Article

Maternal and fetal variation in genes of cholesterol metabolism is associated with preterm delivery

Division of General Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Journal of Perinatology (Impact Factor: 2.35). 12/2007; 27(11):672-80. DOI: 10.1038/sj.jp.7211806
Source: PubMed

ABSTRACT To examine the contribution of variants in fetal and maternal cholesterol metabolism genes in preterm delivery (PTD).
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.
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.
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.

0 Bookmarks
 · 
99 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We examined the genotype-phenotype interactions of Cyp51+/- mice carrying one functional allele of lanosterol 14α-demethylase from cholesterol biosynthesis. No distinct developmental or morphological abnormalities were observed by routine visual inspection of Cyp51+/- and Cyp51+/+ mice and fertility was similar. We further collected a large data-set from female and male Cyp51+/- mice and controls fed for 16 weeks with three diets and applied linear regression modeling. We used 3 predictor variables (genotype, sex, diet), and 39 response variables corresponding to the organ characteristics (7), plasma parameters (7), and hepatic gene expression (25). We observed significant differences between Cyp51+/- and wild-type mice in organ characteristics and blood lipid profile. Hepatomegaly was observed in Cyp51+/- males, together with elevated total and low-density lipoprotein cholesterol. Cyp51+/- females fed high-fat, high-cholesterol diet were leaner and had elevated plasma corticosterone compared to controls. We observed elevated hepatocyte apoptosis, mitosis and lipid infiltration in heterozygous knockouts of both sexes. The Cyp51+/- females had a modified lipid storage homeostasis protecting them from weight-gain when fed high-fat high-cholesterol diet. Malfunction of one Cyp51 allele therefore initiates disease pathways towards cholesterol-linked liver pathologies and sex-dependent response to dietary challenge.
    PLoS ONE 11/2014; 9(11):e112787. DOI:10.1371/journal.pone.0112787 · 3.53 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Single nucleotide polymorphisms (SNPs) represent genetic variation among individuals in a population. In medicine, these small variations in the DNA sequence may significantly impact an individual's response to certain drugs or influence the risk of developing certain diseases. In the field of reproductive medicine, a significant amount of research has been devoted to identifying polymorphisms which may impact steroidogenesis and fertility. This review will focus on our current understanding of the effect of genetic variations in cholesterol metabolic pathways on human fertility, that provide novel linkages between cholesterol metabolism and reproductive health. For example, the role of the LDL receptor (LDLR) in cellular metabolism and human reproduction has been well-studied, whereas there is now an emerging literature on the role of the high density lipoprotein (HDL) receptor, scavenger receptor class B type I (SR-BI), in human lipid metabolism and female reproduction. Identifying and understanding how polymorphisms in the SCARB1 gene or other genes related to lipid metabolism impact human physiology is essential, and will play a major role in the development of personalized medicine for improved diagnosis and treatment of infertility.
    Biology of Reproduction 08/2014; DOI:10.1095/biolreprod.114.119883 · 3.45 Impact Factor

Full-text (2 Sources)

Download
37 Downloads
Available from
Jun 4, 2014