Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis patients

Arthritis Rheum. 2012 Jun;64(6):1720-9. doi: 10.1002/art.34449. Epub 2012 Feb 21.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Autoantibodies / blood
  • Autoantibodies / genetics
  • Autoantibodies / immunology
  • Autoimmunity / genetics*
  • Autoimmunity / immunology
  • C-Reactive Protein / genetics
  • C-Reactive Protein / immunology
  • Cytokines / blood
  • Cytokines / genetics*
  • Cytokines / immunology
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Indians, North American / genetics*
  • Male
  • Middle Aged
  • Peptides, Cyclic / blood
  • Peptides, Cyclic / immunology
  • Rheumatoid Factor / blood
  • Rheumatoid Factor / genetics
  • Rheumatoid Factor / immunology


  • Autoantibodies
  • Cytokines
  • Peptides, Cyclic
  • cyclic citrullinated peptide
  • C-Reactive Protein
  • Rheumatoid Factor