Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA–DRB1 shared epitope for antibodies to citrullinated proteins

Abstract

Objective. The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA-DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti-CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti-CCP antibodies.Methods. HLA-DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population-based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well-established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti-CCP antibodies was determined by enzyme-linked immunosorbent assay.Results. For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti-CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti-CCP-negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti-CCPpositive disease and not with anti-CCP-negative disease. Stratified analyses indicated that anti-CCP antibodies primarily mediated association of the SE with joint damage or disease persistence.Conclusion. HLA-DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype.

High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33

“…40,47 Thus, it is not surprising that linkage evidence at the MHC is strongly influenced by the presence of these autoantibodies. 39 Interestingly, our data provide some evidence that other regions, particularly on chromosomes 4, 5 and 7, may also carry susceptibility alleles that are more closely linked to anti-CCP þ disease. In contrast, neither sex nor HLA status significantly influenced linkage results outside of the MHC.…”

“…38 There is a strong association with the presence of anti-CCP antibodies and the HLA 'SE' alleles that are classically associated with RA. 39,40 Furthermore, anti-CCP antibodies are predictive of progressive erosive disease. 41 Thus, these antibodies may mark a genetically more homogeneous subset of RA.…”

“…Thus, the SE does not explain all of the linkage within this region, as we have recently reported using data from microsatellites. 39 No other chromosomes exhibited significant (Po0.05) heterogeneity when HLA SE status was considered. Consideration of sex as a covariate did not significantly alter linkage evidence, except at the MHC (P ¼ 0.0015).…”

“…38 Rheumatoid arthritis patients with these antibodies tend to have more severe progressive disease. 41 In addition, anti-CCP antibodies are strongly associated with HLA alleles, both positively with SE alleles 39,46 and negatively with HLA-DR3. 40,47 Thus, it is not surprising that linkage evidence at the MHC is strongly influenced by the presence of these autoantibodies.…”

Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti–Cyclic Citrullinated Peptide–Negative Rheumatoid Arthritis

“…Although it was initially thought that HLA did not play a role in the etiology of anti‐CCP–negative RA 12, several studies have now shown its association with seronegative disease 5, 8, 13, 14. More recently, this association has been pinpointed to 2 amino acid positions within HLA molecules: position 11 of HLA–DRB1 and position 9 of HLA–B 15.…”