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Integrative analysis of transcriptomic data for the identification of biomarkers associated with T-cell activation in preterm birth

ABSTRACT: Preterm birth (PTB), defined as birth at less than 37 weeks of gestation, is a major determinant of neonatal mortality and morbidity. Early diagnosis of the PTB followed by protective treatments is essential to reduce neonatal adverse outcomes. However, due to the redundant nature of clinical conditions with other diseases, PTB-associated clinical parameters are poor predictors of the PTB. It has been thus needed to identify molecular biomarkers with high accuracy in diagnosis of PTB. Here, we performed mRNA sequencing analysis of PTB patients and full-term birth (FTB) controls in Korean population and identified differentially expressed genes (DEGs) between PTB and FTB, as well as cellular pathways represented by the DEGs. By integrating two previous gene expression profiles generated from different ethnic groups, we then identified the core T-cell activation pathway associated with the PTB, which was shared among all previous datasets, and selected the three representative DEGs (CYLD, TFRC, and RIPK2) of the core pathway as biomarker candidates for the PTB. We finally confirmed the dysregulations of the biomarker candidates and the core T-cell activation pathway in an independent cohort. Our results suggest that CYLD, TFRC, and RIPK2 can serve as reliable biomarkers for the PTB.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148402 | GEO | 2021/04/06

REPOSITORIES: GEO

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Project description:Preterm birth (PTB, born before 37 weeks of gestation) is a leading cause of neonatal mortality and post-natal morbidity. PTB affects one in nine all live births in the U.S. Notably, the highest rate of PTB occurs among African Americans (one in six). PTB is a complex trait, likely determined by multiple environmental and genetic factors and their interactions. We demonstrated strong familial aggregation of preterm and low birthweight in the US Blacks and Whites (Wang et al, NEJM, <a href="http://www.ncbi.nlm.nih.gov/pubmed/7491139">1995</a>) and conducted the largest candidate gene study of preterm birth at that time (Hao et al, HMG, <a href="http://www.ncbi.nlm.nih.gov/pubmed?cmd=DetailsSearch&term=14976157">2004</a>). We showed that a subset of mothers with certain metabolic gene variants are particularly vulnerable to the adverse effects of cigarette smoking on low birthweight and preterm births (Wang et al, JAMA, <a href="http://www.ncbi.nlm.nih.gov/pubmed?cmd=DetailsSearch&term=11779261">2002</a>). We also published a number of papers that examined the effect of maternal pre-pregnancy BMI, micronutrient status, stress and environmental toxins on the risk of preterm birth and related conditions. This project, supported by a grant from the NICHD (2R01HD41702, PI, Xiaobin Wang), aimed to conduct a genome-wide association study (GWAS) and apply advanced statistical methods to identify susceptibility loci of PTB in a predominantly urban low-income African American sample, a subset of the Boston Birth Cohort. PUBLIC HEALTH REVELANCE: We anticipate that this study will lead to the identification of novel genetic loci of PTB and gene-environment interactions. Such findings not only will provide important insights into mechanisms leading to PTB, but also may help identify women at high-risk of PTB, which in turn, may lead to the development of early and targeted interventions that can prevent PTB or mitigate the severity and consequences of PTB.

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.

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Integrative analysis of transcriptomic data for the identification of biomarkers associated with T-cell activation in preterm birth

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