Dataset Information

The Association of Polymorphisms in Circadian Clock and Lipid Metabolism Genes With 2nd Trimester Lipid Levels and Preterm Birth.

ABSTRACT: Deregulation of the circadian system in humans and animals can lead to various adverse reproductive outcomes due to genetic mutations and environmental factors. In addition to the clock, lipid metabolism may also play an important role in influencing reproductive outcomes. Despite the importance of the circadian clock and lipid metabolism in regulating birth timing few studies have examined the relationship between circadian genetics with lipid levels during pregnancy and their relationship with preterm birth (PTB). In this study we aimed to determine if single nucleotide polymorphisms (SNPs) in genes from the circadian clock and lipid metabolism influence 2nd trimester maternal lipid levels and if this is associated with an increased risk for PTB. We genotyped 72 SNPs across 40 genes previously associated with various metabolic abnormalities on 930 women with 2nd trimester serum lipid measurements. SNPs were analyzed for their relationship to levels of total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglycerides (TG) using linear regression. SNPs were also evaluated for their relationship to PTB using logistic regression. Five SNPs in four genes met statistical significance after Bonferroni correction (p < 1.8 × 10-4) with one or more lipid levels. Of these, four SNPs were in lipid related metabolism genes: rs7412 in APOE with total cholesterol, HDL and LDL, rs646776 and rs599839 in CELSR2-PSRC1-SORT1 gene cluster with total cholesterol, HDL and LDL and rs738409 in PNPLA3 with HDL and TG and one was in a circadian clock gene: rs228669 in PER3 with TG. Of these SNPs only PER3 rs228669 was marginally associated with PTB (p = 0.02). In addition, PER3 rs228669 acts as an effect modifier on the relationship between TG and PTB.

SUBMITTER: Kovac U

PROVIDER: S-EPMC6584752 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Association of Polymorphisms in Circadian Clock and Lipid Metabolism Genes With 2<sup>nd</sup> Trimester Lipid Levels and Preterm Birth.

Kovac Ursa U Jasper Elizabeth A EA Smith Caitlin J CJ Baer Rebecca J RJ Bedell Bruce B Donovan Brittney M BM Weathers Nancy N Prosenc Zmrzljak Ursula U Jelliffe-Pawlowski Laura L LL Rozman Damjana D Ryckman Kelli K KK

Frontiers in genetics 20190613

Deregulation of the circadian system in humans and animals can lead to various adverse reproductive outcomes due to genetic mutations and environmental factors. In addition to the clock, lipid metabolism may also play an important role in influencing reproductive outcomes. Despite the importance of the circadian clock and lipid metabolism in regulating birth timing few studies have examined the relationship between circadian genetics with lipid levels during pregnancy and their relationship with ...[more]

PMID: 31249592

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Project description:Long non-coding RNAs (lncRNAs) have a much higher cell- and/or tissue-specificity compared to mRNAs in most cases, making them excellent candidates for therapeutic applications to reduce off-target effects. Placental long non-coding RNAs have been investigated in the pathogenesis of preeclampsia (often causing preterm birth (PTB)), but less is known about their role in preterm birth. Preterm birth occurs in 11% of pregnancies and is the most common cause of death among infants in the world. We recently identified that genes that drive circadian rhythms in cells, termed molecular clock genes, are deregulated in maternal blood of women with spontaneous PTB (sPTB) and in the placenta of women with preeclampsia. Next, we focused on circadian genes-correlated long intergenic non-coding RNAs (lincRNAs, making up most of the long non-coding RNAs), designated as circadian lincRNAs, associated with sPTB. We compared the co-altered circadian transcripts-correlated lincRNAs expressed in placentas of sPTB and term births using two published independent RNAseq datasets (GSE73712 and GSE174415). Nine core clock genes were up- or downregulated in sPTB versus term birth, where the RORA transcript was the only gene downregulated in sPTB across both independent datasets. We found that five circadian lincRNAs (LINC00893, LINC00265, LINC01089, LINC00482, and LINC00649) were decreased in sPTB vs term births across both datasets (p ≤ .0222, FDR≤.1973) and were negatively correlated with the dataset-specific clock genes-based risk scores (correlation coefficient r = -.65 ∼ -.43, p ≤ .0365, FDR≤.0601). Gene set variation analysis revealed that 65 pathways were significantly enriched by these same five differentially expressed lincRNAs, of which over 85% of the pathways could be linked to immune/inflammation/oxidative stress and cell cycle/apoptosis/autophagy/cellular senescence. These findings may improve our understanding of the pathogenesis of spontaneous preterm birth and provide novel insights into the development of potentially more effective and specific therapeutic targets against sPTB.

