DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.
Patent ductus arteriosus (PDA) is a common morbidity associated with preterm birth. The incidence of PDA increases with decreasing gestational age to about 70% in infants born at 25 weeks gestation. Although medical treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is used to close the ductus arteriosus, approximately 30% of infants with a PDA do not respond to pharmacologic attempts at closure. We investigated whether single nucleotide polymorphisms (SNPs) in genes that regulate smooth muscle contraction, xenobiotic detoxification, inflammation and other processes are markers for persistent patency of the DA. Initially, 377 SNPs from 130 genes of interest were evaluated in DNA samples collected from 204 infants with a gestational age of less than 32 weeks. A family-based association test (FBAT) was performed on genotyping data to evaluate overtransmission of alleles. P-values of less than 0.01 were detected for genetic variations found in seven genes. The analysis was then replicated with an independent set of 162 infants, focusing on the seven markers with initial p-values less than 0.01, and one genetic variant in the angiotensin II type I receptor (AGTR1) previously shown to be related to PDA. Of the initial positive signals, SNPs in the transcription factor AP-2 beta (TFAP2B) and TNF receptor-associated factor 1 (TRAF1) genes remained significant, both with p-values of 0.005. An AGTR1 polymorphism previously reported to be associated with PDA following prophylactic indomethacin administration was not associated with the presence of a PDA in our population (p = 0.48). Overall, our data support a role for a genetic contribution to the risk of PDAs in preterm infants.
Progesterone plays a critical role in the maintenance of pregnancy and has been effectively used to prevent recurrences of preterm labor. We investigated the role of genetic variation in the progesterone receptor (PGR) gene in modulating risks for preterm labor by examining both maternal and fetal effects. Cases were infants delivered prematurely at the University of Iowa. DNA was collected from the mother, infant, and father. Seventeen single nucleotide polymorphisms (SNP) and an insertion deletion variant in PGR were studied in 415 families. Results were then analyzed using transmission disequilibrium tests and log-linear-model-based analysis. DNA sequencing of the PGR gene was also carried out in 92 mothers of preterm infants. We identified significant associations between SNP in the PGR for both mother and preterm infant. No etiologic sequence variants were found in the coding sequence of the PGR gene. This study suggests that genetic variation in the PGR gene of either the mother or the fetus may trigger preterm labor. P reterm labor and preterm birth are major public health problems throughout the world. In the United States, preterm birth has been increasing in birth prevalence over the last two decades and now affects approximately 500,000 infants per year. Besides its association with mortality, there are both acute and chronic morbidities associated with the preterm birth, including long-term sequelae such as cognitive and motor delays. Genetic factors play a strong role in preterm birth (1). The best predictor for preterm delivery is the birth of a previous preterm infant to that woman (2-4). In addition, a family history of preterm delivery in the mother herself (5) or the mother's sister (6) strongly supports an underlying genetic component. In twin studies, the heritability of preterm delivery has been suggested to be approximately 40% (7). Progesterone, and in particular 17-␣ hydroxyprogesterone caproate (17p), has been shown to reduce the risk of a subsequent preterm delivery by approximately 30% in women who have had at least one preterm child (8 -14). Further, the earlier the gestational age of the first infant, the more effective progesterone is in prolonging the gestation of a subsequent pregnancy.While other mammals show a decrease in serum progesterone levels before parturition, no consistent evidence of this has been seen in humans. It has been suggested that changes in isoform ratio and/or the expression of the progesterone receptor may provide a "functional" progesterone withdrawal, leading to the initiation of labor (15)(16)(17)(18)(19)(20).Variation in the genes involved in progesterone synthesis or metabolism could be hypothesized as playing a role in preterm delivery as have single nucleotide polymorphisms (SNP) playing a role in inflammation, fetal membrane stability, immune response, sympathetic nerve action, angiogenesis, and clotting (21). In this report, we evaluated the role of genetic variation in the fetal and maternal progesterone receptor genes to identify women w...
Studies in humans and rats suggest that intrauterine growth retardation (IUGR) permanently resets the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis reprogramming may involve persistently altered expression of the hippocampal glucocorticoid receptor (hpGR), an important regulator of HPA axis reactivity. Persistent alteration of gene expression, long after the inciting event, is thought to be mediated by epigenetic mechanisms that affect mRNA and mRNA variant expression. GR mRNA variants in both humans and rats include eleven 5'-end variants and GRalpha, the predominant 3'-end variant. The 3'-end variants associated with glucocorticoid resistance in humans (GRbeta, GRgamma, GRA, and GRP) have not been reported in rats. We hypothesized that in the rat hippocampus IUGR would decrease total GR mRNA, increase GRbeta, GRgamma, GRA, and GRP, and affect epigenetics of the GR gene at birth (D0) and at 21 days of life (D21). IUGR increased hpGR and exon 1.7 hpGR mRNA in males at D0 and D21, associated with increased trimethyl H3/K4 at exon 1.7 at both time points. IUGR also increased hpGRgamma in males at D0 and D21, associated with increased acetyl H3/K9 at exon 3 at both time points. hpGRA increased in female IUGR rats at D0 and D21. In addition, our data support the existence of hpGRbeta and hpGRP in the rat. IUGR has sex-specific, persistent effects on GR expression and its histone code. We speculate that postnatal changes in hippocampal GR variant and total mRNA expression may underlie IUGR-associated HPA axis reprogramming.
BACKGROUND:Genetic variation in enzymes involved in vitamin metabolism is a candidate for analysis in studies of how nutritional covariates may impact a disease state. The role of folate pathway genes in birth defects and cardiovascular disease in humans has been widely studied. Since incidence rates for these disorders vary by geographic origins, it is useful to know which variants are the best candidates for studies based on genotype and allele frequency, as well as linkage disequilibrium (LD) in founder populations. METHODS: Six polymorphisms in five folate metabolism-related genes (MTHFR, MTHFD, MTRR, GCP2, and RFC1) were genotyped on a collection of 1064 DNA samples from populations around the world, which were made available by the Centre d'É tude du Polymorphisme Humain (CEPH) consortium for analysis. RESULTS: In this study we report the genotype frequencies for variants in the MTHFR, MTHFD, MTRR, GCP2, and RFC1 genes, and the LD for two variants (C677T and A1298C) in MTHFR. CONCLUSIONS: The rare allele frequency for each of the five genes studied varied widely. LD is strongest in Pakistani and Brazilian populations (DЈ ϭ 1.0) and weakest in Mexican populations (DЈ ϭ 0.45). These findings will allow the selection of variants that will provide the most power in studies of folate pathway genes involving different ancestral populations, and contribute to our knowledge of the population distribution of selected nutritional gene variants. Birth Defects Research (Part A) 67:545-549, 2003.
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