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Plunkett J.,Vanderbilt University | Plunkett J.,University of Washington | Doniger S.,University of Washington | Orabona G.,Vanderbilt University | And 26 more authors.
PLoS Genetics | Year: 2011

Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition. © 2011 Plunkett et al.


Menon R.,The Perinatal Research Center | Menon R.,Emory University | Fortunato S.J.,The Perinatal Research Center | Edwards D.R.V.,University of Miami | Williams S.M.,Vanderbilt University
Annals of Human Genetics | Year: 2010

We examined the association of 166 single nucleotide polymorphisms (SNPs) in cytokines and cytokine related genes with cytokine concentrations (IL-1β, IL-8, and IL-10) in the amniotic fluid (AF). These cytokines have been associated with spontaneous preterm birth (PTB) and their genetic regulation may play a role in disease risk. These associations were studied in both PTB and term births in African Americans and Caucasians; maternal and fetal genotypes were studied separately. Analyses modeled genotype, pregnancy status, and marker by pregnancy status (case/control) interaction with cytokine concentration as outcome. Our results indicate that AF cytokines (IL-1β and IL-10) were associated with interactions between pregnancy status and both maternal and fetal SNPs, with the most significant interactions being observed for African Americans with IL-1β concentration (maternal at IL1RAP rs1024941 p < 10-3, fetal IL1RAP rs3773953 p < 10-3). AF IL-10 concentrations also showed evidence for association with SNPs in both ethnicities with the most significant interaction in Caucasian maternal samples (IL10 rs1800896 p < 10-3). Our data indicate that the genetic regulation of cytokine concentrations in PTB likely differs by ethnicity. AF cytokine concentrations were associated with interactions between genotype and PTB in African Americans, but less so in Caucasians. © 2010 Blackwell Publishing Ltd/University College London.


McGregor T.L.,Vanderbilt University | Gurnett C.A.,University of Washington | Dobbs M.B.,University of Washington | Dobbs M.B.,St Louis Shriners Hospital For Children | And 7 more authors.
BMC Medical Genetics | Year: 2011

Background: Although adolescent idiopathic scoliosis affects approximately 3% of adolescents, the genetic contributions have proven difficult to identify. Work in model organisms, including zebrafish, chickens, and mice, has implicated the lysyl oxidase family of enzymes in the development of scoliosis. We hypothesized that common polymorphisms in the five human lysyl oxidase genes (LOX, LOXL1, LOXL2, LOXL3, and LOXL4) may be associated with the phenotype of adolescent idiopathic scoliosis.Methods: This was a case-control genetic association study. A total of 112 coding and tag SNPs in LOX, LOXL1, LOXL2, LOXL3, and LOXL4 were genotyped in a discovery cohort of 138 cases and 411 controls. Genotypes were tested for association with adolescent idiopathic scoliosis by logistic regression with a two degree of freedom genotypic model and gender as a covariate. Fourteen SNPs with p < 0.1 in the discovery phase were genotyped in an independent replication cohort of 400 cases and 506 controls.Results: No evidence for significant association was found between coding or tag SNPs in LOX, LOXL1, LOXL2, LOXL3, and LOXL4 and the phenotype of adolescent idiopathic scoliosis.Conclusions: Despite suggestive evidence in model organisms, common variants and known coding SNPs in the five human lysyl oxidase genes do not confer increased genotypic risk for adolescent idiopathic scoliosis. The above methodology does not address rare variants or individually private mutations in these genes, and future research may focus on this area. © 2011 McGregor et al; licensee BioMed Central Ltd.


Parets S.E.,Emory University | Bedient C.E.,Emory University | Menon R.,University of Texas Medical Branch | Menon R.,The Perinatal Research Center | Smith A.K.,Emory University
Biology | Year: 2014

The epigenetic patterns established during development may influence gene expression over a lifetime and increase susceptibility to chronic disease. Being born preterm (<37 weeks of gestation) is associated with increased risk mortality and morbidity from birth until adulthood. This brief review explores the potential role of DNA methylation in preterm birth (PTB) and its possible long-term consequences and provides an overview of the physiological processes central to PTB and recent DNA methylation studies of PTB. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


Parets S.E.,Emory University | Conneely K.N.,Emory University | Kilaru V.,Emory University | Fortunato S.J.,The Perinatal Research Center | And 4 more authors.
PLoS ONE | Year: 2013

Spontaneous preterm birth (PTB, <37 weeks gestation) is a major public health concern, and children born preterm have a higher risk of morbidity and mortality throughout their lives. Recent studies suggest that fetal DNA methylation of several genes varies across a range of gestational ages (GA), but it is not yet clear if fetal epigenetic changes associate with PTB. The objective of this study is to interrogate methylation patterns across the genome in fetal leukocyte DNA from African Americans with early PTB (241/7-340/7 weeks; N = 22) or term births (390/7-406/7weeks; N = 28) and to evaluate the association of each CpG site with PTB and GA. DNA methylation was assessed across the genome with the HumanMethylation450 BeadChip. For each individual sample and CpG site, the proportion of DNA methylation was estimated. The associations between methylation and PTB or GA were evaluated by fitting a separate linear model for each CpG site, adjusting for relevant covariates. Overall, 29 CpG sites associated with PTB (FDR<.05; 5.7×10-10


Peltier M.R.,Winthrop University | Drobek C.O.,The Perinatal Research Center | Bhat G.,University of Texas Medical Branch | Saade G.,University of Texas Medical Branch | And 3 more authors.
Journal of Reproductive Immunology | Year: 2012

