title: Association of a rheumatoid arthritis susceptibility variant at the CCL21 locus with premature mortality in inflammatory polyarthritis patients.
abstract: OBJECTIVE
  To investigate whether recently identified rheumatoid arthritis (RA) susceptibility loci are also associated with disease severity, specifically all-cause and cardiovascular disease (CVD) mortality, in patients with inflammatory polyarthritis (IP).
  
  
  METHODS
  Subjects with recent-onset IP were recruited from the Norfolk Arthritis Register. Seventeen RA susceptibility single-nucleotide polymorphisms (SNPs) were tested using Sequenom MassArray iPLEX chemistry. Vital status was ascertained from central records. The association of SNP allele carriage with mortality risk was assessed using Cox proportional hazards models after adjusting by sex. The mortality risks of those SNP alleles found to be associated were then stratified by baseline anti-citrullinated peptide (anti-CCP) antibody and shared epitope (SE) status.
  
  
  RESULTS
  All SNPs were successfully genotyped in 2,324 IP subjects. The presence of 2 copies of the risk allele rs2812378 mapping to the CCL21 gene predicted all-cause mortality (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.04-1.87), whereas risk allele carriage also predicted increased CVD mortality (HR 1.33, 95% CI 1.01-1.75). The highest mortality risks were seen in anti-CCP antibody-positive subjects with 2 copies of the CCL21 risk alleles and 2 copies of the SE (all-cause HR 3.20, 95% CI 1.52-6.72; CVD HR 3.73, 95% CI 1.30-10.72).
  
  
  CONCLUSIONS
  In this large study, we found that carriage of CCL21 risk alleles was associated with premature mortality in IP independently of anti-CCP antibody and SE status. Interestingly, CCL21 expression has been reported in atherosclerotic plaques supporting the thesis that the increased CVD mortality in IP patients may be mediated by shared inflammatory mechanisms.
authors.affiliation: arc Epidemiology Unit, The University of Manchester, Manchester, UK.
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Farragher
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.forename: Edward
authors.initials: E
authors.lastname: Flynn
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.forename: Diane
authors.initials: D
authors.lastname: Bunn
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Deborah
authors.initials: D
authors.lastname: Symmons
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
mesh_terms: D000328:Adult; D000368:Aged; D001168:Arthritis / Q000150:complications / Q000235:genetics* / Q000401:mortality; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics* / Q000401:mortality; D054421:Chemokine CCL21 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models
chemical_list: C515478:CCL21 protein, human; D054421:Chemokine CCL21
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