Background: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with the phenotype of CCP+ RA.
Objective: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine if radiographic erosions and age of diagnosis are associated with these risk alleles.
Methods: 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE alleles by low-resolution genotyping, and for PTPN22 (rs2476601) and CTLA4 (rs3087243) by Sequenom genotyping. Association between genotypes and phenotypes for CCP, RF and erosive RA were assessed with logistic regression models adjusting for age, sex, and disease duration. Associations between genotype and age at diagnosis of RA were assessed with general linear models. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions.
Results: In multivariable analysis adjusting for age, sex, and disease duration, presence of any HLA-SE was strongly associated with CCP+ phenotype (OR 3.05 (2.18-4.25)), and RF+ phenotype (OR 2.53 (1.83-3.5)); presence of any PTPN22 T allele was associated with CCP+ phenotype (OR 1.81 (1.24-2.66)) and RF+ phenotype (1.84 (1.27-2.66)). CTLA4 was not associated with CCP or RF phenotypes in our dataset. While HLA-SE was associated with erosive RA phenotype (OR 1.52 (1.01-2.17)), this association was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. The presence of any HLA-SE was associated with on average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs. 44.9 years, p=0.003) and PTPN22 was associated with 4.2 years earlier age of diagnosis (39.5 vs. 43.6 years, p=0.002). CTLA4 genotypes were not associated with age at diagnosis of RA.
Conclusion: In this large clinical cohort, we replicated the association between HLA-SE, and PTPN22 but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for genotype-phenotype associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is no longer significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.
- age at diagnosis
- rheumatoid arthritis
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