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Genetics of Rheumatoid Arthritis — A Comprehensive Review

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Abstract

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.

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Acknowledgments

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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Authors and Affiliations

  1. Department of Rheumatology, Institute of Medicine, University of Debrecen Medical and Health Science Center, Nagyerdei str 98, Debrecen, 4032, Hungary

    Júlia Kurkó, Timea Besenyei & Zoltán Szekanecz

  2. 1st Department of Medicine, Institute of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary

    Timea Besenyei

  3. Department of Medical Expertise, Clinical Auditing and Analysis, National Health Insurance Fund Administration, Budapest, Hungary

    Judit Laki

  4. Section of Molecular Medicine, Departments of Orthopedic Surgery, Biochemistry, and Rheumatology, Rush University Medical Center, Chicago, IL, 60612, USA

    Tibor T. Glant & Katalin Mikecz

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  1. Júlia Kurkó
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Correspondence to Zoltán Szekanecz.

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Kurkó, J., Besenyei, T., Laki, J. et al. Genetics of Rheumatoid Arthritis — A Comprehensive Review. Clinic Rev Allerg Immunol 45, 170–179 (2013). https://doi.org/10.1007/s12016-012-8346-7

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