Quantitative Heritability of Anti-Citrullinated Protein Antibody-Positive and Anti-Citrullinated Protein Antibody-Negative Rheumatoid Arthritis

Leiden University Medical Center, Leiden, The Netherlands.
Arthritis & Rheumatology (Impact Factor: 7.76). 05/2009; 60(4):916-23. DOI: 10.1002/art.24385
Source: PubMed


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.

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    • "SE alleles, lymphoid-specific tyrosine phosphatase (LYP)/protein tyrosine phosphatase, nonreceptor type (PTPN) 22, and cigarette smoking are risk factors for the development of ACPA positive RA patients [47] [60]. Further, it has been reported that also the noninherited maternal HLA antigens (NIMA), originally discovered in transplantation immunology [61], containing the RA-protective DERAA sequence, protect DERAA-negative children against RA [49] [62]. It has been recently reported that the gene polymorphism may not only be associated with the pathogenesis of SAIRDs, but also with the outcome of the treatment and the progression of the disease. "
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    • "Indeed for several complex disorders, genetic factors play only a role in a subset of the cases. One example is Rheumatoid Arthritis for which the underlying genetic mechanisms appear to be different in CCP positive compared to CCP negative patients (Van der Woude et al., 2009). If gene covariate interaction is present, the test statistic will have a different mean for different covariate values. "
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