title: Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis.
abstract: OBJECTIVE
  There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by beta-chemokines is a feature of autoimmunity, and that the CCR5Delta32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D).
  
  
  METHODS
  We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian.
  
  
  RESULTS
  A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08-1.66, p = 0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75-1.60, p = 0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98-2.20, p = 0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00-1.54, p = 0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 (CCR5Delta32).
  
  
  CONCLUSIONS
  These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5Delta32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.
authors.affiliation: Department of Biochemistry, University of Otago, PO Box 56, Dunedin, New Zealand.
authors.forename: C
authors.initials: C
authors.lastname: McKinney
authors.forename: M E
authors.initials: ME
authors.lastname: Merriman
authors.forename: P T
authors.initials: PT
authors.lastname: Chapman
authors.forename: P J
authors.initials: PJ
authors.lastname: Gow
authors.forename: A A
authors.initials: AA
authors.lastname: Harrison
authors.forename: J
authors.initials: J
authors.lastname: Highton
authors.forename: P B B
authors.initials: PB
authors.lastname: Jones
authors.forename: L
authors.initials: L
authors.lastname: McLean
authors.forename: J L
authors.initials: JL
authors.lastname: O'Donnell
authors.forename: V
authors.initials: V
authors.lastname: Pokorny
authors.forename: M
authors.initials: M
authors.lastname: Spellerberg
authors.forename: L K
authors.initials: LK
authors.lastname: Stamp
authors.forename: J
authors.initials: J
authors.lastname: Willis
authors.forename: S
authors.initials: S
authors.lastname: Steer
authors.forename: T R
authors.initials: TR
authors.lastname: Merriman
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D019742:Chemokines, CC / Q000235:genetics*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D019713:Receptors, CCR5 / Q000235:genetics; D012307:Risk Factors
chemical_list: C492767:CCL3L1 protein, human; D019742:Chemokines, CC; D019713:Receptors, CCR5