Project description:ObjectivesPreterm birth (PTB) is a major public health problem worldwide. It can occur spontaneously or be medically indicated for obstetric complications, such as pre-eclampsia (PE) or fetal growth restriction. The main objective of this study was to investigate whether there is a shared uteroplacental etiology in the first trimester of pregnancy across PTB subtypes.MethodsThis was a retrospective cohort study of singleton pregnancies that underwent screening for preterm PE as part of their routine first-trimester ultrasound assessment at a tertiary center in London, UK, between March 2018 and December 2020. Screening for preterm PE was performed using the Fetal Medicine Foundation algorithm, which includes maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and pregnancy-associated plasma protein-A (PAPP-A). Women with a risk of ≥ 1 in 50 for preterm PE were classified as high risk and offered prophylactic aspirin (150 mg once a day) and serial ultrasound assessments. The following delivery outcomes were evaluated: PTB < 37 weeks, iatrogenic PTB (iPTB) and spontaneous PTB (sPTB). Logistic regression analyses were performed to assess the association of PTB, iPTB and sPTB with an increased risk of preterm PE. A model for prediction of PTB < 37 weeks and < 33 weeks was developed and its performance was compared with that of an existing model in the literature.ResultsA total of 11 437 women were included in the study, of whom 475 (4.2%) had PTB. Of these, 308 (64.8%) were sPTB and 167 (35.2%) were iPTB. Patients with PTB had a higher body mass index, were more likely to be of black or Asian ethnicity, be smokers, have pregestational hypertension or diabetes, or have a history of previous PTB. They also had higher MAP (87.7 vs 86.0 mmHg, P < 0.0001), higher UtA-PI multiples of the median (MoM) (0.99 vs 0.92, P < 0.0001) and lower PAPP-A MoM (0.89 vs 1.08, P < 0.0001) compared to women with a term birth. In women at high risk of PE, the odds ratio for iPTB was 6.0 (95% CI, 4.29-8.43; P < 0.0001) and that for sPTB was 2.0 (95% CI, 1.46-2.86; P < 0.0001). A prediction model for PTB < 37 weeks and < 33 weeks, developed based on this cohort, included previous PTB, black ethnicity, chronic hypertension, diabetes mellitus, PAPP-A MoM and UtA-PI MoM. The performance of the model was similar to that of an existing first-trimester prediction model for PTB < 33 weeks (area under the curve, 0.704 (95% CI, 0.653-0.754) vs 0.694 (95% CI, 0.643-0.746)).ConclusionsIncreased first-trimester risk for uteroplacental dysfunction was associated with both iPTB and sPTB, implying a shared etiological pathway. The same factors used to predict PE risk show acceptable discrimination to predict PTB at < 33 weeks. Women at high risk of uteroplacental dysfunction may warrant additional monitoring and management for an increased risk of sPTB. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Project description:IntroductionThe global sequence of the pathogenesis of preterm labor remains unclear. This study aimed to compare amniotic fluid concentrations of extracellular matrix-related proteins (procollagen, osteopontin and IL-33), and of cytokines (IL-19, IL-6, IL-20, TNFα, TGFβ, and IL-1β) in asymptomatic women with and without subsequent spontaneous preterm delivery.Material and methodsWe used amniotic fluid samples of singleton pregnancy, collected by amniocentesis between 16 and 20 weeks' gestation, without stigmata of infection (i.e., all amniotic fluid samples were tested with broad-range 16 S rDNA PCR to distinguish samples with evidence of past bacterial infection from sterile ones), during a randomized, double-blind, placebo-controlled trial to perform a nested case-control laboratory study. Cases were women with a spontaneous delivery before 37 weeks of gestation (preterm group). Controls were women who gave birth at or after 39 weeks (full term group). Amniotic fluid concentrations of the extracellular matrix-related proteins and cytokines measured by immunoassays were compared for two study groups.Clinicaltrialsgov: NCT00718705.ResultsBetween July 2008 and July 2011, in 12 maternal-fetal medicine centers in France, 166 women with available PCR-negative amniotic fluid samples were retained for the analysis. Concentrations of procollagen, osteopontin, IL-19, IL-6, IL-20, IL-33, TNFα, TGFβ, and IL-1β were compared between the 37 who gave birth preterm and the 129 women with full-term delivery. Amniotic fluid levels of procollagen, osteopontin, IL-19, IL-33, and TNFα were significantly higher in the preterm than the full-term group. IL-6, IL-20, TGFβ, and IL-1β levels did not differ between the groups.ConclusionsIn amniotic fluid 16 S rDNA PCR negative samples obtained during second-trimester amniocentesis, extracellular matrix-related protein concentrations (procollagen, osteopontin and IL-33), together with IL-19 and TNFα, were observed higher at this time in cases of later spontaneous preterm birth.

Dataset Information

The Association of Polymorphisms in Circadian Clock and Lipid Metabolism Genes With 2nd Trimester Lipid Levels and Preterm Birth.

Publications

The Association of Polymorphisms in Circadian Clock and Lipid Metabolism Genes With 2<sup>nd</sup> Trimester Lipid Levels and Preterm Birth.

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