Candidate Genes and Cerebral Palsy: A Population-Based Study

Abstract

Interference with delivery of oxygen to the fetus or infant and other environmental risk factors have been associated with the development of cerebral palsy (CP). Several lines of evidence suggest that genetic risk factors are also involved; genes associated with vascular disease or inflammation, the fetal inflammatory response, and the apolipoprotein E genotype are all associated with increased susceptibility to CP. In addition, increased risk of CP has been demonstrated among groups with high rates of consanguinity and in certain families. This population-based study evaluated the association of selected genetic polymorphisms with later-diagnosed CP among 413 South Australian children born to Caucasian mothers between 1986 and 1999. Blood samples obtained from newborn screening blood spots were tested for 28 single-nucleotide polymorphisms (SNPs) using TaqMan assays. The genotype frequencies were evaluated in all cases of cerebral palsy, and in subgroups based on gestational age (<37 or ≥37 weeks), the type of cerebral palsy (diplegia, hemiplegia, or quadriplegia), and gender. Logistic regression models were used to assess associations between genotypic distributions and CP. The risk for CP in both gestational age groups was significantly associated with polymorphisms of 2 SNPs: inducible nitric oxide synthase (iNOS) and lymphotoxin a (also called LTA or tumor necrosis factor β (TNF-β). For iNOS, presence of the T allele was more common in all children with CP and among heterozygotes born at term. Homozygous variant status for LTA was associated with risk for CP and with spastic hemiplegic or quadriplegic CP. In addition to iNOS, heterozygosity for the endothelial protein C receptor SNP was more frequent among children with CP. Among infants born preterm, the variant A allele of interleukin 8 and heterozygosity for the β-2 adrenergic receptor were associated with CP. Interleukin 8 heterozygosity was associated with spastic diplegia. Some gene variants were found in girls with CP but not in boys. These findings, together with previous studies, suggest that certain genes are associated with increased susceptibility to CP.