Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis

Arthritis Rheum. 2008 Feb;58(2):359-69. doi: 10.1002/art.23149.


Objective: To examine the role of the variants of the PTPN22 and HLA-DRB1 genes as predictors of mortality in inflammatory polyarthritis (IP) and rheumatoid arthritis (RA).

Methods: Patients were recruited from a primary care-based inception cohort of patients with IP and were followed up prospectively. For patients who died, the cause and date of death was obtained. Cox proportional hazards regression models were used to assess the association of the HLA-DRB1 (including the shared epitope [SE]) and PTPN22 genes with the risk of death from all causes and from cardiovascular disease (CVD) and to assess the interactions between SE, smoking, and anti-cyclic citrullinated peptide (anti-CCP) status, adjusted by age at symptom onset and sex.

Results: DNA samples were available from 1,022 IP patients. During followup, 751 of them (74%) satisfied the American College of Rheumatology 1987 criteria for RA, and 242 of them (24%) died. Carriage of 2 copies of SE alleles predicted death from all causes (hazard ratio [HR] 1.57 [95% confidence interval (95% CI) 1.1-2.2]) and from CVD (HR 1.68 [95% CI 1.1-2.7]). This effect was most marked for individuals with the HLA-DRB1*01/*04 combination. An interaction of smoking, SE alleles, and anti-CCP antibodies was observed and was associated with the greatest risk of death from CVD (HR 7.81 [95% CI 2.6-23.2]). No association of the PTPN22 gene with mortality was detected.

Conclusion: SE alleles, particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoantibody status. However, the combination of SE, smoking, and anti-CCP antibodies is associated with a high risk of premature death in patients with IP and RA, which raises the possibility of a targeted strategy to prevent CVD in these patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Arthritis / genetics
  • Arthritis / immunology
  • Arthritis / mortality
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / mortality*
  • C-Reactive Protein / metabolism
  • Cardiovascular Diseases / genetics*
  • Cardiovascular Diseases / immunology
  • Cardiovascular Diseases / mortality*
  • Epitopes / genetics
  • Female
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genotype
  • HLA-DR Antigens / genetics*
  • HLA-DRB1 Chains
  • Humans
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics
  • Rheumatoid Factor / blood
  • Smoking / mortality


  • Epitopes
  • Genetic Markers
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • C-Reactive Protein
  • Rheumatoid Factor
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22