DNA Methylation Levels of the TBX5 Gene Promoter Are Associated with Congenital Septal Defects in Mexican Paediatric Patients

Abstract

The TBX5 gene regulates morphological changes during heart development, and it has been associated with epigenetic abnormalities observed in congenital heart defects (CHD). The aim of this research was to evaluate the association between DNA methylation levels of the TBX5 gene promoter and congenital septal defects. DNA methylation levels of six CpG sites in the TBX5 gene promoter were evaluated using pyrosequencing analysis in 35 patients with congenital septal defects and 48 controls. Average methylation levels were higher in individuals with congenital septal defects than in the controls (p < 0.004). In five CpG sites, we also found higher methylation levels in patients than in the controls (p < 0.05). High methylation levels were associated with congenital septal defects (OR = 3.91; 95% CI = 1.02–14.8; p = 0.045). The analysis of Receiver Operating Characteristic (ROC) showed that the methylation levels of the TBX5 gene could be used as a risk marker for congenital septal defects (AUC = 0.68, 95% CI = 0.56–0.80; p = 0.004). Finally, an analysis of environmental factors indicated that maternal infections increased the risk (OR = 2.90; 95% CI = 1.01–8.33; p = 0.048) of congenital septal defects. Our data suggest that a high DNA methylation of the TBX5 gene could be associated with congenital septal defects.

Discovery and functional investigation of BMP4 as a new causative gene for human congenital heart disease

“…A finely-coordinated sophisticated signaling network, which principally consists of transforming growth factor-β (TGFβ), bone morphogenetic protein (BMP), Wnt family member (WNT), nodal growth differentiation factor (NODAL), and fibroblast growth factor (FGF), induces expression of a key cluster of cardiac transcription factors encompassing NKX2.5, TBX20/5/1, and GATA5/6/4 that work in a mutually-reinforcing cascade to drive cellular lineage restriction and proliferation, differentiation, and migration of different progenitor cell populations to the proper chambers for specific types of cardiac cells [66]. Both environmental pathogenic factors and inheritable defects can disturb the heart-development process, giving rise to a diverse array of CHD [1,3,[66][67][68][69][70][71]. It is believed that non-inherited risk factors account for about 30% of CHD, although the molecular mechanisms of CHD caused by detrimental environmental exposure are largely elusive [71].…”

Discovery of BMP10 as a new gene underpinning congenital heart defects

“…In vertebrate embryos, the heart is the first functioning organ to develop, and cardiac development experiences an exceedingly sophisticated biological process that involves a finely controlled sophisticated network, principally comprising cardiac structural proteins, transcription factors, signal-transducing molecules, and epigenetic modifiers [1,[60][61][62][63][64]. It has been validated that both non-heritable risk factors and inherited defectives may perturb this heart-forming process, leading to an extensive assortment of CHD [1,3,[60][61][62][63][64][65][66]. It is estimated that acquired/environmental pathogenic factors contribute to ~10% of CHD, though their molecular mechanisms underlying CHD are largely obscure [1].…”

“…It is estimated that acquired/environmental pathogenic factors contribute to ~10% of CHD, though their molecular mechanisms underlying CHD are largely obscure [1]. Well-established non-genetic factors that predispose someone to CHD include maternal disorders (obesity, essential hypertension, hyperlipidemia, diabetes mellitus, hyperhomocysteinemia, phenylketonuria, acute febrile illness, viral infections, epilepsy, pre-eclampsia, autoimmune imbalance, connective tissue disease, thyroid disease, and mental health disease), maternal medications (anti-depressant, anti-hypertensive, anti-convulsant, and anti-infective drugs), maternal ingestion of toxic substance (marijuana, alcohol, and tobacco), maternal malnutrition (folate deficiency), and maternal exposure of air pollutants, toxic chemicals, and heavy metals during the first trimester of pregnancy [1,64,[67][68][69][70]. However, an ever-growing body of evidence substantiates that inherited components exert a predominant impact on the incidence of CHD [1,3,[60][61][62].…”

Somatic GATA4 mutation contributes to tetralogy of Fallot

“…In vertebrates, embryonic cardiac organogenesis arises from complicated biological processes that involve cellular commitment, differentiation, proliferation, apoptosis and migration (46); both non-inheritable/environmental predisposing factors and heritable abnormal components may interrupt the finely controlled process, leading to congenital heart disease (2,(47)(48)(49)(50)(51). Environmental precipitating factors may contribute to ~10% of congenital heart disease cases, although their underlying mechanisms are largely unclear (2).…”