Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile

Abstract

Objectives To increase understanding of the aetiology and pathogenesis of rheumatoid arthritis (RA), genetic and environmental risk factors for RA subsets, defi ned by the presence or absence of different anticitrullinated protein/peptide antibodies (ACPAs) targeting citrullinated peptides from α-enolase, vimentin, fi brinogen and collagen type II, were investigated. Methods 1985 patients with RA and 2252 matched controls from the EIRA case-control cohort were used in the study. Serum samples were assayed by ELISA for the presence of anticyclic citrullinated peptides (anti-CCP) antibodies and four different ACPA fi ne specifi cities. Cross-reactivity between ACPAs was examined by peptide absorption experiments. Genotyping was performed for HLA-DRB1 shared epitope (SE) alleles and the PTPN22 gene, while information regarding smoking was obtained by questionnaire. The association of genetic and environmental risk factors with different subsets of RA was calculated by logistic regression analysis. Results Limited cross-reactivity was observed between different ACPA fi ne specifi cities. In total, 17 RA subsets could be identifi ed based on their different ACPA fi ne specifi city profi les. Large differences in association with genetic and environmental determinants were observed between subsets. The strongest association of HLA-DRB1 SE, PTPN22 and smoking was identifi ed for the RA subset which was defi ned by the presence of antibodies to citrullinated α-enolase and vimentin. Conclusion This study provides the most comprehensive picture to date of how HLA-DRB1 SE, PTPN22 and smoking are associated with the presence of specifi c ACPA reactivities rather than anti-CCP levels. The new data will form a basis for molecular studies aimed at understanding disease development in serologically distinct subsets of RA.

The Association Between Schizophrenia and Rheumatoid Arthritis: A Nationwide Population-Based Swedish Study on Intraindividual and Familial Risks

“…For example, smoking is more common in schizophrenia patients than in their first-degree relatives, 35 and the risk of developing ACPA-positive RA is associated with a gene-environment interaction between smoking and the HLA-DRB1 SE alleles. 36 Hence, it is possible that the estimated relative risk for seropositive RA in schizophrenia patients (but perhaps not in their first-degree relatives) was inflated by uncontrolled confounding from smoking. Of note, we also observed a significantly increased risk of seropositive RA in schizophrenia siblings.…”

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

“…Not surprisingly, the prevalence of RA is increased in patients with P. gingivalis -associated chronic periodontitis, which correlates with circulating levels of ACPA [45,46]. Citrullination of periodontal proteins such as filaggrin, vimentin and enolase, as well as bacterial antigens, results in a range of different ACPA specificities with antibodies to citrullinated enolase peptides most strongly associated with RA [47].…”

Genetic markers and clinical relevance in rheumatoid arthritis

“…7 Furthermore, a strong interaction of DRb1-SE, the protein tyrosine phosphatase non-receptor 22 (PTPN22) and smoking was identified for development of RA in the presence of specific ACPA reactivities, that is, the presence of antibodies to citrullinated a-enolase and vimentin. 8 Non-HLA genes: One of the putative non-HLA genes that is associated with RA is PTPN22. The PTPN22 association concerns the minor allele of the non-synonymous single nucleotide polymorphism (SNP) rs2476601 (C1858T, R620W).…”