The heritability of anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA) is similar to that of ACPA-negative RA, suggesting that genetic predisposition plays an important role in both disease subtypes.
“The majority of genetic risk factors for rheumatoid arthritis (RA) are associated with (ACPA)-positive RA, while far fewer genetic risk factors have been identified for ACPA-negative RA,” note Diane van der Woude (Leiden University Medical Center, The Netherlands) and colleagues.
To determine the heritability of ACPA-positive and ACPA-negative RA, van der Woude and team applied quantitative genetic methods to data from 148 RA twin pairs, in which at least one twin of each pair had RA. In addition, they assessed the contribution of the predisposing HLA-DRB1 shared epitope (SE) alleles to the genetic variance in both subsets of RA.
The researchers report that the concordance of RA, which represents the frequency with which the twin brothers or sisters of RA patients were also affected, was 15.6% for monozygotic twins (n=64 pairs) and 3.6% for dizygotic twins (n=84 pairs).
The overall the heritability of RA among the twin pairs was 66%. For ACPA-positive RA, the heritability was 68%, and for ACPA-negative RA it was 66%.
Genotyping of HLA-DRB1 revealed that 89% of patients with ACPA-positive RA carried one or two SE alleles compared with 47% of patients with ACPA-negative RA.
The contribution of the HLA-DRB1 SE alleles to the total genetic variance of RA was 11%, which is lower than that reported by others. van der Woude et al suggest the difference “may be due to the fact that the methods used to calculate the contribution of the HLA SE alleles may not be completely comparable.”
The presence of the HLA-DRB1 SE alleles contributed 18% to the heritability of ACPA-positive RA, but only 2.4% to the heritability of ACPA-negative RA.
“The observation that the heritability of ACPA-negative RA is similar to the heritability of ACPA-positive RA is intriguing,” remark the researchers in the journal Arthritis and Rheumatism.
They conclude: “This suggests that most genetic risk factors for ACPA-negative RA are still unknown and remain to be discovered.”