Abstract
Preterm delivery is associated with neurodevelopmental impairment caused by environmental and genetic factors. Dysfunction of the excitatory amino acid transporter 2 (EAAT2) and the resultant impaired glutamate uptake can lead to neurological disorders. In this study, we investigated the role of single nucleotide polymorphisms (SNPs; g.-200C>A and g.-181A>C) in the EAAT2 promoter in susceptibility to brain injury and neurodisability in very preterm infants born at or before 32-week gestation. DNA isolated from newborns’ dried blood spots were used for pyrosequencing to detect both SNPs. Association between EAAT2 genotypes and cerebral palsy, cystic periventricular leukomalacia and a low developmental score was then assessed. The two SNPs were concordant in 89.4% of infants resulting in three common genotypes all carrying two C and two A alleles in different combinations. However, in 10.6% of cases, non-concordance was found, generating six additional rare genotypes. The A alleles at both loci appeared to be detrimental and consequently, the risk of developing cerebral palsy increased four- and sixfold for each additional detrimental allele at -200 and -181 bp, respectively. The two SNPs altered the regulation of the EAAT2 promoter activity and glutamate homeostasis. This study highlights the significance of glutamate in the pathogenesis of preterm brain injury and subsequent development of cerebral palsy and neurodevelopmental disabilities. Furthermore, the described EAAT2 SNPs may be an early biomarker of vulnerability to neurodisability and may aid the development of targeted treatment strategies.
Highlights
Progress in perinatal care over the last three decades has led to greater survival rates in infants born prematurely [1, 2]
We identified that single nucleotide polymorphisms (SNPs) g.200C>A in the excitatory amino acid transporter 2 (EAAT2) promoter is strongly linked to the previously described functional SNP g.-181A>C [19], which has not been reported in earlier studies [19, 20, 35]
We have found that g.-200C>A and 181A>C SNPs are associated with both clinical neurodevelopmental outcomes and measurable in vitro effects on glutamate homeostasis
Summary
Progress in perinatal care over the last three decades has led to greater survival rates in infants born prematurely [1, 2]. The incidence of premature birth in developed countries varies from 7.6–12% of all births [3]. While 90% of very preterm infants (below 32-week gestation) survive beyond the postpartum period, ~35% have neurodisabilities [4]. These disabilities include cerebral palsy, cognitive- and behavioural problems [5]. Better diagnostic approaches for the early identification of infants with higher risk of neurodisability are important to facilitate the development and application of appropriate treatment strategies
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