Genetic susceptibility to viral exposure may increase the risk of cerebral palsy.
OBJECTIVE
Cytokine polymorphisms may alter the fetal inflammatory response, increasing susceptibility to cerebral palsy (CP). This study investigates associations between selected inflammatory mediator and cytokine gene polymorphisms (Toll-like receptor-4 (TLR-4) Asp299Gly, interleukin-6 G-174C and interleukin-4 C-589T) and CP from 443 CP infants and 883 control infants. Results were correlated with viral nucleic acids in the same samples.


RESULTS
At all gestational ages (GA), TLR-4 was associated with a decreased risk of developing CP (homozygous/heterozygous odds ratio (OR) 0.70, 95% confidence interval (CI) 0.50-0.98) and interleukin (IL)-6 was associated with an increased risk of developing hemiplegia (OR 1.38, 95% CI 1.05-1.83). For infants born 32-36 weeks GA, there was a tenfold increase in the risk of quadriplegic CP with homozygous/heterozygous IL-6 (OR 10.42, 95% CI 1.34-80.82). Viral exposure in combination with IL-4 in preterm infants was associated with a fourfold increased risk of quadriplegia (homozygous/heterozygous OR 4.25, 95% CI 1.21-14.95). In very preterm infants, the absence of detectable viral exposure in combination with IL-4 decreased the risk of developing CP (homozygous/heterozygous OR 0.31, 95% CI 0.13-0.76).


CONCLUSIONS
Polymorphisms in TLR-4 may be associated with a decreased risk of CP. Polymorphisms in IL-6 or IL-4 may act as susceptibility genes, in the presence of viral exposure, for the development of hemiplegic and quadriplegic CP. These associations require confirmation but they suggest a hypothesis for CP causation due to double jeopardy from neurotropic viral exposure and genetic susceptibility to infection.
Djukic
Michael
M
Discipline of Obstetrics and Gynaecology, The University of Adelaide, South Australia, Australia.
Gibson
Catherine S
CS
Maclennan
Alastair H
AH
Goldwater
Paul N
PN
Haan
Eric A
EA
McMichael
Gai
G
Priest
Kevin
K
Dekker
Gustaaf A
GA
Hague
William M
WM
Chan
Annabelle
A
Rudzki
Zbigniew
Z
VAN Essen
Phillipa
P
Khong
T Yee
TY
Morton
Mark R
MR
Ranieri
Enzo
E
Scott
Heather
H
Tapp
Heather
H
Casey
Graeme
G
D016022:Case-Control Studies; D002547:Cerebral Palsy / Q000235:genetics* / Q000821:virology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D015847:Interleukin-4 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000821:virology*; D012042:Registries; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014777:Virus Diseases / Q000150:complications*
C508598:IL4 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D051197:Toll-Like Receptor 4; D015847:Interleukin-4