title: Anti-CarP antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors, cigarette smoking and other autoantibodies.
abstract: BACKGROUND
  In rheumatoid arthritis (RA), several genetic risk factors and smoking are strongly associated with the presence of anticitrullinated protein antibodies (ACPA), while much less is known about risk factors for ACPA-negative RA. Antibodies against carbamylated proteins (anti-CarP) have been described in both ACPA-positive and ACPA-negative RA patients. In this study, we have analysed the relationships among anti-CarP antibodies, ACPA, genetic risk factors (HLA-DRB1 alleles and PTPN22) and smoking in RA.
  
  
  METHODS
  Presence of antibodies to carbamylated fetal calf serum (CarP-FCS) and fibrinogen (CarP-Fib) was determined by inhouse ELISAs among RA cases in the Leiden Early Arthritis Clinic (n=846) and in the Swedish Epidemiological Investigation of Rheumatoid Arthritis (n=1985) cohorts. ORs for associations with different HLA-DRB1 alleles, PTPN22 genotypes and smoking were calculated separately for each cohort as well as in meta-analysis in RA subsets defined by the presence/absence of anti-CarP and anticyclic citrullinated peptide (anti-CCP) antibodies.
  
  
  RESULTS
  In both cohorts, anti-CarP antibody positivity was mainly detected in the anti-CCP-positive population (49%-73%), but also in the anti-CCP-negative population (8%-14%). No associations between anti-CarP antibodies and HLA-DRB1 shared epitope alleles could be identified, while there were data to support an association between anti-CarP-FCS and HLA-DRB1*03. Further analyses did not reveal any specific associations of anti-CarP antibodies with other HLA-DRB1 alleles, PTPN22 genotypes or smoking.
  
  
  CONCLUSIONS
  Anti-CarP antibodies were present in both ACPA-positive and ACPA-negative RA. There were no significant associations among anti-CarP antibodies and HLA-DRB1 alleles, PTPN22 or smoking. These data suggest that different biological mechanisms may underlie anti-CarP versus anti-CCP antibody formation.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Leendert A
authors.initials: LA
authors.lastname: Trouw
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tineke J
authors.initials: TJ
authors.lastname: van Wesemael
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Bengtsson
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Källberg
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vivi
authors.initials: V
authors.lastname: Malmström
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Israelsson
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hulda
authors.initials: H
authors.lastname: Hreggvidsdottir
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: Verduijn
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Lundberg
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Diane
authors.initials: D
authors.lastname: van der Woude
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000276:immunology*; D009687:Nuclear Proteins / Q000276:immunology*; D010456:Peptides, Cyclic / Q000276:immunology; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D012097:Repressor Proteins / Q000276:immunology*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000276:immunology*; D055815:Young Adult
chemical_list: C491304:ANKRD1 protein, human; D001323:Autoantibodies; D059811:HLA-DRB1 Chains; D007074:Immunoglobulin G; D009124:Muscle Proteins; D009687:Nuclear Proteins; D010456:Peptides, Cyclic; D012097:Repressor Proteins; C487763:cyclic citrullinated peptide; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: Autoantibodies; Epidemiology; Gene Polymorphism; Rheumatoid Arthritis