Polymorphisms of the endothelin-1 gene associate with hypertension in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) associates with excess cardiovascular (CV) morbidity and mortality. Hypertension, a highly prevalent entity in RA, has been associated with the endothelin-1 (ET-1) gene locus (EDN1) in some groups, such as Afro-Caribbean, the obese, and in low-renin states, but not in the general population as a whole. High levels of plasma ET-1 have been observed in RA. This study evaluated the potential association of EDN1 gene locus and serum ET-1 levels with hypertension in patients with RA. Genomic DNA and serum samples were collected from 397 well-characterized RA patients; DNA was also available from 401 local general population controls without RA. To explore the overall relevance of EDN1, two suitable single-nucleotide polymorphisms (SNPs), rs1800541 and rs5370, were selected and haplotype analysis was performed. Both SNPs were identified using real-time polymerase chain reaction (PCR) and melting curve analysis. Genetic analysis was related to hypertension as dichotomous trait and to blood pressure indices as continuous variables. Serum endothelin levels were also assessed in the RA patients. No genotype or haplotype differences were observed between RA and control subjects. Within RA, logistic regression analysis of each SNP separately revealed a threefold increase in the adjusted odds of being hypertensive of rs5370 TT homozygotes compared to GG homozygotes (OR = 2.89, 95%CI: 1.02 to 8.19). After adjustment for multiple potential confounders, haplotype analysis revealed an additive effect of the rs1800541-rs5370 T-T haplotype on hypertension (OR = 2.96, 95%CI: 1.28 to 6.86; p = .011), systolic blood pressure (SBP) (beta = 6.75 +/- 2.57 mm Hg; p = .009), and pulse pressure (PP) (beta = 4.37 +/- 2.12 mm Hg; p = .040). There was an increased prevalence of raised ET-1 levels amongst hypertensive RA patients, whereas a similar trend was observed for T-T haplotype carriers. RA patients who carry the rs1800541-rs5370 T-T EDN1 haplotype appear more likely to be hypertensive with an increased SBP and PP. These findings, if replicated in future studies, could be used as a screening tool for RA patients at increased hypertension, and thus cardiovascular, risk.