia and rheumatoid arthritis (RA) and identify promising therapeutic targets.

Methods

We assessed the phenotypic linkage between anemia and RA. Using the largest genome-wide association studies (GWAS) summary statistics of European populations, we scrutinized the causal association and shared genetic architecture between the two conditions using multiple complementary approaches.

Results

Logistic regression analysis confirmed a strong clinical association between anemia and RA. Using GWAS data, we identified a significant causal effect of RA on anemia and positive global genetic correlations between the two conditions (r_g (genotype) = 0.28, P = 9.6 × 10⁻⁷; r_g (gene expression) = 0.45, P = 2 × 10⁻³). After dividing the genome into 2495 independent regions, we identified 15 significant regions associated with both conditions, with 14 showing concordant effects. Fine-mapping at the SNP level revealed 72 % of RA-associated SNPs overlapped with anemia, most with concordant effects. Stratified Q-Q plots visualized the shared genetic enrichment, showing a 12-fold enrichment for RA conditional on anemia and 100-fold enrichment for anemia conditional on RA. Further analysis using conjFDR method pinpointed 14 pleiotropic loci, including several novel loci. Gene mapping identified 33 shared genes, with BLK and FAM167A further prioritized as the top two genes by SMR analysis. Enrichment analysis highlighted pathways related to inflammation, immune response, and iron metabolism. Blood and T cells showed significant tissue- and cell-type-specific enrichment.

Conclusions

This study provides novel insights into anemia-RA comorbidity mechanisms and identifies new drug targets for RA.