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Genetics of ACPA-positive rheumatoid arthritis: the beginning of the end?
  1. René R P de Vries1,
  2. Diane van der Woude2,
  3. Jeanine J Houwing3,
  4. Rene E M Toes2
  1. 1Department of Immunohematology and Blood transfusion, University Medical Center, Leiden, The Netherlands
  2. 2Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Professor Dr R R P De Vries, Leiden University Medical Center, Department of Immunohematology and Bloodtransfusion, E3-Q, PO Box 9600, 2300 RC Leiden, The Netherlands; rrpdevries{at}lumc.nl

Abstract

Heritability is a measure for the contribution of genetic variation to the variation in liability to disease and for rheumatoid arthritis (RA) had previously been estimated to be about 60%. This has been recently confirmed and could show that the heritability of anti-citrullinated protein autoantibody (ACPA)-positive and ACPA-negative RA is similar. Apart from gender, the main known genetic factor is HLA, and its contribution to genetic variation has previously been estimated as 37% but recent studies indicate that this figure may be too high. HLA-linked genes, and in particular the HLA-DRB1 SE alleles, predispose much more strongly to ACPA-positive than to ACPA-negative RA. The same is true for the protective effect of DERAA-positive DRB1 alleles. It has been calculated that the contribution of the protective and predisposing HLA alleles to genetic variance is about 40% for ACPA-positive and 2% for ACPA-negative RA. A meta-analysis indicated that the protective effect may be confined to the HLA-DRB1*1301 allele. The search for non-HLA genes contributing to the genetic variation in RA susceptibility has implicated about 30 other loci/genes. The OR of the associations with these non-HLA polymorphisms is considerably lower than the ORs of sex and HLA as is their contribution to the genetic variation—namely, altogether only about 5%. This means that known genetic factors do not explain much more than 50% of the genetic variance of ACPA-positive RA. Until recently, the only established non-genetic factor contributing to RA susceptibility was smoking. It has recently been shown that non-inherited maternal HLA-DRB1 DERAA-positive antigens (NIMA) should be added to the environmental factors affecting RA susceptibility.

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Footnotes

  • Funding Supported by the Dutch Arthritis Foundation (Reumafonds LLP-16).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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