Abstract
Perinatal asphyxia in the neonatal brain triggers a robust inflammatory response in which nitric oxide (NO) generation plays a hazardous role. Increased levels of NO can be maintained by the activity of inducible NO synthase (NOS2A) on its own or activated by IL-1beta (IL-1β) gene transcription and positive back stimulation of the NOS2 (CCTTT)n microsatellite by IL-1β, thus potentiating brain injury after ischemic perinatal asphyxia. We investigated whether the risk for cerebral palsy (CP) increases when an expansion of the − 2.5 kb (CCTTT)n microsatellite in the NOS2A gene and a single nucleotide polymorphism (SNP) in -C511T of the IL- IL-1β gene promoter occur in patients after perinatal hypoxic-ischemic encephalopathy. Genomic DNA was purified from peripheral leukocytes of 48 patients with CP and of 57 healthy control children. IL-1β SNP genotypes were established using a real-time PCR technique and fluorogenic probes and were validated by restriction fragment length polymorphism (RFLP) analysis using the AvaI restriction enzyme. The length of the CCTTTn microsatellite in the NOS2 gene promoter was determined by automated sequencing. The 14 repeat-long allele of the CCTTTn NOS2A microsatellite was present in 27% of CP patients vs 12.3% of controls, showing an odds ratio (OR) = 2.6531 and 95% confidence interval (CI) = 0.9612–7.3232 (P < 0.0469). The -511 TT genotype frequency showed an OR = 2.6325 (95% CI = 1.1348–6.1066, P = 0.0189). Interestingly, the haplotype CCTTT14/TT showed an OR = 9.561 (95%, CI = 1.1321–80.753; P = 0.0164). The haplotype (CCTTT)14/TT, formed by the expansion of the − 2.5 kb (CCTTT)n microsatellite in the NOS2A gene promoter and the -511 C➝ T SNP of the IL-1β gene promoter, might be a useful marker to identify patients who are at high risk for developing CP after hypoxic-ischemic encephalopathy.
Highlights
Intrauterine, partum, and neonatal asphyxia results in hypoxicischemic encephalopathy (HIE), which is the leading cause of cerebral palsy (CP) in developing countries [1]
The promoter of NOS2A at position − 2.5 kb presents the expansion of pentanucleotide polypyrimidine microsatellite CCTTT that has been associated with nitric oxide (NO) overproduction [12], which depends on the number of repeats of the motif
The CP group was composed of 48 children who met the following criteria: (1) term product with more than 36 gestation weeks, (2) record of perinatal hypoxia/ischemia in neonatal medical records, (3) no genetic diseases, and (4) no brain malformations
Summary
Intrauterine, partum, and neonatal asphyxia results in hypoxicischemic encephalopathy (HIE), which is the leading cause of cerebral palsy (CP) in developing countries [1]. The production of nitric oxide (NO) increases the levels of peroxynitrites [2] that, together with superoxides [3, 4], cause neuronal damage by inducing lipid peroxidation, chromatinorrhexis, and structural protein degradation [5]. Previous studies have determined that the specific haplotype T allele at − 511 and C allele at − 31 in the IL1β gene promoter increase the production and release of IL-1β by two- to threefold under inflammatory conditions [18]. Patients carrying the single nucleotide polymorphism (SNIP) at the − 511 position of the IL-1β gene promoter together with the expansion of the CCTTT microsatellite in the NOS2A promoter might be more susceptible to develop CP after HIE. Our main aim was to explore this possibility by comparing CP children with healthy control children
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