The genetics of preterm birth: using what we know to design better association studies.
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ABSTRACT:
SUBMITTER: Weinberg CR
PROVIDER: S-EPMC2800265 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Preterm birth (PTB), defined as the birth of a child before 37 completed weeks gestation, affects approximately 11% of live births and is the leading cause of death in children under 5 years. PTB is a complex disease with multiple risk factors including genetic variation. Much research has aimed to establish the biological mechanisms underlying PTB often through identification of genetic markers for PTB risk. The objective of this review is to present a comprehensive and updated summary of the published data relating to the field of PTB genetics. A literature search in PubMed was conducted and English studies related to PTB genetics were included. Genetic studies have identified genes within inflammatory, immunological, tissue remodeling, endocrine, metabolic, and vascular pathways that may be involved in PTB. However, a substantial proportion of published data have been largely inconclusive and multiple studies had limited power to detect associations. On the contrary, a few large hypothesis-free approaches have identified and replicated multiple novel variants associated with PTB in different cohorts. Overall, attempts to predict PTB using single "-omics" datasets including genomic, transcriptomic, and epigenomic biomarkers have been mostly unsuccessful and have failed to translate to the clinical setting. Integration of data from multiple "-omics" datasets has yielded the most promising results.
| S-EPMC10692032 | biostudies-literature
Project description:Preterm birth contributes significantly to neonatal mortality and morbidity. Despite its global significance, there has only been limited progress in preventing preterm birth. Spontaneous preterm birth (sPTB) results from a wide variety of pathological processes. Although many non-genetic risk factors influence the timing of gestation and labor, compelling evidence supports the role of substantial genetic and epigenetic influences and their interactions with the environment contributing to sPTB. To investigate a common and complex disease such as sPTB, various approaches such as genome-wide association studies, whole-exome sequencing, transcriptomics, and integrative approaches combining these with other 'omics studies have been used. However, many of these studies were typically small or focused on a single ethnicity or geographic region with limited data, particularly in populations at high risk for sPTB, or lacked a robust replication. These studies found many genes involved in the inflammation and immunity-related pathways that may affect sPTB. Recent studies also suggest the role of epigenetic modifications of gene expression by the environmental signals as a potential contributor to the risk of sPTB. Future genetic studies of sPTB should continue to consider the contributions of both maternal and fetal genomes as well as their interaction with the environment.
| S-EPMC9509423 | biostudies-literature
Project description:Preterm birth (PTB) is defined as childbirth occurring at less than 37 completed weeks or 259 days of gestation. Premature babies have higher rates of cerebral palsy, sensory deficits, learning disabilities and respiratory illnesses that extend into adulthood. This lifelong morbidity results in high economic and social costs to families and communities. PTB is a syndrome initiated by multiple mechanisms, including infection or inflammation, uteroplacental ischaemia or haemorrhage, uterine overdistension, stress, and other immunologically mediated processes. Identifying and monitoring molecular signals in easily accessible body fluids that can diagnose or predict the risk of preterm labor in pregnant women will reduce or prevent PTBs. A number of studies reported the identification of putative biomarkers for PTB including protein, miRNA and hormone from different body fluids such as serum/plasma, cervical vaginal fluid, saliva and amniotic fluids. These putative biomarkers identified can largely be grouped into three main functional categories: inflammatory related molecules, placenta or fetal derived molecules and stress related molecules. In the past few years next generation sequencing (NGS) has become the major platform for miRNA analysis especially with body fluids. However, studies have shown significant sequence bias among different small RNA library preparation protocols. We have modified the small RNA library construction protocol which greatly reduces the sequence bias and increase miRNA coverage in sample. We also adapted a newly developed size exclusion chromatography (SEC) based EV purification protocol which can provide cleaner EVs compared to other methods. We are using these improved approaches to gain more reliable profile of circulating RNA in body fluid as well as its associated EVs. With these new approaches, we explore the possibility of using specific circulating miRNAs, specifically those encapsulated in EVs, as a noninvasive biomarker for PTB by comparing the miRNA profiles in maternal plasma, EV and EV-depleted plasma between individuals who had a spontaneous preterm birth and uncomplicated pregnancies.
