Relevance of Interleukin-1 Receptor Antagonist Intron-2 Polymorphism in Ischemic Stroke

Abstract

Evidence of inflammatory phenomena associated with atherosclerotic plaques is extensive. Interleukin-1 (IL-1) is one of the key modulators of the inflammatory response, and its activity is critically regulated by its receptor antagonist (IL-1Ra). A variable number of tandem repeats (VNTR) in intron 2 of the human IL-1Ra shows a common polymorphism that has been related to different production of IL-1Ra and IL-1 proteins. In monocytes, the less common allele 2 has been associated with an increased production of IL-1Ra and a decreased production of IL-1. Moreover, a cooperative effect with a C to T polymorphism in the promoter of IL-1β gene (C^–511→T) has been described. In the present study, we investigated the frequency of these polymorphisms in 110 subjects who survived an ischemic stroke, in 101 healthy age-matched individuals, and in a population-based sample of 1,303 healthy Italians. The frequency of the IL- 1Ra 1/1 genotype was significantly higher in stroke survivors with respect to age-matched controls (77.2 and 45.5%, respectively; p < 0.001), and to the wide group of healthy Italians (77.2 and 51.9%, respectively; p < 0.001). As expected, the estimated frequency of the IL-1Ra allele 1 (Ra*1 allele) in stroke survivors was higher than in age-matched controls (0.851 and 0.664, respectively; p < 0.001) and in healthy Italians (0.851 and 0.717, respectively; p < 0.001). Thus, ischemic stroke survivors that carry the Ra*1 allele showed a strong association with the disease with respect to age-matched controls [odds ratio (OR) = 3.905; 95% confidence interval (CI), 2.110–7.229] and healthy Italians [OR = 3.256 (95% CI, 1.971–5.379)]. No significant association was seen for the IL-1β (C^–511→T) polymorphism. However, in stroke survivors, an association between the Ra*1 allele and the C allele of the IL-1β (-511) polymorphism was found (p < 0.001). Our results implicate the IL-1Ra gene in the susceptibility to ischemic stroke, and suggest that IL-1Ra genotyping may be useful in the identification of patient subgroups for pharmacological intervention in IL-1 production or actions.

Interleukin 1 Beta Polymorphism (–511) and Risk of Stroke due to Small Vessel Disease

“…Previous studies did not find any significant association between the IL-1β polymorphism (–511) and ischemic stroke [8, 9]. Although the IL-1β polymorphism seems not to be a risk factor for ischemic stroke in the general population, it could be associated with a particular stroke subtype.…”

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines

“…29 Furthermore, studies of the IL-1 and IL-1RA genes suggest that polymorphisms in both IL-1a and IL-1RA genes may be associated with increased risk of stroke. [30][31][32] Similarly, TNF-a has been hypothesized to play an important role in neurodegeneration. 33 TNF-a release from blood cells and serum levels of TNF-a were found to be elevated during the acute phase following stroke compared with healthy controls.…”

IL1RN VNTR Polymorphism in Ischemic Stroke

“…25 Our results contrast with those reported in an earlier Italian study that found a higher frequency of both carriage of the IL1RN*1 allele and homozygosity for IL1RN*1 among stroke survivors than in a control group. 26 However, the impact of survival bias must be considered. IL1RN*2 is associated with increased susceptibility to cerebral ischemia, 23 which may impact stroke severity and survival.…”