Genetic variation at the interleukin-1 locus is a determinant of changes in soluble endothelial factors in patients with acute coronary syndromes

Acute coronary syndromes (ACSs) are associated with both systemic inflammatory activation and endothelial cell activation, and both of these are linked to patient outcome. Genetic variation at the interleukin-1 (IL-1) locus influences the clinical patterns of inflammatory disease. We therefore examined the association between IL-1 gene polymorphisms and levels of systemic inflammatory activation markers [C-reactive protein (CRP) and IL-1 receptor antagonist (IL-1ra)] and of soluble endothelial activation markers [von Willebrand factor (vWF) and E-selectin], in a cohort of 63 patients presenting with non-ST-elevation ACS. The IL-1 locus did not significantly influence any of the markers studied at 24h after presentation. Associations of IL-1 polymorphisms with the changes (Δ) in CRP, IL-1ra, E-selectin and vWF levels between 24 and 48h were examined in later studies. ΔCRP and ΔIL-1ra showed no significant association with any of the polymorphisms studied. There was a strong association between carriage of the rare allele (allele 2) of the intron 2 variable number of tandem repeats polymorphism of IL-1RN (designated IL-1RN*2) and ΔE-selectin levels: {carriage of *2, 3.03 ng/ml [95% confidence interval (CI) 6.26 to 1.51ng/ml]; non-carriage of *2, 0.12ng/ml (95% CI 1.07 to -1.76ng/ml); P = 0.0016}, and also between carriage of IL-1RN*2 and ΔvWF levels [carriage of *2, 0.78i.u./ml (95% CI 0.96 to 0.44i.u./ml); non-carriage of *2, 0.1i.u./ml (95% CI 0.19 to -0.1i.u./ml); P = 0.0003]. A composite analysis consisting of carriage of IL-1RN*2 and the genotype at position -511 in the IL-1B gene suggests the existence of haplotypes that influence ΔvWF and ΔE-selectin in patients with ACS. Carriage of IL-1RN*2 was also associated with a 2-fold increased likelihood of a troponin-positive status compared with non-carriage (P = 0.0385). These data indicate that, in the setting of non-ST-elevation ACS, genetic variation at the IL-1 gene locus contributes to the changes in soluble markers of endothelial inflammation.