Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile.
OBJECTIVE
To increase understanding of the aetiology and pathogenesis of rheumatoid arthritis (RA), genetic and environmental risk factors for RA subsets, defined by the presence or absence of different anticitrullinated protein/peptide antibodies (ACPAs) targeting citrullinated peptides from α-enolase, vimentin, fibrinogen 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 fine specificities. 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 fine specificities. In total, 17 RA subsets could be identified based on their different ACPA fine specificity profiles. Large differences in association with genetic and environmental determinants were observed between subsets. The strongest association of HLA-DRB1 SE, PTPN22 and smoking was identified for the RA subset which was defined by the presence of antibodies to citrullinated α-enolase and vimentin.


CONCLUSIONS
This study provides the most comprehensive picture to date of how HLA-DRB1 SE, PTPN22 and smoking are associated with the presence of specific 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.
Rheumatology Unit, Department of Medicine, Karolinska Institute, Stockholm 171 76, Sweden. karin.lundberg@ki.se
Karin
K
Lundberg
Camilla
C
Bengtsson
Nastya
N
Kharlamova
Evan
E
Reed
Xia
X
Jiang
Henrik
H
Kallberg
Iskra
I
Pollak-Dorocic
Lena
L
Israelsson
Christoph
C
Kessel
Leonid
L
Padyukov
Rikard
R
Holmdahl
Lars
L
Alfredsson
Lars
L
Klareskog
D001172:Arthritis, Rheumatoid / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D002956:Citrulline / Q000276:immunology* / Q000378:metabolism; D024043:Collagen Type II / Q000276:immunology / Q000378:metabolism; D003429:Cross Reactions / Q000276:immunology; D000939:Epitopes / Q000235:genetics; D005340:Fibrinogen / Q000276:immunology / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000276:immunology / Q000378:metabolism; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012307:Risk Factors; D016036:Seroepidemiologic Studies; D012907:Smoking / Q000453:epidemiology; D013548:Sweden / Q000453:epidemiology; D014746:Vimentin / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; D024043:Collagen Type II; D000939:Epitopes; D059811:HLA-DRB1 Chains; D010455:Peptides; D014746:Vimentin; D002956:Citrulline; D005340:Fibrinogen; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D010751:Phosphopyruvate Hydratase