Genetics of ACPA-positive rheumatoid arthritis: the beginning of the end?

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.