Genetic Polymorphisms and Cerebral Palsy in Very Preterm Infants

Abstract

In the present study, we examine whether selected genetic polymorphisms contribute to the development of cerebral palsy (CP) in very preterm infants. Subjects were 96 singleton infants with later-diagnosed CP and 119 control children, white nonHispanic (n for CP ϭ 74, controls ϭ 88) or white Hispanic (CP ϭ 22, controls ϭ 31), born Ͻ32 wk gestation. Presence of CP was identified through state service agencies, with review of medical records. DNA extracted from archived neonatal blood was genotyped using multi-locus polymerase chain reaction amplification and immobilized sequence-specific oligonucleotide probes. Single nucleotide polymorphisms (SNPs) showing evidence of association with development of CP were endothelial nitric oxide synthase (eNOS) A(-922)G, factor 7 (F7) arg353gln and del(-323)10bp-ins, and lymphotoxin A (LTA) thr26asn. In white non-Hispanic children, beta-2 adrenergic receptor gln27glu was associated with CP risk; in Hispanic children, plasminogen activator inhibitor-1 (PAI-1) 4G(-675)5G and G11053T were associated with risk of CP. In a logistic regression considering these SNPs simultaneously in non-Hispanics, an association with CP was observed for heterozygotes of eNOS -922 (OR 3.0, CI 1.4 -6.4), F7 (OR 2.7, CI 1.1-6.5), LTA (OR 2.1, CI 1.0 -4.6), and PAI-1 (OR 3.2, CI 1.2-8.7). Factor 5, Factor 2, methylene tetrahydrofolate reductase, tumor necrosis factor-alpha, and other SNPs tested were not significantly associated with CP risk. We conclude that further study of genetic factors that may influence susceptibility to CP in very preterm infants is warranted. Abbreviations ADRB-2, adrenergic receptor beta-2 CI, confidence interval CP, cerebral palsy eNOS, endothelial nitric oxide synthase (NOS3) F2, coagulation factor 2, prothrombin F7, coagulation factor 7 LTA, lymphotoxin OR, odds ratio PAI-1, plasminogen activator inhibitor 1 SNP, single nucleotide polymorphism TNF, tumor necrosis factor Genomic analysis has been applied to a wide range of complex disorders, including asthma, cystic fibrosis, cancer, arthritis, and also schizophrenia and autism. We could identify no study that has taken cerebral palsy (CP) as a phenotype for genomic investigation. Given the paucity of known prenatal predictors of CP in very preterm infants, the apparent differences in vulnerability of different infants, and the possibility of racial/ethnic differences in susceptibility to CP and to chronic lung disease, we considered the possibility that genetic factors might play a role in CP occurring in children born very preterm. We report a pilot study using a candidate single nucleotide polymorphism (SNP) approach in children born before 32 wk gestation.Infants born very prematurely are at relatively high risk for CP. To explore the possibility that genetic factors contribute to CP in these very preterm infants, we undertook a study of SNPs in neonatal blood, using a research panel of candidate SNPs developed for the investigation of cardiovascular disease. Many of the SNPs included are potentially relevant to pediat...

Vulnerability of white matter towards antenatal hypoxia is linked to a species-dependent regulation of glutamate receptor subunits

“…Specific genetic polymorphisms for endothelial nitric oxide synthase (eNOS) or plasminogen activator inhibitor-2 in human infants may contribute to spontaneous preterm birth followed by a diagnosis of CP. CP was associated with the beta-2 adrenergic receptor gln27glu in white non-Hispanic children and with the plasminogen activator inhibitor-1 in Hispanic children (17,18). Similarly, common genetic variants in genes encoding pro or antiinflammatory cytokines may influence the risk for spontaneous preterm birth.…”

“…Because excitotoxicity and genetic regulation of glutamatereceptor expression are known to have a key role in brain damage (8,14,17,18), we investigated whether glutamate-receptor expression was altered by hypoxia, and whether these alterations differed between rats and mice, potentially explaining the phenotypic differences noted between these 2 species. We assessed the expression of glutamate-receptor subtypes in rat and mouse at early, intermediate, and late stages of brain development.…”

Methylenetetrahydrofolate reductase gene polymorphisms and cerebral palsy in Chinese infants

“…The genetic influences affecting CP have been the subject of much attention in recent years. [10][11][12]20,21 Several genes have been identified as risk factors, and have been categorized as thrombophilic, cytokine, apolipoprotein E and a group related to cardiovascular physiology and the functioning of the immune system. 21 Among the candidate genes, several SNPs of the MTHFR genes have been investigated either in normal populations or CP patients.…”

“…6 A mounting body of recent evidence points to genetic influences on the occurrence of CP. This evidence includes familial data, 7 twin studies 8 and specific genetic factors, [9][10][11][12] and indicate that CP may be related to genomic factors, as well as to environmental incursions during brain development.…”

β2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort

“…Literature review reveals just one study relating the Glu27 polymorphism and cerebral palsy in very premature infants ( < 32 weeks). 62 Future work in models relevant to the developing nervous system will be needed to determine the biological relevance of these results.…”