2018-03-19 | GSE106224 | GEO
Project description:A strength of time-series analyses is the inherent control of individual-level risk factors that do not vary temporally. However, in studies of adverse pregnancy outcomes, risk factors considered time-invariant at the individual level may vary seasonally when aggregated into a pregnancy risk set. To illustrate, we describe the seasonal patterns of birth in Atlanta and demonstrate how these patterns could lead to confounding in time-series studies of seasonally-varying exposures and preterm birth.The study cohort included all births in 20-county metropolitan Atlanta delivered during the period 1994-2004 (n = 715,875). We assessed the seasonal patterns of estimated conception and birth for the full cohort and for subgroups stratified by sociodemographic factors. Based on the observed patterns, we quantified the degree of potential confounding created by (1) differences in the gestational age distribution in the risk set across calendar months and (2) differences in the sociodemographic composition of the risk set across calendar months.The overall seasonal pattern of birth was characterized by a peak in August-September and troughs in April-May and November-January. Seasonal patterns differed among racial and ethnic groups, maternal education levels, and marital status. As a consequence of these seasonal patterns, systematic seasonal differences in the gestational age distribution and the sociodemographic composition of the risk set led to differences in expected rates of preterm birth across calendar months.Time-series investigations of seasonally-varying exposures and adverse pregnancy outcomes should consider the potential for bias due to seasonal heterogeneity in the risk set.
| S-EPMC3743217 | biostudies-literature
Project description:Preterm birth (PTB) can be defined as the endpoint of a complex process that could be influenced by maternal and environmental factors. Epigenetics recently emerged as an interesting field of investigation since it represents an important mechanism of regulation. This study evaluates epigenetic impact of preterm birth on DNA methylation. Genome-wide DNAm was measured using the Illumina 450K array in cord blood samples obtained from 72 full term and 18 preterm newborns. Lymphocyte composition was calculated based on specific epigenetic markers that are present on the 450k array. Differential methylation analysis was performed both at site and region level, moreover Stochastic Epigenetic Mutations (SEMs) were also evaluated. The study showed significant differences in blood cell composition between the two groups. Moreover, after multiple testing correction, statistically significant differences in DNA methylation levels emerged between the two groups both at site and region levels. Results obtained have been compared to those obtained by previous EWAS and a list of genes have been found to be consistent. The SEMs analysis revealed that the burden of SEMs resulted significantly higher in the preterm group. In conclusion, PTB resulted associated to specific epigenetic signatures that involve immune system. Moreover, SEMs analysis revealed an increased epigenetic drift at birth in the preterm group.
2020-07-20 | GSE152380 | GEO
Project description:Transcriptome analysis of preterm and term placentas
2021-08-10 | GSE120480 | GEO
Project description:Preterm birth, defined as birth <37 weeks of gestation, is a leading cause of infant morbidity and mortality. In the United States, approximately 12% of all births are preterm.1 Despite decades of research, there has been little progress in developing effective interventions to prevent preterm birth. In fact, the rate of preterm birth has increased slightly over the last several decades.2 The ultimate goal of the Genomic and Proteomic Network for Preterm Birth Research (GPN-PBR) is to identify possible biomarkers that could predict the susceptibility to spontaneous preterm birth (SPTB) as well as to shed light on the molecular mechanisms involved in its etiologies. Understanding those mechanisms will help us predict SPTB and may facilitate the introduction of more effective prevention and treatment strategies.
2014-08-28 | PXD001268 | Pride
Project description:Next-generation sequencing is becoming the primary discovery tool in human genetics. There have been many clear successes in identifying genes that are responsible for Mendelian diseases, and sequencing approaches are now poised to identify the mutations that cause undiagnosed childhood genetic diseases and those that predispose individuals to more common complex diseases. There are, however, growing concerns that the complexity and magnitude of complete sequence data could lead to an explosion of weakly justified claims of association between genetic variants and disease. Here, we provide an overview of the basic workflow in next-generation sequencing studies and emphasize, where possible, measures and considerations that facilitate accurate inferences from human sequencing studies.
