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Review
. 2025 Jul 21:43:102148.
doi: 10.1016/j.bbrep.2025.102148. eCollection 2025 Sep.

The genetic puzzle of rheumatoid arthritis: Causes, progression, and treatment

Maryam Masoumi  1 , Mahdi Solaymani  2 , Mitra Abbasifard  3 , Sheyda Houshmandfar  4 , Parnia Iravani  2 , Ali Saeedi-Boroujeni  4 , Jafar Karami  5
Affiliations
Review

The genetic puzzle of rheumatoid arthritis: Causes, progression, and treatment

Maryam Masoumi et al. Biochem Biophys Rep. .

Abstract

Rheumatoid arthritis (RA) is a multifaceted autoimmune disorder characterized by chronic inflammation and progressive joint destruction, influenced by a complex interplay of genetic and environmental factors. Substantial evidence highlights a significant genetic contribution to RA pathogenesis, with key genetic risk factors including human leukocyte antigen (HLA) genes and non-HLA variants. These genetic elements are intricately involved in immune dysregulation, antigen presentation, and signaling pathways. The genetic heterogeneity of RA is further accentuated by gene-gene and gene-environment interactions, while biomarkers and genetic profiles associated with disease progression and joint damage continue to be rigorously explored. Additionally, the evolving field of pharmacogenomics sheds light on the challenges and prospects of developing personalized therapeutic approaches for RA. Genetic markers are being explored to predict response to various RA therapies, including DMARDs and biologics. Understanding genetic risk factors and pharmacogenomic insights can support early diagnosis, predict disease severity and progression, and improve therapeutic decisions in RA patients. The main objective of this review is to comprehensively explore current knowledge regarding the genetic factors contributing to RA susceptibility, progression, and treatment response. Furthermore, by addressing genetic risk factors, gene-environment interactions, and emerging pharmacogenomic insights, the review aims to highlight critical gaps and future directions in genetic researches related to RA.

Keywords: Genetic susceptibility; HLA genes; Pharmacogenomics biomarker; Rheumatoid arthritis.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
HLA and non-HLA genes involved in RA pathogenesis. HLA genes are the primary genetic risk factors for RA development. Non-HLA genes are classified based on their roles in RA pathogenesis. The figure illustrates both HLA and non-HLA genes and their functions in RA pathogenesis.
Fig. 2
Fig. 2
Genetic risk factors contributing to radiological damage in RA patients are shown in the figure. Known loci associated with radiographic progression and joint damage include HLA-DRB1, PTGER4, TNF-α, C5-TRAF1, LRP5, C5orf30, IL-6, and IL-10. Studies suggest that genetic background can influence clinical manifestations, particularly bone destruction, in RA patients.
Fig. 3
Fig. 3
This figure illustrates the associations between genetic factors and variations in drug response among RA patients. Certain genes are linked to improved responses, while others are associated with drug toxicity.
Fig. 4
Fig. 4
The figure shows the associations of genetic risk factors with extra-articular manifestations (EAMs) and comorbidities in RA.
See this image and copyright information in PMC

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