Relevance of interleukin-1 receptor antagonist intron-2 polymorphism in ischemic stroke.
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-1beta 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-1beta (C(-511)-->T) polymorphism. However, in stroke survivors, an association between the Ra*1 allele and the C allele of the IL-1beta (-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.
Seripa
Davide
D
Molecular Pathology and Gene Therapy Unit, IRCCS H. 'Casa Sollievo della Sofferenza', Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, Italy.
Dobrina
Aldo
A
Margaglione
Maurizio
M
Matera
Maria Giovanna
MG
Gravina
Carolina
C
Vecile
Elena
E
Fazio
Vito Michele
VM
D000328:Adult; D000368:Aged; D002545:Brain Ischemia / Q000150:complications* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics*; D007438:Introns / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020521:Stroke / Q000209:etiology* / Q000235:genetics*; D017741:Survivors
D007375:Interleukin-1; D017472:Receptors, Interleukin-1