CARD8 and IL1B Polymorphisms Influence MRI Brain Patterns in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Hypothermia

Abstract

Inflammation and oxidative stress are recognized as important contributors of brain injury in newborns due to a perinatal hypoxic-ischemic (HI) insult. Genetic variability in these pathways could influence the response to HI and the outcome of brain injury. The aim of our study was to evaluate the impact of common single-nucleotide polymorphisms in the genes involved in inflammation and response to oxidative stress on brain injury in newborns after perinatal HI insult based on the severity and pattern of magnetic resonance imaging (MRI) findings. The DNA of 44 subjects was isolated from buccal swabs. Genotyping was performed for NLRP3 rs35829419, CARD8 rs2043211, IL1B rs16944, IL1B rs1143623, IL1B rs1071676, TNF rs1800629, CAT rs1001179, SOD2 rs4880, and GPX1 rs1050450. Polymorphism in CARD8 was found to be protective against HI brain injury detected by MRI overall findings. Polymorphisms in IL1B were associated with posterior limb of internal capsule, basal ganglia, and white matter brain patterns determined by MRI. Our results suggest a possible association between genetic variability in inflammation- and antioxidant-related pathways and the severity of brain injury after HI insult in newborns.

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

“…In our study, CARD8 rs2043211 T allele was associated with a lower frequency of epilepsy after HIE after the adjustment for neonatal convulsion, but its association was nominally significant only in interaction with IL1B rs16944 after adjustment for neonatal convulsions. Consistent with these results, in our previous study, CARD8 rs2043211 T allele was associated with lower overall rates of brain injury according to the MRI brain injury patterns after HIE in newborns treated with TH [ 32 ]. CARD8 is a component of a multiprotein complex inflammasome, which plays an important role in central nervous system inflammation [ 43 , 44 ].…”

“…CARD8 and IL1B polymorphisms were previously associated with MRI brain injury patterns [32], that were important predictors of epilepsy and CP in our study. We therefore examined the interactions between CARD8 and IL1B polymorphisms and epilepsy or CP.…”

“…Carriers of at least one polymorphic IL1B rs16944 allele were more likely to develop epilepsy only when carrying at least one polymorphic CARD8 rs2043211, further emphasizing the important role of CARD8 - IL1B gene–gene interaction. In our previous study, IL1B rs16944 was associated with an increased risk of posterior limb of internal capsule (PLIC) injury [ 32 ]. Additionally, IL1B rs16944 was associated with development of CP after HIE in a previous study [ 26 ], consistent with our results, and also various other diseases, including mental disorders [ 53 , 54 ].…”

“…The MRI was conducted in line with our previously described protocol [ 32 ]. The patterns of brain injury were classified according to the Rutherford classification [ 33 ].…”

Gene Polymorphism as a Predictor Development of the Children Disease

“…Поліморфізм промотора IL1B (rs1143623) пов'язаний із більш помірними-важкими аномаліями в загальній оцінці МРТ, і новонароджені з принаймні одним поліморфним алелем були більш схильні до пошкоджень базальних гангліїв на основі МРТ. Доведено зв'язок між генетичною мінливістю шляхів, пов'язаних із запаленням і тяжкістю ураження головного мозку у новонароджених [33]. З літературних даних відомо, що індивідууми, гомо-або гетерозиготні за високопродуктивним алелем IL-1 бета (C3953T), продукують відповідно в 4 і 2 рази більше цитокінів, ніж індивідууми з нормальним варіантом досліджуваного гена.…”