PEDIATRICS Vol. 122 No. 5 November 2008, pp. 1079-1085 (doi:10.1542/peds.2007-3758)
ARTICLE |
Candidate Genes and Cerebral Palsy: A Population-Based Study
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
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ABSTRACT |
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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 
, 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 • TNF-—tumor necrosis factor • 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
The earliest discussion of the cause of cerebral palsy (CP)1 and much of the literature subsequently have centered on environmental risk factors, especially those that involve interference with delivery of oxygen to the fetus or infant. Increasing use of neuroimaging has led to awareness that often hemiparetic CP and sometimes quadriplegic CP are caused by perinatal ischemic stroke.2 Perinatal stroke, in turn, is sometimes or often related to inherited thrombophilias.3 Other genetic factors may also be linked with CP risk: Australian4 and American5 studies have observed that certain genes that are associated with vascular disease or inflammation, and the fetal inflammatory response, were risk factors for CP, and an apolipoprotein E genotype is associated with increased vulnerability to CP.6,7 Additional evidence that genetic factors may contribute to CP risk is suggested by familial aggregation of CP in groups with high consanguinity8 and by the observation of increased familial risk for CP in a national Swedish database.9
We report an examination of selected genetic variants in a population-based study of South Australian children who previously were investigated for cytokine4 and thrombophilic variants10 in CP. Candidate single-nucleotide polymorphism (SNPs) were chosen because of their published association with CP5 or with stroke in relatively young patients. Our objective was to reevaluate previous findings and to identify other possible candidate genes that may be associated with CP to help in development of a priori hypotheses for future genomic studies.
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METHODS |
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Subjects
The study population consisted of all children who had CP and were born in 1986–1999 in South Australia to white mothers (n = 443), ascertained by the South Australia Cerebral Palsy Register from notifications by pediatricians, hospitals, and child treatment centers. A total of 883 infants who did not have CP and were born to white mothers between the 1986 and 1999 were selected for comparison. Newborn screening cards were identified by the South Australia Newborn Screening Program for each case. Potential control subjects were 4 infants who survived at least to 1 year of age, whose dates of birth were within a few days of each child with CP, whose hospital where blood was sampled was of the same category (metropolitan teaching, metropolitan private, or country), and whose blood was sampled on approximately the same day of life as the case patients. The control population included a higher proportion of preterm infants than in the general population, because many of the patients with CP were born preterm and had been referred to metropolitan teaching hospitals. Linkage was attempted for all case patients and potential control subjects to the South Australia Perinatal Data Collection of births, with its large number of sociodemographic and clinical variables. This was successful for all case patients and 1691 control subjects. A total of 268 (15.8%) of these 1691 control subjects were excluded because they were children of nonwhite mothers (n = 102), had a birth defect as identified from the South Australia Birth Defects Register (n = 161), or died in the first year of life (n = 37). Some control subjects were excluded for >1 reason. Two control subjects were then selected from the remaining control subjects in each group of 4, using random numbers, to form the control population of 886. Because 3 control subjects had inadvertently been selected more than once, the final number of control subjects was 883. The data from all case patients and control subjects were de-identified before testing for polymorphisms and statistical analysis. This research was approved by the Children, Youth and Women's Health Service (Adelaide, Australia).
Genotyping
The 5' nuclease assay was used, with oligonucleotide probes labeled with 2 fluorescent dyes, FAM and VIC, to distinguish between the 2 alleles of each biallelic SNP. All assays were designed and developed either using Assay-by Design (Applied Biosystem Inc, Foster City, CA) or Primer Express software 2.0 (Applied Biosystem). All oligo primers and probes were synthesized by Applied Biosystem, Inc. Assays were validated and optimized using in-house samples of DNA collected from European individuals, with a no-template control and control DNAs of known genotype run on each assay plate for quality control. Assays were set up in 384-well plates by using 2.5 µL of 2x the TaqMan Universal Master Mix (No AmpErase UNG), which contains all 4 deoxynucleotides, Taq polymerase, and TaqMan buffer, 0.125 µL of 40x Assay Mix including forward/reverse primers and FAM- and VIC-labeled probes, and 1 to 5 ng of genomic DNA diluted in dH2O in a final volume of 5 µL reactions. The thermal cycling conditions for the ABI 7900HT sequence detector were an initial denaturation step, 95°C for 5 minutes followed by 40 cycles each of 92°C for 15 seconds and 60°C for 1 minute.