| S-EPMC4117319 | biostudies-literature
Project description:ImportanceEndometriosis is an inflammatory disease with a heterogeneous presentation that affects women of childbearing age. Given the limitations of previous retrospective studies, it is still unclear whether endometriosis has adverse implications for pregnancy outcomes.ObjectiveTo evaluate the association between the presence of endometriosis and preterm birth and whether the risk varied according to the disease phenotype.Design, setting, and participantsThis cohort study with exposed and unexposed groups was conducted in 7 maternity units in France from February 4, 2016, to June 28, 2018. Participants included women with singleton pregnancies who were followed up before 22 weeks' gestation along with their newborns delivered at or after 22 weeks' gestation. The final follow-up occurred in July 2019. Data were analyzed from October 7, 2020, to February 7, 2021.ExposuresWomen in the endometriosis group had a documented history of endometriosis and were classified according to 3 endometriosis phenotypes: isolated superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA; potentially associated with SUP), and deep endometriosis (DE; potentially associated with SUP and OMA). Women in the control group did not have a history of clinical symptoms of endometriosis before their current pregnancy.Main outcomes and measuresThe primary outcome was preterm birth between 22 weeks and 36 weeks 6 days of gestation. Association between endometriosis and the primary outcome was assessed through univariate and multivariate logistic regression analyses and was adjusted for the following risk factors associated with preterm birth: maternal age, body mass index (calculated as weight in kilograms divided by height in meters squared) before pregnancy, country of birth, parity, previous cesarean delivery, history of myomectomy and hysteroscopy, and preterm birth. The same analysis was performed according to the 3 endometriosis phenotypes (SUP, OMA, and DE).ResultsOf the 1351 study participants (mean [SD] age, 32.9 [5.0] years) who had a singleton delivery after 22 weeks of gestation, 470 were assigned to the endometriosis group (48 had SUP [10.2%], 83 had OMA [17.7%], and 339 had DE [72.1%]) and 881 were assigned to the control group. No difference was observed in the rate of preterm deliveries before 37 weeks 0 days of gestation between the endometriosis and control groups (34 of 470 [7.2%] vs 53 of 881 [6.0%]; P = .38). After adjusting for confounding factors, endometriosis was not associated with preterm birth before 37 weeks' gestation (adjusted odds ratio, 1.07; 95% CI, 0.64-1.77). The results were comparable for the different disease phenotypes (SUP: 6.2% [3 of 48]; OMA: 7.2% [6 of 83]; and DE: 7.4% [25 of 339]; P = .84).Conclusions and relevanceThis cohort study found no association between endometriosis and preterm birth, and the disease phenotype did not appear to alter the result. Monitoring the pregnancy beyond the normal protocols or changing management strategies for women with endometriosis may not be warranted to prevent preterm birth.
| S-EPMC8826171 | biostudies-literature
Project description:ImportanceLow birth weight and preterm birth are associated with adverse consequences including increased risk of infant mortality and chronic health conditions. Black infants are more likely than white infants to be born prematurely, which has been associated with disparities in infant mortality and other chronic conditions.ObjectiveTo evaluate whether Medicaid expansion was associated with changes in rates of low birth weight and preterm birth outcomes, both overall and by race/ethnicity.Design, setting, and participantsUsing US population-based data from the National Center for Health Statistics Birth Data Files (2011-2016), difference-in-differences (DID) and difference-in-difference-in-differences (DDD) models were estimated using multivariable linear probability regressions to compare birth outcomes among infants in Medicaid expansion states relative to non-Medicaid expansion states and changes in relative disparities among racial/ethnic minorities for singleton live births to women aged 19 years and older.ExposuresState Medicaid expansion status and racial/ethnic category.Main outcomes and measuresPreterm birth (<37 weeks' gestation), very preterm birth (<32 weeks' gestation), low birth weight (<2500 g), and very low birth weight (<1500 g).ResultsThe final sample of 15 631 174 births (white infants: 8 244 924, black infants: 2 201 658, and Hispanic infants: 3 944 665) came from the District of Columbia and 18 states that expanded Medicaid (n = 8 530 751) and 17 states that did not (n = 7 100 423). In the DID analyses, there were no significant changes in preterm birth in expansion relative to nonexpansion states (preexpansion to postexpansion period, 6.80% to 6.67% [difference: -0.12] vs 7.86% to 7.78% [difference: -0.08]; adjusted DID: 0.00 percentage points [95% CI, -0.14 to 0.15], P = .98), very preterm birth (0.87% to 0.83% [difference: -0.04] vs 1.02% to 1.03% [difference: 0.01]; adjusted DID: -0.02 percentage points [95% CI, -0.05 to 0.02], P = .37), low birth weight (5.41% to 5.36% [difference: -0.05] vs 6.06% to 6.18% [difference: 0.11]; adjusted DID: -0.08 percentage points [95% CI, -0.20 to 0.04], P = .20), or very low birth weight (0.76% to 0.72% [difference: -0.03] vs 0.88% to 0.90% [difference: 0.02]; adjusted DID: -0.03 percentage points [95% CI, -0.06 to 0.01], P = .14). Disparities for black infants relative to white infants in Medicaid expansion states compared with nonexpansion states declined for all 4 outcomes, indicated by a negative DDD coefficient for preterm birth (-0.43 percentage points [95% CI, -0.84 to -0.02], P = .05), very preterm birth (-0.14 percentage points [95% CI, -0.26 to -0.02], P = .03), low birth weight (-0.53 percentage points [95% CI, -0.96 to -0.10], P = .02), and very low birth weight (-0.13 percentage points [95% CI, -0.25 to -0.01], P = .04). There were no changes in relative disparities for Hispanic infants.Conclusions and relevanceBased on data from 2011-2016, state Medicaid expansion was not significantly associated with differences in rates of low birth weight or preterm birth outcomes overall, although there were significant improvements in relative disparities for black infants compared with white infants in states that expanded Medicaid vs those that did not.
| S-EPMC6487545 | biostudies-literature