title: Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: results of eighteen years of followup from the early rheumatoid arthritis study.
abstract: OBJECTIVE
  To determine whether the HLA-DRB1 shared epitope (SE) is associated with early mortality and specific causes of death in rheumatoid arthritis (RA).
  
  
  METHODS
  HLA-DRB1 genotyping was carried out on blood samples from 767 patients recruited for the Early RA Study (ERAS), a multicenter, inception cohort study with followup over 18 years. Dates and causes of death (n = 186) were obtained from the Office of National Statistics. The association of HLA-DRB1 alleles with risk of mortality was assessed using Cox proportional hazards regression analyses. Multivariate stepwise models were used to assess the predictive value of HLA-DRB1 genotypes compared with other potential baseline risk factors.
  
  
  RESULTS
  The SE was not significantly associated with overall mortality. However, the presence of 2 SE alleles was associated with risk of mortality from ischemic heart disease (hazard ratio [HR] 2.02 [95% confidence interval 1.04-3.94], P = 0.04), and malignancy (HR 2.18 [95% confidence interval 1.17-4.08], P = 0.01). Analysis of specific SE genotypes (corrected for age and sex) revealed that the HLA-DRB1*0101/*0401 and 0404/*0404 genotypes were the strongest predictors of mortality from ischemic heart disease (HR 5.11 and HR 7.55, respectively), and DRB1*0101/*0401 showed a possible interaction with smoking. Male sex, erythrocyte sedimentation rate, and Carstairs Deprivation Index were also predictive, but the Health Assessment Questionnaire score, rheumatoid factor, nodules, and swollen joint counts were not. Mortality due to malignancy was particularly associated with DRB1*0101 genotypes.
  
  
  CONCLUSIONS
  The risk of mortality due to ischemic heart disease or cancer in RA is increased in patients carrying HLA-DRB1 genotypes with particular homozygous and compound heterozygous SE combinations.
authors.affiliation: University Hospital of North Staffordshire, Stoke-on-Trent, UK. d.l.mattey@keele.ac.uk
authors.forename: D L
authors.initials: DL
authors.lastname: Mattey
authors.forename: W
authors.initials: W
authors.lastname: Thomson
authors.forename: W E R
authors.initials: WE
authors.lastname: Ollier
authors.forename: M
authors.initials: M
authors.lastname: Batley
authors.forename: P G
authors.initials: PG
authors.lastname: Davies
authors.forename: A K
authors.initials: AK
authors.lastname: Gough
authors.forename: J
authors.initials: J
authors.lastname: Devlin
authors.forename: P
authors.initials: P
authors.lastname: Prouse
authors.forename: D W
authors.initials: DW
authors.lastname: James
authors.forename: P L
authors.initials: PL
authors.lastname: Williams
authors.forename: J
authors.initials: J
authors.lastname: Dixey
authors.forename: J
authors.initials: J
authors.lastname: Winfield
authors.forename: N L
authors.initials: NL
authors.lastname: Cox
authors.forename: G
authors.initials: G
authors.lastname: Koduri
authors.forename: A
authors.initials: A
authors.lastname: Young
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000401:mortality*; D002423:Cause of Death; D015331:Cohort Studies; D000939:Epitopes / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009026:Mortality / Q000639:trends; D015999:Multivariate Analysis; D017202:Myocardial Ischemia / Q000401:mortality; D009369:Neoplasms / Q000401:mortality; D012307:Risk Factors; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains