title: A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis.
abstract: BACKGROUND
  The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.
  
  
  METHODS
  In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.
  
  
  RESULTS
  No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10(-7)); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10(-8). Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.
  
  
  CONCLUSIONS
  Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.
authors.forename: Hanna W
authors.initials: HW
authors.lastname: van Steenbergen
authors.forename: Luis
authors.initials: L
authors.lastname: Rodríguez-Rodríguez
authors.forename: Ewa
authors.initials: E
authors.lastname: Berglin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: Rachel
authors.initials: R
authors.lastname: Knevel
authors.forename: Jose
authors.initials: J
authors.lastname: Ivorra-Cortés
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fernández-Gutiérrez
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
mesh_terms: D000328:Adult; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D003182:Complement C5 / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007596:Joints / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D011971:Receptors, Immunologic / Q000235:genetics*; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D003182:Complement C5; C457775:FCRL3 protein, human; D015850:Interleukin-6; D010456:Peptides, Cyclic; D011971:Receptors, Immunologic; D047990:TNF Receptor-Associated Factor 1; C487763:cyclic citrullinated peptide; D016753:Interleukin-10