Vpliv izbranih polimorfizmov v genih za antioksidativne encime in provnetne dejavnike na razvoj cerebralne paralize po neonatalni hipoksično-ishemični encefalopatiji

Esih, Katarina (author), Rener Primec, Zvonka (mentor), Goričar, Katja (comentor)

Neonatalna hipoksično-ishemična encefalopatija (HIE) je posledica obporodnega pomanjkanja kisika v osrednjem živčevju ter je eden najbolj pogostih vzrokov za trajno nevrološko okvaro otrok. Pri nekaterih otrocih se kasneje razvije cerebralna paraliza (CP). Pri HIE pride do povečanega nastanka reaktivnih kisikovih spojin in aktivacije vnetnih procesov. Genetska variabilnost v teh poteh bi lahko vplivala na nastanek CP po HIE. V raziskavi smo se osredotočili na pogoste polimorfizme v ključnih genih, ki sodelujejo pri antioksidativni obrambi in pri vnetnem odgovoru po HIE. Vključili smo 90 otrok z zmerno in hudo HIE. S kompetitivnim alelno-specifičnim PCR smo določili polimorfizme v izbranih genih za antioksidativne encime (SOD2 rs4880, CAT rs1001179, GPX1 rs1050450) in provnetne dejavnike (NLRP3 rs35829419, CARD8 rs2043211, IL1B rs1143623, IL1B rs16944, IL1B rs1071671, TNF rs1800629). Pri otrocih, ki so bili zdravljeni s TH in so po rojstvu opravili MR slikanje glave, je bila stopnja možganske okvare opredeljena po klasifikaciji Rutheford. Povezanost polimorfizmov z razvojem CP po HIE in z izidom na MR smo analizirali z uporabo standardnih statističnih testov. Povezave med izbranimi polimorfizmi in nastankom CP nismo dokazali. V skupini otrok, ki ni bila zdravljena s TH, je bil polimorfen alel NLRP3 rs35829419 nominalno značilno povezan z večjim tveganjem za nastanek CP (p = 0,034). V skupini, zdravljeni s TH, pa preučevani polimorfizmi niso bili povezani s pojavom CP. V skupini, zdravljeni s TH, je bil polimorfni alel CARD8 rs2043211 nominalno značilno povezan z normalno/blago možgansko poškodbo na MR glave (p = 0,040), IL1B rs1143623 C alel pa je bil nominalno povezan z zmerno/hudo možgansko poškodbo na MR (p = 0,040). Hipoteze, da so polimorfizmi v izbranih genih povezani s pojavom CP po HIE, nismo potrdili. Vpliv polimorfizmov na izid po HIE je bil do sedaj slabo poznan, zato rezultati predstavljajo izhodišče za nadaljnja raziskovanja na tem področju z večjim številom preiskovancev.

• Language: Slovenian
• Keywords: hipoksično-ishemična-encefalopatija, cerebralna paraliza, oksidativni stres, vnetje, polmorfizmi, novorojenček, terapevtska hipotermija.
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2022
• PID: 20.500.12556/RUL-143491
• COBISS.SI-ID: 146295299
• Publication date in RUL: 23.12.2022

Secondary language

• Language: English
• Title: ​The impact of selected polymorphisms in antioxidative enzymes and proinflammatory genes on the development of cerebral palsy after neonatal hypoxic-ischemic encephalopathy

Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) results from peripartum or intrapartum brain tissue hypoxia and ischemia and is a common cause of long-term neurologic sequelae, including cerebral palsy (CP). Hypoxic-ischemic (HI) insult results in oxidative stress and activation of inflammatory processes. Genetic variability in these pathways could influence the development of CP after HIE. The aim of our study was to evaluate the association of the selected single nucleotide polymorphisms (SNPs) in the genes involved in response to oxidative stress and inflammation with the development of CP after HIE. Ninety children with moderate and severe HIE were included in the study. Genotyping using competitive allele-specific PCR was performed for polymorphisms in genes encoding antioxidant enzymes (SOD2 rs4880, CAT rs1001179, GPX1 rs1050450) and proinflammatory factors (NLRP3 rs35829419, CARD8 rs2043211, IL1B rs1143623, IL1B rs16944, IL1B rs1071676, TNF rs1800629) that could contribute to the development of CP after HIE. In children treated with TH where MRI was performed, it was classified according to the Rutheford classification. Standard statistical tests were used to evaluate the association of selected SNPs with the development of CP. No association between the selected SNPs and the development of CP was found. Polymorphic NLRP3 rs35829419 allele was nominally significantly associated with the development of CP in children who were not treated with TH (p = 0.034). None of the SNPs were associated with CP in children treated with TH. Among children treated with TH polymorphic allele CARD8 rs2043211 was nominally significantly associated with normal/mild MRI overall findings (p = 0.040) and IL1B rs1143623 C allele was nominally significantly associated with moderate/severe MRI overall findings (p = 0.040). The association of genetic variability with the outcome after HIE has so far not been well established, therefore the results of our study represent foundations for future research in larger studies.

• Keywords: hypoxic-ischemic encephalopathy, cerebral palsy, inflammation, oxidative stress, inflammation, polymorphism, newborn, therapeutic hypothermia.