Genetic Polymorphisms, Gene–Gene Interactions and Neurologic Sequelae at Two Years Follow-Up in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia

Katarina Esih,Aneta Soltirovska-Šalamon,Vita Dolžan,Zvonka Rener-Primec,Katja Goričar

doi:10.3390/antiox10091495

Katarina Esih, Aneta Soltirovska-Šalamon + Show 3 more

Open Access

https://doi.org/10.3390/antiox10091495

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Abstract

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 (SOD2 rs4880, CAT rs1001179, GPX1 rs1050450) and inflammatory (NLRP3 rs35829419, CARD8 rs2043211, IL1B rs1143623, IL1B rs16944, IL1B rs10716 76, TNF rs1800629) pathways. Polymorphic CARD8 rs2043211 T allele was less frequent in patients with epilepsy, but the association was not statistically significant. The interaction between CARD8 rs2043211 and IL1B rs16944 was associated with epilepsy after HIE: CARD8 rs2043211 was associated with lower epilepsy risk, but only in carriers of two normal IL1B rs16944 alleles (ORadj = 0.03 95% CI = 0.00–0.55; padj = 0.019). Additionally, IL1B rs16944 was associated with higher epilepsy risk only in carriers of at least one polymorphic CARD8 rs2043211 (ORadj = 13.33 95% CI = 1.07–166.37; padj = 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.

Highlights

Perinatal hypoxic-ischemic encephalopathy (HIE) is one of the well-known causes of chronic neurological disability in children, such as epilepsy and/or cerebral palsy (CP) [1].Therapeutic hypothermia (TH) improves survival after HIE, lowers long-term disability rates, lowers the incidence of epilepsy and CP, lessens the severity of CP [2,3], and reduces the frequency of seizures [4], but it is only partly effective [5]
In newborns treated with TH and the development of epilepsy or CP within two years
Our present study investigated the association of the common polymorphisms in antioxidant and inflammatory genes, haplotypes and gene–gene interactions with development of epilepsy and CP after perinatal HIE treated with TH

Summary

Introduction

Perinatal hypoxic-ischemic encephalopathy (HIE) is one of the well-known causes of chronic neurological disability in children, such as epilepsy and/or cerebral palsy (CP) [1]. Therapeutic hypothermia (TH) improves survival after HIE, lowers long-term disability rates, lowers the incidence of epilepsy and CP, lessens the severity of CP [2,3], and reduces the frequency of seizures [4], but it is only partly effective [5]. In newborns with HIE treated with hypothermia epilepsy develops in about 10% [6] and CP in 20% of children [7,8]. The key proteins implicated in these processes are antioxidant enzymes, e.g., superoxide-dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX) [15], Antioxidants 2021, 10, 1495.

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