Research Article
Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: Results of eighteen years of followup from the early rheumatoid arthritis study
D. L. Mattey,
W. Thomson,
W. E. R. Ollier,
M. Batley, P. G. Davies, A. K. Gough, J. Devlin, P. Prouse, D. W. James, P. L. Williams, J. Dixey,
J. Winfield, N. L. Cox, G. Koduri,
A. Young,
Corresponding Author
D. L. Mattey
University Hospital of North Staffordshire, Stoke-on-Trent, UK
Staffordshire Rheumatology Centre, Haywood Hospital, High Lane, Burslem, Stoke-on-Trent, Staffordshire ST6 7AG, UKSearch for more papers by this authorW. Thomson
Centre for Integrated Genomic Medical Research, Manchester, UK
Search for more papers by this authorW. E. R. Ollier
Centre for Integrated Genomic Medical Research, Manchester, UK
Search for more papers by this authorJ. Dixey
Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK
Search for more papers by this authorG. Koduri
City Hospital, WHHT National Health Service Trust, St Albans, UK
Search for more papers by this authorA. Young
City Hospital, WHHT National Health Service Trust, St Albans, UK
Search for more papers by this authorD. L. Mattey,
W. Thomson,
W. E. R. Ollier,
M. Batley, P. G. Davies, A. K. Gough, J. Devlin, P. Prouse, D. W. James, P. L. Williams, J. Dixey,
J. Winfield, N. L. Cox, G. Koduri,
A. Young,
Corresponding Author
D. L. Mattey
University Hospital of North Staffordshire, Stoke-on-Trent, UK
Staffordshire Rheumatology Centre, Haywood Hospital, High Lane, Burslem, Stoke-on-Trent, Staffordshire ST6 7AG, UKSearch for more papers by this authorW. Thomson
Centre for Integrated Genomic Medical Research, Manchester, UK
Search for more papers by this authorW. E. R. Ollier
Centre for Integrated Genomic Medical Research, Manchester, UK
Search for more papers by this authorJ. Dixey
Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK
Search for more papers by this authorG. Koduri
City Hospital, WHHT National Health Service Trust, St Albans, UK
Search for more papers by this authorA. Young
City Hospital, WHHT National Health Service Trust, St Albans, UK
Search for more papers by this authorAbstract
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.
Conclusion
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.
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