Spontaneous preterm birth (PTB) and preterm prelabor rupture of membranes (pPROM) occur more frequently in African-American women than in other racial groups. This may be due to an enhanced inflammatory response to pathogens associated with the condition. It is also possible that amniotic fluid (AF) has different immunomodulatory properties in African-American women that increase their risk of PTB and pPROM. To test this, we cultured fetal membranes from European-American and African-American women with sterile medium (control), Escherichia coli, Gardnerella vaginalis, Group B streptococci (GBS), Polyporphorans gingivalis, Mycoplasma hominis, Ureaplasma urealyticum or Ureaplasma parvum in the presence and absence of 50% autologous AF. Cytokine concentrations were quantified in the conditioned medium. All bacterial species increased IL-8 production. IL-1β and TNF-α production were stimulated by LPS, E. coli, and G. vaginalis compared with control, but responses to Group B streptococci and P. gingivalis were limited to IL-1β and TNF-α respectively. Genital mycoplasmas stimulated TNF-α and IL-10 but had no effect on IL-1β production. African-Americans had twice the IL-1β response to E. coli as European-Americans (P= 0.031). Conversely, European-Americans produced more IL-8 in response to LPS than African-Americans (P= 0.026). AF had both pro- and anti-inflammatory properties that varied between races and pathogens. These results suggest that the host response to fetal membrane infections is complex and not generalizable. Interventions to prevent PTB and pPROM may need to be customized based on a patient's race, type of bacterial infection and factors in her AF. © 2012 Elsevier Ireland Ltd.


Menon R.,University of Texas Medical Branch | Yu J.,Emory University | Basanta-Henry P.,Emory University | Brou L.,Emory University | And 3 more authors.
PLoS ONE | Year: 2012

Background: Rupture of the fetal membranes is a common harbinger of imminent labor and delivery. Telomere shortening is a surrogate for oxidative stress (OS) and senescence. Fetal leukocyte and placental membrane DNA telomere lengths were evaluated to determine their association with preterm prelabor rupture of the membranes (pPROM) or spontaneous preterm births with intact membranes (PTB), compared to term birth. Methods: Telomere lengths were quantified in cord blood leukocytes (n = 133) from three major groups: 1) pPROM (n = 28), 2) PTB (n = 69) and 3) uncomplicated full term births (controls, n = 35), using real-time quantitative PCR. Placental membrane specimens (n = 18) were used to correlate fetal leukocyte and placental telomere lengths. Telomere length differences among the groups were analyzed by ANOVA. Pearson correlation coefficients determined relationships between leukocyte and placental membrane telomere lengths. Results: In pregnancies with intact membranes, fetal leukocyte telomere length was inversely proportional to gestational age. The mean telomere length decreased as gestation progressed, with the shortest at term. pPROM had telomere lengths (9962±3124 bp) that were significantly shorter than gestational age-matched PTB (11546±4348 bp, p = 0.04), but comparable to term births (9011±2497 bp, p = 0.31). Secondary analyses revealed no effects of race (African American vs. Caucasian) or intraamniotic infection on telomere length. A strong Pearson's correlation was noted between fetal leukocyte and placental membrane telomere lengths (ρ = 0.77; p<0.01). Conclusions: Fetal leukocyte telomere length is reduced in pPROM compared to PTB but is similar to term births. pPROM represents a placental membrane disease likely mediated by OS-induced senescence. © 2012 Menon et al.


PubMed | The Perinatal Research Center
Type: Journal Article | Journal: Annals of human genetics | Year: 2010

We examined the association of 166 single nucleotide polymorphisms (SNPs) in cytokines and cytokine related genes with cytokine concentrations (IL-1beta, IL-8, and IL-10) in the amniotic fluid (AF). These cytokines have been associated with spontaneous preterm birth (PTB) and their genetic regulation may play a role in disease risk. These associations were studied in both PTB and term births in African Americans and Caucasians; maternal and fetal genotypes were studied separately. Analyses modeled genotype, pregnancy status, and marker by pregnancy status (case/control) interaction with cytokine concentration as outcome. Our results indicate that AF cytokines (IL-1beta and IL-10) were associated with interactions between pregnancy status and both maternal and fetal SNPs, with the most significant interactions being observed for African Americans with IL-1beta concentration (maternal at IL1RAP rs1024941 p < 10(-3), fetal IL1RAP rs3773953 p < 10(-3)). AF IL-10 concentrations also showed evidence for association with SNPs in both ethnicities with the most significant interaction in Caucasian maternal samples (IL10 rs1800896 p < 10(-3)). Our data indicate that the genetic regulation of cytokine concentrations in PTB likely differs by ethnicity. AF cytokine concentrations were associated with interactions between genotype and PTB in African Americans, but less so in Caucasians.


Gracie S.,University of Alberta | Pennell C.,University of Western Australia | Ekman-Ordeberg G.,Karolinska University Hospital | Lye S.,University of Toronto | And 8 more authors.
BMC Pregnancy and Childbirth | Year: 2011

Preterm birth is the leading cause of neonatal mortality and perinatal morbidity. The etiology of preterm is multi-factorial and still unclear. As evidence increases for a genetic contribution to PTB, so does the need to explore genomics, transcriptomics, proteomics and metabolomics in its study. This review suggests research guidelines for the conduct of high throughput systems biology investigations into preterm birth with the expectation that this will facilitate the sharing of samples and data internationally through consortia, generating the power needed to study preterm birth using integrated "-omics" technologies. The issues to be addressed include: (1) integrated "-omics" approaches, (2) phenotyping, (3) sample collection, (4) data management-integrative databases, (5) international consortia and (6) translational feasibility. This manuscript is the product of discussions initiated by the "-Omics" Working Group at the Preterm Birth International Collaborative Meeting held at the World Health Organization, Geneva, Switzerland in April 2009. © 2011 Gracie et al; licensee BioMed Central Ltd.

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