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Inflammation and oxidative stress after hypoxic-ischemic brain injury may be modified by genetic variability in addition to therapeutic hypothermia. The aim of our study was to evaluate the association between the polymorphisms in genes of antioxidant and inflammatory pathways in newborns treated with therapeutic hypothermia and the development of epilepsy or CP at two years follow-up. The DNA of 55 subjects was isolated from buccal swabs. Genotyping using competitive allele-specific PCR was performed for polymorphisms in antioxidant (<i>SOD2</i> rs4880, <i>CAT</i> rs1001179, <i>GPX1</i> rs1050450) and inflammatory (<i>NLRP3</i> rs35829419, <i>CARD8</i> rs2043211, <i>IL1B</i> rs1143623, <i>IL1B</i> rs16944, <i>IL1B</i> rs10716 76, <i>TNF</i> rs1800629) pathways. Polymorphic <i>CARD8</i> rs2043211 T allele was less frequent in patients with epilepsy, but the association was not statistically significant. The interaction between <i>CARD8</i> rs2043211 and <i>IL1B</i> rs16944 was associated with epilepsy after HIE: <i>CARD8</i> rs2043211 was associated with lower epilepsy risk, but only in carriers of two normal <i>IL1B</i> rs16944 alleles (OR_adj = 0.03 95% CI = 0.00–0.55; p_adj = 0.019). Additionally, <i>IL1B</i> rs16944 was associated with higher epilepsy risk only in carriers of at least one polymorphic <i>CARD8</i> rs2043211 (OR_adj = 13.33 95% CI = 1.07–166.37; p_adj = 0.044). Our results suggest that gene–gene interaction in inflammation pathways might contribute to the severity of brain injury in newborns with HIE treated with therapeutic hypothermia.