POS0471 ASSOCIATION OF HLA-DRB1 HAPLOTYPES WITH CARDIOVASCULAR MORTALITY IN INFLAMMATORY POLYARTHRITIS: RESULTS FROM THE NORFOLK ARTHRITIS REGISTER
Authors: S. Sharma, D. Plant, J. Bowes, A. MacGregor, S. Verstappen, A. Barton, S. Viatte
Journal: Annals of the Rheumatic Diseases (2021)

Background: Haplotypes defined by amino acids at HLA-DRB1 positions 11, 71 and 74 associated with susceptibility to rheumatoid arthritis (RA), are associated with radiological outcome, anti-TNF response and all cause-mortality in RA.( 1, 2 ) RA is associated with cardiovascular (CV) morbidity and mortality, but the increased prevalence of risk factors of CV disease in RA only partially explains this association. Objectives: The aim was to investigate whether haplotypes associated with RA disease susceptibility and disease severity are also associated with CV mortality. Methods: The Norfolk Arthritis register (NOAR) is a primary care-based inception cohort of patients with inflammatory polyarthritis (IP).( 1, 2 ) NOAR patients with at least 2 years of follow-up and available mortality and genetic data were included in this study. Mortality data was provided by the Office for National Statistics. Univariate Cox proportional hazard models were applied using STATA/IC 14.0. Models for CV mortality were adjusted for CV risk factors selected using stepwise regression: namely obesity, gender and hypertension. Hazard models were applied to the entire cohort of patients with inflammatory polyarthritis (IP). When calculating differences between highest and lowest risk genetic factors, bivariate analysis was used. Results: HLA-DRB1 amino acids, haplotypes or haplotype groups associated with RA susceptibility are also associated with CV mortality as shown in the table 1. HLA-DRB1 polymorphisms encoding amino-acid haplotypes associated with an increased or decreased susceptibility to RA consistently show the same magnitude and direction of association for overall and CV mortality in IP. For example, the SEA-haplotype, associated with the lowest susceptibility to RA, and the best radiographic outcome, was found to be associated with decreased CV mortality (HR 0.67, 95% CI 0.47, 0.91, p=0.023). The relative difference in CV mortality between carriers of the high susceptibility VKA haplotype and carriers of the SEA haplotype was significant (HR 1.67, 95% CI 1.13, 2.48, p=0.01). Table 1. Hazard ratios for CV mortality by genetic factors among patients with IP. Total number (n) of deaths are also displayed alongside the total number (n) of patients included in each analysis. Amino acid / Haplotype /Group Hazard Ratio (95% CI) N valine 11 1.10 (0.93, 1.30) 343 (2514) serine 11 0.82 (0.70, 0.96)* 343 (2514) Difference 1.23 (1.01, 1.49)* VKA haplotype 1.16 (0.94, 1.43) 310 (2328) SEA haplotype 0.67 (0.47, 0.94) * 310 (2328) Difference 1.67 (1.13, 2.48)* Group 1 † 1.10 (0.93, 1.31) 319 (2328) Group 4 † 0.73 (0.60, 0.89)* 319 (2328) Difference 1.37 (1.09, 1.72)* * p&lt;0.05 † Haplotype groups as defined previously (2 ) HLA-DRB1 haplotypes can be ranked according to the magnitude of their association with RA susceptibility and this hierarchy is conserved for various measures of disease outcome and overall mortality.( 2, 3 ) The figure 1 shows that this risk hierarchy is also conserved for CV mortality: HLA-DRB1 haplotypes that predispose to RA also predispose to increased CV mortality, independent of known CV risk factors. Figure 1. Haplotypes with frequency &gt;12% in NOAR are shown. X axis: susceptibility to ACPA-positive RA as ORs.(2) Y axis: CV mortality risk in IP as HRs, derived from multi-variate cox-proportional hazard models adjusted for CV risk factors. Values are on a logarithmic scale. A one-tailed p value was calculated using linear regression to determine the association between β coefficients of susceptibility and CV mortality. Conclusion: The originally reported genetic associations between HLA-DRB1 polymorphisms and overall mortality were likely driven by associations with CV mortality. References: [1]S. Viatte et al. , JAMA 313 , 1645-1656 (2015). [2]S. Raychaudhuri et al. , Nat Genet 44 , 291-296 (2012). [3]D. P. Symmons, A. J. Silman, Clin Exp Rheumatol 21 , S94-99 (2003). Disclosure of Interests: None declared