• Cardiovascular Disease
• Gene Polymorphism
• Rheumatoid Arthritis

In patients with rheumatoid arthritis (RA), chronic inflammation on a background of established cardiovascular disease (CVD) risk factors is thought to contribute to atherosclerosis, resulting in the observed increased mortality from CVD.1

Recent studies suggest a role for interleukin-6 receptor (IL6R) in both CVD2 ,3 and RA.4 A functional, non-synonymous genetic variant found within the IL6R gene (rs2228145) conferring an amino acid change (Asp358Ala) influential in determining levels of soluble IL6R5 has been convincingly associated with both CVD occurrence2 ,3 and RA.4 This amino acid change within the IL6R gene has a similar effect to the RA therapy, tocilizumab, which targets the IL6R pathway, leading to an increase in IL6R and soluble IL6 levels, as well as a decrease in C-reactive protein (CRP) levels. Although unlikely to be causal in disease,6 CRP levels in healthy individuals have been shown to correlate with CVD risk, and we have previously reported that CRP concentrations ≥5 mg/L at presentation of inflammatory polyarthritis (IP) are associated with an increased risk of subsequent CVD mortality.7

The aims of this study were to determine the effect of the functional, non-synonymous IL6R single nucleotide polymorphism (SNP) (rs2228145) on CRP levels in patients with IP and to determine whether this variant correlated with all-cause or CVD mortality in a UK population.

Details of the methods used in this study have been described previously.8 Briefly, the rs2228145 SNP was genotyped in DNA samples from the Norfolk Arthritis Register, a primary care-based inception cohort of Caucasian patients with IP, described elsewhere.9 The association between rs2228145 and serum CRP was evaluated by zero-inflated negative binomial regression, and Cox proportional hazard models were used to investigate the association between IL6R genotype and risk of all-cause and CVD mortality.

Genetic data and baseline CRP measurements were available for 1948 patients. By 30 June 2011, 528 (23%) had died, and CVD was recorded on the death certificate for 286 (13%; 54% of all deaths). Median CRP level was 8 mg/L (IQR 2–19). The study was powered at ∼80% (at the 5% significance threshold) to detect HR of 1.3 and 1.4, assuming that 23% and 13% of individuals had died by the end of the study, in keeping with observed deaths from all-cause and CVD mortality, respectively.

Genotype frequencies conformed to Hardy–Weinberg expectations and allelic frequencies were similar to those reported in European populations. No association was observed between rs2228145 and baseline levels of CRP (p=0.14) (table 1). Further, rs2228145 did not correlate with all-cause mortality (p=0.76) or CVD mortality (p=0.45) (table 1), even after adjusting for known CVD risk factors and markers previously associated with disease severity (data not shown).

A limitation of the study is that we could not examine the association of the SNP with CVD occurrence but only CVD mortality as the data capture method used information from death certificates. Hence, we are unable to exclude association with CVD morbidity.

In conclusion, our findings in a UK population of patients with IP support a previous report10 showing no association between IL6R SNPs and CVD mortality in patients with RA. Given that the SNP variant mimics tocilizumab action, this study provides no strong indication that the drug will influence CVD mortality in this already high-risk group, but long-term observational studies from National Biologics Registries will be required to fully assess this risk.