title: Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis patients.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is prevalent in North American Native populations, with a high frequency of multicase families and seropositivity in first-degree relatives. This study was undertaken to determine whether the serum cytokine profile of first-degree relatives of North American Native patients with RA differed from that of individuals with no family history of autoimmunity and whether there was an association with RA autoantibodies.
  
  
  METHODS
  North American Native patients with RA (n = 105), their first-degree relatives (n = 273), healthy North American Native controls (n = 200), and Caucasian controls (n = 150) were studied. Serum levels of 42 cytokines were tested using a multiplex laser bead assay. Rheumatoid factor (RF), anti-cyclic citrullinated peptide 2 (anti-CCP-2), monocyte chemotactic protein 1 (MCP-l), and high-sensitivity C-reactive protein (hsCRP) were tested by enzyme-linked immunosorbent assay, and HLA-DRB1 alleles by specific primers. Discriminant analysis and logistic regression classified individuals based on their cytokine profile.
  
  
  RESULTS
  The prevalence of RF (cutoff level predetermined to include 5% of Caucasian controls) and anti-CCP (cutoff level of ≥40 units) was, respectively, 88% and 81% in the RA patients, 34% and 9% in first-degree relatives, and 9% and 4% in North American Native controls; the prevalence of anti-CCP was 0% in Caucasian controls. Levels of most cytokines were highest in RA patients; 17 of 40 cytokines (43%) were significantly higher in first-degree relatives than in controls, including multiple proinflammatory cytokines. Discriminant analysis showed a notable distinction between the groups, with 85% classification accuracy. First-degree relatives had markedly higher MCP-1 and hsCRP levels than North American Native controls, but there was no consistent association with RA autoantibodies.
  
  
  CONCLUSIONS
  Our findings indicate that levels of multiple cytokines and hsCRP are higher in first-degree relatives of North American Native patients with RA compared to individuals from a nonautoimmune background. These data suggest that elevated baseline cytokine levels may be part of the risk profile for developing RA.
authors.affiliation: University of Manitoba, Winnipeg, Manitoba, Canada. elgabalh@cc.umanitoba.ca
authors.forename: Hani S
authors.initials: HS
authors.lastname: El-Gabalawy
authors.forename: David B
authors.initials: DB
authors.lastname: Robinson
authors.forename: Irene
authors.initials: I
authors.lastname: Smolik
authors.forename: Donna
authors.initials: D
authors.lastname: Hart
authors.forename: Brenda
authors.initials: B
authors.lastname: Elias
authors.forename: Keng
authors.initials: K
authors.lastname: Wong
authors.forename: Christine A
authors.initials: CA
authors.lastname: Peschken
authors.forename: Carol A
authors.initials: CA
authors.lastname: Hitchon
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.forename: Charles N
authors.initials: CN
authors.lastname: Bernstein
authors.forename: Marianna M
authors.initials: MM
authors.lastname: Newkirk
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Fritzler
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D002097:C-Reactive Protein / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000097:blood / Q000276:immunology; D012217:Rheumatoid Factor / Q000097:blood / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D002097:C-Reactive Protein; D012217:Rheumatoid Factor