Data output was processed and downloaded electronically into analysis programs. The SDS 2.1 was used to determine the genotypes of the samples. Some data points did not cluster well; these were eliminated in the analysis. The final sample consisted of 413 children with CP and 856 control subjects. All testing for polymorphisms was performed blind to CP/control status. Indecisive calls were excluded, leading to slightly different numbers for different SNPs. The SNPs tested and their abbreviations, gene locations, and identifying numbers are presented in Table 1.
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Statistical Analysis
The associations between genotypic distributions and CP were assessed using logistic regression models. In addition to overall models that assessed the difference in genotypic distributions between CP case patients and control subjects, separate models were fitted according to gestational age (GA) of case patients and control subjects (<37 or
37 weeks), CP type (diplegia, hemiplegia, or quadriplegia) and gender. P < .05 was considered to be statistically significant. No adjustments for multiple comparisons were made. All calculations were performed by using SAS 9.1 (SAS Institute, Inc, Cary, NC). |
RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Of the 413 children with CP in this study, 31.5% had spastic diplegia (SD), 28.8% had congenital hemiplegic CP, and 27.1% had quadriplegic CP. The CP was other or unclassified in an additional 52 children, a heterogeneous group not considered further. SD was the dominant form of CP in preterm-born infants, present in 51% of infants who had CP and were born before 37 weeks' GA.
Genotypic distribution differed in children with CP as compared with control children in both GA groups with respect to 2 of the tested SNPs (Table 2): inducible nitric-oxide synthase (iNOS; –231 C/T) and lymphotoxin (LTA [also called tumor necrosis factor β (TNF-β)]; T60N). For iNOS, possession of the T allele in either heterozygous or homozygous state was more common in children with CP in both GA groups (odds ratio [OR]: 1.290 [confidence interval (CI): 1.003–1.670]; P = .048), the difference being more marked for heterozygotes born at term (OR: 1.57 [95% CI: 1.12–2.23]; P = .009). For LTA, homozygous AA status was associated with risk for CP (OR: 1.490 [95% CI: 1.012–2.180]; P = .043) and with spastic hemiplegic or quadriplegic CP (Table 3).
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Among infants who were born after 37 weeks' GA, in addition to iNOS, heterozygosity for the endothelial protein C receptor SNP (EPCR) (4600 A/G) was more frequent in children with CP (OR: 1.58 [95% CI: 1.05–2.33]; P = .028). Among preterm infants, the variant A allele of interleukin 8 (IL-8; –251 A/T; for heterozygote or homozygote versus wild-type; OR: 2.11 [95% CI: 1.29–3.43]; P = .027) and heterozygosity for the β-2 adrenergic receptor (ADRB2; Q27E; OR: 1.65 [95% CI: 1.04–2.63]; P = .032) were associated with CP risk. The IL-8 heterozygote was especially associated with SD.
When all types of spastic CP in both GA groups were examined within gender (Table 4), variants of iNOS (NOS2A), the plasminogen activator inhibitor type 1 (PAI-1; 675 4G/5G), of arachidonate 5-lipoxygenase activating protein (ALOX5AP-2; or LPGA SG13S32), and methylene tetrahydrofolate reductase (677 C/T) were observed more frequently in girls with CP than in female control subjects but not in boys. ORs for girls ranged from 1.74 to 2.77. One or another CP subgroup was associated with PAI-1 675 4/5G and with PAI-1 11053 G/T in girls and SD with PAI-1 675 4G/5G, PAI-1 asn120asp and PAI-1 ser413cys in boys. ALOX5AP-2 was associated with SD in boys. Factor 2 and factor 5 were examined previously10 and were not associated with CP risk in the total or in any subgroup examined.
