Gene Variant Affecting the Hippo Signaling Pathway Is Correlated With Bronchopulmonary Dysplasia in Extremely Low Birthweight Infants

Author Type(s)

Faculty

Document Type

Abstract

Publication Date

2022

DOI

10.1136/jim-2022-ERM.25

Journal Title

Journal of Investigative Medicine

Department

Pediatrics

Abstract

Purpose of Study Bronchopulmonary dysplasia (BPD) is one of the most common causes of death and morbidity in extremely low birth weight (ELBW) infants. It is characterized by exposure to environmental stimuli such as: mechanical ventilationpressure, volume; hyperoxia; and inflammation; within a background of genetic susceptibility. Impaired lung development affects the respiratory epithelium, the vascular endothelium, and the extracellular matrix. The Hippo signaling pathway is known to play a key role in tissue growth suppression and modulation in lung development, physiology, and injury. Specifically, variants of yes-associated protein (YAP), transcriptional co-activator with PDZ-binding motif (TAZ) and transcription enhancer factor (TEA/ATTS) domain (TEAD) are important regulators of the Hippo pathway and are associated with changes in lung function in asthma and in small-cell lung cancer. Perturbations to YAP, TAZ and TEAD of the Hippo pathway result in altered pulmonary tissue growth and vascular development. Because alterations in pulmonary lung and vascular development are also characteristic of BPD, we hypothesize that genetic variants in YAP, TAZ and TEAD of the Hippo pathway are associated with the development of BPD in ELBW infants. Methods Used DNA extracted from buccal swabs collected from ELBW infants following IRB-approved parental consent was subjected to allelic discrimination using specific Taqman probes for rs10895256, rs2846836, rs1820453, rs16861979, rs2304733, rs6918698 and rs11225163 during RT-PCR. Statistics included Chi-square, t-test, and z-test, with significant p value £0.05. Summary of Results Demographic characteristics did not differ between those with BPD and those without BPD except for gestational age and postnatal steroids (table 1). TEAD variant rs2304733 was found to have a significantly different genotype distribution in the BPD group compared to the Non-BPD group (p=0.05) (table 2). There were no statistical differences in the genotype distributions of the other YAP1 or TAZ variants tested. Conclusions The TEAD variant rs2304733 is associated with BPD in ELBW infants. We speculate that while preterm birth perturbs the HIPPO pathway and accelerates pulmonary growth suppression, this specific TEAD genetic variant may play a role in modulating YAP/TAZ nuclear localization, contributing to increased susceptibility to BPD. (Table Presented).

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