Published online October 31, 2008
PEDIATRICS Vol. 122 No. 5 November 2008, pp. 1079-1085 (doi:10.1542/10.1542/peds.2007-3758)
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ARTICLE

Candidate Genes and Cerebral Palsy: A Population-Based Study

Catherine S. Gibson, PhDa, Alastair H. MacLennan, MDa, Gustaaf A. Dekker, MD, PhDa, Paul N. Goldwater, MDa,b, Thomas R. Sullivan, Bma&CompScc, David J. Munroe, PhDd, Shirley Tsang, PhDd, Claudia Stewart, BSd and Karin B. Nelson, MDe,f

Schools of a Paediatrics and Reproductive Health
c Population Health and Clinical Practice, University of Adelaide, Adelaide, Australia
b Department of Microbiology and Infectious Diseases, Women's and Children's Hospital, Adelaide, Australia
d Laboratory of Molecular Technology, SAIC-Frederick, Inc, National Cancer Institute, Frederick, Maryland
e National Institute of Neurological Disorders and Stroke, Bethesda, Maryland
f Department of Neurology, Children's National Medical Center, Washington, DC

OBJECTIVE. The objective of this study was to examine whether selected genetic polymorphisms in the infant are associated with later-diagnosed cerebral palsy.

METHODS. A population-based case-control study was conducted of 28 single-nucleotide polymorphisms measured in newborn screening blood spots. A total of 413 children with later-diagnosed cerebral palsy were born to white women in South Australia in 1986–1999, and there were 856 control children. Distributions of genotypic frequencies were examined in total cerebral palsy, in gestational age groups, and by types of cerebral palsy and gender. Genotyping was performed by using a TaqMan assay.

RESULTS. For inducible nitric-oxide synthase, possession of the T allele was more common in all children with cerebral palsy and for heterozygotes who were born at term. For lymphotoxin {alpha}, homozygous variant status was associated with risk for cerebral palsy and with spastic hemiplegic or quadriplegic cerebral palsy. Among term infants, heterozygosity for the endothelial protein C receptor single-nucleotide polymorphism was more frequent in children with cerebral palsy. In preterm infants, the variant A allele of interleukin 8 and heterozygosity for the β-2 adrenergic receptor were associated with cerebral palsy risk. Interleukin 8 heterozygote status was associated with spastic diplegia. Variants of several genes were associated with cerebral palsy in girls but not in boys.

CONCLUSIONS. Two of the 28 single-nucleotide polymorphisms examined were associated with all types of spastic cerebral palsy in both gestational age groups and others with cerebral palsy in gestational age or cerebral palsy subgroups. Some of these associations support previous findings. There may be a genetic contribution to cerebral palsy risk, and additional investigation is warranted of genes and gene-environment interactions in cerebral palsy.

Key Words: cerebral palsy • genetics • prematurity • nitric-oxide synthase • IL-8

Abbreviations: CP—cerebral palsy • SNP—single-nucleotide polymorphism • GA—gestational age • SD—spastic diplegia • iNOS—inducible nitric-oxide synthase • LTA—lymphotoxin {alpha} • TNF-{alpha}—tumor necrosis factor {alpha} • OR—odds ratio • CI—confidence interval • EPCR—endothelial protein C receptor • IL-8—interleukin 8 • ADRB2—β-2 adrenergic receptor • PAI-1—plasminogen activator inhibitor type 1 • ALOX5AP-2—arachidonate 5-lipoxygenase activating protein • eNOS—endothelial nitric-oxide synthase • APC—activated protein C

Accepted Mar 3, 2008.


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