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

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology Pub Date : 2025-02-27 DOI:10.1016/j.molimm.2025.02.011

Cun Li , Xiongzhi Shi, Shou Chen , Xiaoming Peng , Shaohui Zong

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引用次数: 0

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.

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来源期刊

Molecular immunology 医学-免疫学

CiteScore

6.90

自引率

2.80%

发文量

324

审稿时长

50 days

期刊介绍： Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to: Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology Mechanisms of induction, regulation and termination of innate and adaptive immunity Intercellular communication, cooperation and regulation Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc) Mechanisms of action of the cells and molecules of the immune system Structural analysis Development of the immune system Comparative immunology and evolution of the immune system "Omics" studies and bioinformatics Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc) Technical developments.