Clinical Reviews in Allergy & Immunology

, Volume 45, Issue 2, pp 170–179 | Cite as

Genetics of Rheumatoid Arthritis — A Comprehensive Review

  • Júlia Kurkó
  • Timea Besenyei
  • Judit Laki
  • Tibor T. Glant
  • Katalin Mikecz
  • Zoltán SzekaneczEmail author


The “Bermuda triangle” of genetics, environment and autoimmunity is involved in the pathogenesis of rheumatoid arthritis (RA). Various aspects of genetic contribution to the etiology, pathogenesis and outcome of RA are discussed in this review. The heritability of RA has been estimated to be about 60 %, while the contribution of HLA to heritability has been estimated to be 11–37 %. Apart from known shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, other HLA alleles, such as HLA-DRB1*13 and DRB1*15 have been linked to RA susceptibility. A novel SE classification divides SE alleles into S1, S2, S3P and S3D groups, where primarily S2 and S3P groups have been associated with predisposition to seropositive RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. HLA and some non-HLA genes may differentiate between anti-citrullinated protein antibody (ACPA) seropositive and seronegative RA. Genetic susceptibility has also been associated with environmental factors, primarily smoking. Some GWAS studies carried out in rodent models of arthritis have confirmed the role of human genes. For example, in the collagen-induced (CIA) and proteoglycan-induced arthritis (PgIA) models, two important loci — Pgia26/Cia5 and Pgia2/Cia2/Cia3, corresponding the human PTPN22/CD2 and TRAF1/C5 loci, respectively — have been identified. Finally, pharmacogenomics identified SNPs or multiple genetic signatures that may be associated with responses to traditional disease-modifying drugs and biologics.


Rheumatoid arthritis Murine arthritis Animal models Genetics Single nucleotide polymorphisms HLA-DR GWAS 



This work was supported by research grants ETT 315/2009 from the Medical Research Council of Hungary (Z.S.); by the TÁMOP 4.2.1/B-09/1/KONV-2010-0007 and TÁMOP-4.2.2.A-11/1/KONV-2012-0031 projects co-financed by the European Union and the European Social Fund (Z.S.), the Bridging Fund provided by the University of Debrecen, Medical and Health Sciences Center (Z.S.), and a grant (R01 AR059356) awarded by the National Institutes of Health, USA (T.T.G.).


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Júlia Kurkó
    • 1
  • Timea Besenyei
    • 1
    • 2
  • Judit Laki
    • 3
  • Tibor T. Glant
    • 4
  • Katalin Mikecz
    • 4
  • Zoltán Szekanecz
    • 1
    Email author
  1. 1.Department of Rheumatology, Institute of MedicineUniversity of Debrecen Medical and Health Science CenterDebrecenHungary
  2. 2.1st Department of Medicine, Institute of MedicineUniversity of Debrecen Medical and Health Science CenterDebrecenHungary
  3. 3.Department of Medical Expertise, Clinical Auditing and AnalysisNational Health Insurance Fund AdministrationBudapestHungary
  4. 4.Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry, and RheumatologyRush University Medical CenterChicagoUSA

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