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In summary, 2 SNPs, iNOS and LTA, were associated with total CP as were an additional 4 SNPs in girls but not in boys. CP was associated in term infants with variants of iNOS and EPCR and in preterm with IL-8 and ADRB2 variants.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This exploratory population-based study, the largest to date of genetic factors in CP, investigated candidate SNPs in infants of all GAs. Two of the 28 SNPs examined (iNOS and LTA) were associated with CP in the total population, and iNOS and EPCR variants were related to CP risk in term infants and ADRB and IL-8 in infants who were born preterm. A previous and considerably smaller study in very preterm infants in northern California had observed associations of CP with variants of endothelial nitric-oxide synthase (eNOS), LTA, factor 7, and ADRB2.5 In a previous study in this South Australian cohort, the cytokines TNF-
and mannose-binding lectin (MBL) were related to CP subgroups,10 and this investigation adds IL-8 to the list of cytokine (chemokine) genes related to CP risk in preterm infants. Thus, there is support for the association of CP with NOSs and certain cytokines, suggesting relevance of nitratoxic and inflammatory processes. The association of CP with an ADRB2 variant suggests a role for control of blood flow in placenta and brain as a potential contributor to CP. In addition, EPCR and several of the other genes that were found to be associated with CP in our study are active at the endothelial surface, suggesting endothelial dysfunction in the vasculature of placenta and brain as a process to be considered in CP pathobiology. Our findings do not establish, however, that it is the named genes, rather than those in linkage disequilibrium with them, that are involved in the mechanisms underlying CP. These findings do suggest that these genes or others near them play some role. There are genetic contributions to a number of obstetric risk factors for CP, including preterm birth, abruption of the placenta, breech presentation, preeclampsia, fetal growth restriction, chorioamnionitis, and others. It is likely that genes can influence vulnerability to CP at a number of points along the causal pathway.
Gender differences have been described in some of the pathophysiologic processes that are thought to underlie CP,11,12 but this is the first study to examine gender differences in genetic susceptibility to CP. We observed 4 SNPs that were associated with CP in girls but not in boys.
The greatest limitation of this study is that the associations observed between genotype and CP might have arisen by chance, in the absence of statistical adjustment for multiple comparisons. It is reassuring that a previous study noted some of these associations,5 but obviously additional studies in other populations are needed to confirm or refute the genetic associations described in this study. Definitive study will also require information on potential sources of variance in mother, child, and environment; a huge sample size; and adjustment of statistical testing for multiple comparisons. Such a prospective 3-year study by this group was recently funded and will allow a priori testing of the candidate genes highlighted by this research. A more immediate option may be to combine these data and those from other observational studies in a HuGE review.13 Large geographically defined CP registries and large national birth cohorts that can provide huge sample size for future studies are now being collected. This study, considered with those preceding it, should stimulate future investigations of genotype and CP.
Other limitations of this study include the absence of neuroimaging information so that subgrouping of case children could be based only on GA and clinical CP subtype, not on morphologic substrate. Sample size did not permit analysis by GA and subtype simultaneously. No information on maternal genotype or environmental risk factors was available. Our study included the single racial group that makes up the majority of the population of the study region but does not provide information on non-European–derived individuals.
The risk for CP in both GA groups was associated with iNOS and LTA polymorphisms. In addition to its major effects on vasomotor regulation, NO is of great importance in inflammation, coagulation via platelet aggregation, and leukocyte adhesion to vascular endothelium.14 NOS activity is higher in brain than in any other tissue.15 iNOS is especially involved in inflammatory responses and after ischemic injury and, when excessive, can lead to formation of peroxynitrite and thus to additional injury.16 Shen et al17 concluded that "iNOS might be a key mediator between intrauterine infection and oligodendrocyte injury in the developing brain." Overexpression of iNOS has been observed in regions of white matter injury in infants18 and in adult brain after infarction.19
LTA (also called TNF-β) is a cytokine that shares receptors with TNF-. A TNF- variant, –308, was previously noted to be associated with CP risk in this population.4 LTA is critically related to the inflammatory response. Polymorphism of the thr26asn SNP is associated with secretion of higher levels of TNF and of adhesion molecules, contributing to the inflammatory response.20 LTA variants are also associated with higher levels of C-reactive protein, an inflammatory marker, with increased risk for ischemic stroke or myocardial infarction in adults,21,22 and with susceptibility to and adverse outcome in sepsis.
Term CP was associated with iNOS and EPCR variants. The EPCR polymorphisms could potentially affect the protein C pathway, but its exact actions remain unknown. Activated protein C (APC) is a natural anticoagulant and is anti-inflammatory and antiapoptotic. The action of APC depends on binding to EPCR, which acts in concert with thrombomodulin. APC reduced lipopolysaccharide-induced white matter injury in fetal rat brain23 and has been proposed as treatment for perinatal white matter injury.24 The tested EPCR variant was not associated with a specific CP subtype.
