Quantitative heritability of anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis
Article first published online: 30 MAR 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 4, pages 916–923, April 2009
How to Cite
van der Woude, D., Houwing-Duistermaat, J. J., Toes, R. E. M., Huizinga, T. W. J., Thomson, W., Worthington, J., van der Helm-van Mil, A. H. M. and de Vries, R. R. P. (2009), Quantitative heritability of anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis. Arthritis & Rheumatism, 60: 916–923. doi: 10.1002/art.24385
- Issue published online: 30 MAR 2009
- Article first published online: 30 MAR 2009
- Manuscript Accepted: 17 DEC 2008
- Manuscript Received: 2 OCT 2008
- Dutch Organization for Scientific Research (AGIKO grant)
- Dutch Organization for Scientific Research (a VIDI grant to each)
- European Community Seventh Framework Programme, Coordination Theme 1 (Health). Grant Number: HEALTH-F2-2007-2.4.5-12 [Masterswitch]
- Netherlands Organization of Health Research and Development
- Dutch Arthritis Foundation (Reumafonds)
The majority of genetic risk factors for rheumatoid arthritis (RA) are associated with anti–citrullinated protein antibody (ACPA)–positive RA, while far fewer genetic risk factors have been identified for ACPA-negative RA. This study was undertaken to quantify the contribution of genetic risk factors in general, and of the predisposing HLA–DRB1 shared epitope (SE) alleles in particular, to the ACPA-positive and ACPA-negative subsets of RA, by computing their heritability and assessing the contribution of the HLA SE alleles.
One hundred forty-eight RA twin pairs, in which at least 1 twin of each pair had RA, were tested for ACPAs and typed for HLA–DRB1 genotypes. Heritability was assessed in a logistic regression model including a bivariate, normally distributed random effect, representing the contribution of unobserved genetic factors to RA susceptibility, with the correlation of the random effects fixed according to twin zygosity. The contribution of the HLA SE alleles to genetic variance was assessed using a similar model, except that estimates were based on genotype-specific population prevalences.
The heritability of RA among the twin pairs was 66% (95% confidence interval [95% CI] 44–75%). For ACPA-positive RA, the heritability was 68% (95% CI 55–79%), and for ACPA-negative RA it was 66% (95% CI 21–82%). Presence of the HLA SE alleles explained 18% (95% CI 16–19%) of the genetic variance of ACPA-positive RA but only 2.4% (95% CI 1.6–10%) of the genetic variance of ACPA-negative RA.
The heritability of ACPA-positive RA is comparable with that of ACPA-negative RA. These data indicate that genetic predisposition plays an important role in the pathogenesis of ACPA-negative RA, for which most individual genetic risk factors remain to be identified.