Association of polymorphisms in neuroprotection and oxidative stress genes and neurodevelopmental outcomes after preterm birth.
OBJECTIVE
To estimate the associations between polymorphisms in neuronal homeostasis, neuroprotection, and oxidative stress candidate genes and neurodevelopmental disability.


METHODS
This was a nested case-control analysis of a randomized trial of magnesium sulfate administered to women at imminent risk for early (before 32 weeks) preterm birth for the prevention of death or cerebral palsy in their offspring. We evaluated 21 single-nucleotide polymorphisms (SNPs) in 17 genes associated with neuronal homeostasis, neuroprotection, or oxidative stress in umbilical cord blood. Cases included infant deaths (n=43) and children with cerebral palsy (n=24), mental delay (Bayley Mental Developmental Index less than 70; n=109), or psychomotor delay (Bayley Psychomotor Developmental Index less than 70; n=91) diagnosed. Controls were race-matched and sex-matched children with normal neurodevelopment. Associations between each SNP and each outcome were assessed in logistic regression models assuming an additive genetic pattern, conditional on maternal race and infant sex, and adjusting for study drug assignment, gestational age at birth, and maternal education.


RESULTS
The odds of cerebral palsy were increased more than 2.5 times for each copy of the minor allele of vasoactive intestinal polypeptipe (VIP, rs17083008) (adjusted odds ratio 2.67, 95% confidence interval 1.09-6.55, P=.03) and 4.5 times for each copy of the minor allele of N-methyl-D-aspartate receptor subunit 3A (GRIN3A, rs3739722) (adjusted odds ratio 4.67, 95% CI 1.36-16.01, P=.01). The association between the advanced glycosylation end product-specific receptor (AGER, rs3134945) SNP and mental delay was modulated by study drug allocation (P=.02).


CONCLUSIONS
Vasoactive intestinal polypeptipe and GRIN3A SNPs may be associated with cerebral palsy at age 2 in children born preterm.
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, USA. mmcostan@utmb.edu
Maged M
MM
Costantine
Erin A S
EA
Clark
Yinglei
Y
Lai
Dwight J
DJ
Rouse
Catherine Y
CY
Spong
Brian M
BM
Mercer
Yoram
Y
Sorokin
John M
JM
Thorp
Susan M
SM
Ramin
Fergal D
FD
Malone
Marshall
M
Carpenter
Menachem
M
Miodovnik
Mary J
MJ
O'Sullivan
Alan M
AM
Peaceman
Steve N
SN
Caritis
D016022:Case-Control Studies; D002547:Cerebral Palsy / Q000235:genetics*; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000235:genetics* / Q000401:mortality; D008607:Intellectual Disability / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D018384:Oxidative Stress / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011581:Psychological Tests; D011596:Psychomotor Disorders / Q000235:genetics*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D014660:Vasoactive Intestinal Peptide / Q000235:genetics*
C548929:GRIN3A protein, human; D005819:Genetic Markers; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016194:Receptors, N-Methyl-D-Aspartate; D014660:Vasoactive Intestinal Peptide