Preterm CP was associated with IL-8 and ADRB2 polymorphisms. IL-8 levels are higher in neonates who are born preterm than in term infants and higher in term neonates than in adults.25 In preterm infants, IL-8 levels were higher in cerebrospinal fluid than in blood, compatible with a source within the central nervous system.26 In infants with later CP, levels of inflammatory cytokines including IL-8 were higher in children with CP27,28 and highest in those with SD, the CP subtype most common in preterm infants. Chemokine receptors are found in microglia, astrocytes, and neurons, and their activation may alter neuronal migration, cell proliferation, and synaptic activity.29 The variant A allele of IL-8, observed in our study to be linked with risk for CP in preterm infants and with SD, is associated with overproduction of IL-8 protein.
ADRB2 is involved in regulation of cerebral blood flow and is thought to play an important role in brain injury in preterm infants. Receptor-dependent responsiveness of cerebral blood flow to adrenergic stimulation is essential for fetal and neonatal adaptation to the stresses of birth, infection, hypoxia, and hyperoxia. β-Adrenergic receptor stimulation also influences placental circulation,30 modulates inflammatory responses to infection,31 and influences the secretion of C-reactive protein, a marker and participant in inflammation.32 We33 and others have reported that polymorphisms of ADRB2 are associated with spontaneous preterm birth, and this study also shows that ADRB2 and eNOS were associated with CP risk among children who were born preterm.
SD is the CP subtype most prevalent in preterm-born infants. Neuroimaging studies observe disorders of cerebral white matter in most children with SD and in a smaller proportion of those with other spastic CP subtypes.34,35 The white matter lesions underlying SD are thought to arise before 
34 weeks' GA, but fetuses with such lesions can go on to deliver at term. Inflammation is a common cause of preterm birth and an important risk factor for white matter disorder. Inflammation induces increased levels of a number of cytokines in infant blood, including IL-8 and LTA. Overexpression of iNOS, which can be induced by products of infection, has been observed in brain in perinatal white matter disorder, in brain regions in which there was apoptosis.18 We found an iNOS polymorphism to be associated with CP in total and in term infants and another NOS isoform, eNOS, to be related to SD.
Quadriplegic CP is characterized by severe and bilateral abnormality of brain, rather than by a specific pathologic mechanism. Spastic quadriplegia and hemiplegic CP were associated in this study with a variant of LTA, a cytokine of the TNF family.
In hemiplegic CP, the pathology in term and near-term infants is most commonly arterial ischemic stroke or congenital malformation, whereas in preterm infants, congenital hemiparesis may more often be attributable to asymmetric white matter disorder.36 Hemiplegic CP was associated in this study with a variant of LTA. The several thrombophilic gene variants that we examined, including factor 2 (the prothrombin mutation) and factor 5 (the Leiden mutation), proved not to be associated with hemiparesis or total CP; neither were they in previous studies.5,10,37 Other SNPs that were selected for their association with adult stroke risk did not relate to risk for CP in this study.
In this study, which examined the association of SNPs that were selected for their link with CP or with stroke in previous studies, positive associations with CP were observed for genes that are involved in inflammation, coagulation, and vascular responsivity. Most of the SNPs that were associated with CP in this study are also related to disease resistance in infectious or inflammatory disorders.
The increases in CP risk that are associated with the genetic variants and were investigated in this study were modest, with ORs in the range 1.3 to 2.4, suggesting that in CP, as in other common complex disorders, genetic influences will probably be small effects of many genes, with gene–gene and gene-environment interactions being important determinants of whether disease will occur.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study adds to current evidence that certain gene variants may contribute to CP risk. Additional investigation of genetic factors to test their involvement in CP and identification of the environmental factors that interact with them will be key in future efforts to prevent CP.
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ACKNOWLEDGMENTS |
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Other contributing members of the South Australian Cerebral Palsy Research Group were A. Chan, E.A. Haan, K. Priest, E. Ranieri, H. Scott, and P. Sharpe. This project was funded by the Australian National Health and Medical Research Council, the Channel Seven Children's Research Foundation, and the South Australian Government Captive Insurance Corporation and by funds from the National Cancer Institute and National Institute of Neurological Disorders and Stroke, the former under contract NO1-CO-12400.
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FOOTNOTES |
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Accepted Mar 3, 2008.
Address correspondence to Karin B. Nelson, MD, National Institutes of Health, Building 31, Room 8A03, Bethesda, MD 20892-2540. E-mail: knelson{at}helix.nih.gov or kn17n{at}nih.gov
The authors have indicated they have no financial relationships relevant to this article to disclose.
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services; and mention of trade names, commercial products, or organizations does not imply endorsement by the US government.
| What's Known on This Subject A few—but only a few—genetic factors have been identified for CP.
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| What This Study Adds This study confirms and extends some previous observations.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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