Maternal and fetal variation in genes of cholesterol metabolism is associated with preterm delivery.
OBJECTIVE
To examine the contribution of variants in fetal and maternal cholesterol metabolism genes in preterm delivery (PTD).


METHODS
A total of 40 single-nucleotide polymorphisms (SNPs) in 16 genes related to cholesterol metabolism were examined for 414 preterm infants (gestational ages 22 to 36 weeks; comprising 305 singletons and 109 twins) and at least 1 parent. Fetal effects were assessed using the transmission disequilibrium test (TDT) for each SNP, followed by a log linear model-based approach to utilize families with missing parental genotypes for those SNPs showing significance under TDT. Genetic variant effects were examined for a role in PTD, gestational age and birth weight. Maternal effects were estimated using a log linear model-based approach.


RESULTS
Among singleton gestations, suggestive association (P<0.01 without adjusting for multiple comparisons) was found between birth weight and fetal DHCR7 gene/SNP combinations (rs1630498, P=0.002 and rs2002064, P=0.003). Among all gestations, suggestive associations were found between PTD and fetal HMGCR (rs2303152, P=0.002) and APOA1 (rs 5070, P=0.004). The result for HMGCR was further supported by the log linear model-based test in the single births (P=0.007) and in all births (P=0.006). New associations (APOE and ABCA1) were observed when birth weight was normalized for gestational age suggesting independent effects of variants on birth weight separate from effects on PTD. Testing for maternally mediated genetic effects has identified suggestive association between ABCA1 (rs4149313, P=0.004) and decreased gestational age.


CONCLUSIONS
Variants in maternal and fetal genes for cholesterol metabolism were associated with PTD and decreased birth weight or gestational age in this study. Genetic markers may serve as one mechanism to identify high-risk mothers and fetuses for targeted nutritional treatment and/or prevention of low birth weight or PTD.
Steffen
K M
KM
University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Cooper
M E
ME
Shi
M
M
Caprau
D
D
Simhan
H N
HN
Dagle
J M
JM
Marazita
M L
ML
Murray
J C
JC
D000293:Adolescent; D000328:Adult; D016632:Apolipoprotein A-I / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D004200:Diseases in Twins / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D005865:Gestational Age; D006239:Haplotypes; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D007231:Infant, Newborn; D019102:Infant, Very Low Birth Weight; D015810:Linkage Disequilibrium; D008297:Male; D008423:Maternal Age; D008431:Maternal-Fetal Exchange / Q000235:genetics; D007752:Obstetric Labor, Premature / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy
D016632:Apolipoprotein A-I; D005819:Genetic Markers; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase