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Relevance of Interleukin-1 Receptor Antagonist Intron-2 Polymorphism in Ischemic StrokeSeripa D.a · Dobrina A.b · Margaglione M.c,d · Matera M.G.a · Gravina C.a · Vecile E.b · Fazio V.M.a,e
aMolecular Pathology and Gene Therapy Unit, IRCCS H. ‘Casa Sollievo della Sofferenza’, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, bDepartment of Physiology and Pathology, University of Trieste, cAtherosclerosis and Thrombosis Unit, IRCCS H. ‘Casa Sollievo della Sofferenza’, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, dGenetica Medica, University of Foggia, Foggia, and eLaboratory of Molecular Medicine and Biotechnology, Università Campus Bio-Medico, Rome, Italy
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.
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