Structural Abnormalities of the Pulmonary Trunk in Tetralogy of Fallot and Potential Clinical Implications

Bédard, Élisabeth; McCarthy, Karen; Dimopoulos, Konstantinos; Giannakoulas, George; Gatzoulis, Michael Α.; Ho, Siew Yen

doi:10.1016/j.jacc.2009.06.040

Cited by 50 publications

(35 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…About 19–75 people per 1000 are born with CHD each year, depending on which types of defects are included [1] and the incidence is higher if stillbirths were included [2]. Tetralogy of Fallot (TOF) is the most common complex congenital heart disease [3], accounting for 10% of all congenital heart diseases [4]. The four distinct anatomical features that characterize TOF are pulmonary outflow tract obstruction, ventricular septal defect, overriding aortic root and right ventricular hypertrophy [5].…”

Section: Introductionmentioning

confidence: 99%

Association of promoter methylation statuses of congenital heart defect candidate genes with Tetralogy of Fallot

Wei

Qian

Zhang³

et al. 2014

J Transl Med

View full text Add to dashboard Cite

BackgroundAlthough a lower methylation level of whole genome has been demonstrated in Tetralogy of Fallot (TOF) patients, little is known regarding changes in specific gene DNA methylation profiles and the possible associations with TOF. In current study, the promoter methylation statuses of congenital heart defect (CHD) candidate genes were measured in order to further understand epigenetic mechanisms that may play a role in the development of TOF.MethodsThe methylation levels of CHD candidate genes were measured using the Sequenom MassARRAY platform. QRT-PCR was used to analyze the mRNA levels of CHD candidate genes in the right ventricular myocardium of TOF cases and normal controls.ResultsMethylation status analysis was performed on the promoter regions of 71 CHD candidate genes (113 amplicons). We found significant differences in methylation status, between TOF cases and controls, in 26 amplicons (26 genes) (p < 0.05). Of the 26 amplicons, 17 were up regulated and 9 were down regulated. Additionally, 14 of them were located in the CpG islands, 7 were located in the CpG island shores, and 5 were covering the regions near the transcription start site (TSS). The methylation status was subsequently confirmed and mRNA levels were measured for 7 represented candidate genes, including EGFR, EVC2, NFATC2, NR2F2, TBX5, CFC1B and GJA5. The methylation values of EGFR, EVC2, TBX5 and CFC1B were significantly correlated with their mRNA levels (p < 0.05).ConclusionsAberrant promoter methylation statuses of CHD candidate genes presented in TOF cases may contribute to the TOF development and have potential prognostic and therapeutic significance for TOF disease.

show abstract

Section: Introductionmentioning

confidence: 99%

Association of promoter methylation statuses of congenital heart defect candidate genes with Tetralogy of Fallot

Wei

Qian

Zhang³

et al. 2014

J Transl Med

View full text Add to dashboard Cite

show abstract

“…TOF occurs in 3.6 of every 10,000 live births and accounts for 10% of all congenital heart defects (CHD) [2]. TOF is a complex heart condition that is characterized by a malalignment of the conal septum, which leads to a rightward deviation of the aorta and results in a large ventricular septal defect, along with varying degrees of right ventricular outflow tract narrowing [3].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation status of NKX2-5, GATA4 and HAND1in patients with tetralogy of fallot

et al. 2013

View full text Add to dashboard Cite

BackgroundNKX2-5, GATA4 and HAND1 are essential for heart development, however, little is known regarding their epigenetic regulation in the pathogenesis of tetralogy of fallot (TOF).MethodsMethylation levels were measured in three regions of NKX2-5 (M1: -1596 bp ~ -1374 bp, M2: -159 bp ~ 217 bp and M3: 1058 bp ~ 1524 bp), one region of GATA4 (M: -392 bp ~ 107 bp) and three regions of HAND1 (M1: -887 bp ~ -414 bp, M2: -436 bp ~ 2 bp and M3: 37 bp ~ 398 bp) using the Sequenom MassARRAY platform. QRT-PCR was used to analyze NKX2-5 and HAND1 mRNA levels in the right ventricular myocardium of TOF patients.ResultsTOF patients had a significantly higher NKX2-5_M3 median methylation level than controls (41.65% vs. 22.18%; p = 0.0074; interquartile range [IQR]: 30.46%–53.35%, N = 30 and 20.07%–24.31%, N = 5; respectively). The HAND1_M1 median methylation level was also significantly higher in TOF patients than controls (30.05% vs. 17.54%; p = 0.0054; IQR: 20.77%–40.89%, N = 30 and IQR: 14.69%–20.64%; N = 6; respectively). The methylation statuses of NKX2-5_M1, NKX2-5_M2, GATA4_M, HAND1_M2 or HAND1_M3 were not significantly different in TOF patients compared to controls. The methylation values for NKX2-5_M3 were negatively correlated with mRNA levels (r = - 0.463, p = 0.010, N = 30) and there was a significant association between HAND1_M1 methylation status and mRNA levels (r = - 0.524, p = 0.003, N = 30) in TOF patients.ConclusionsAberrant methylation statuses of the NKX2-5 gene body and HAND1 promoter regions are associated with the regulation of gene transcription in TOF patients and may play an important role in the pathogenesis of TOF.

show abstract

“…TOF accounts for 10% of all congenital heart defects, with an incidence of 3.6 per 10,000 live births [2]. It is characterized by four distinct anatomical features: pulmonary outflow tract obstruction, ventricular septal defects (VSD), overriding aortic roots, and right ventricular hypertrophy [3].…”

Section: Introductionmentioning

confidence: 99%

LINE-1 methylation status and its association with tetralogy of fallot in infants

Sheng

Wang

et al. 2012

BMC Med Genomics

View full text Add to dashboard Cite

BackgroundMethylation levels of long interspersed nucleotide elements (LINE-1) are representative of genome-wide methylation status and play an important role in maintaining genomic stability and gene expression. To derive insight into the association between genome-wide methylation status and tetralogy of fallot (TOF), we compared the methylation status of LINE-1 element between TOF patients and controls. The methylation of the NKX 2–5, HAND 1, and TBX 20 promoter regions was also evaluated.MethodsGenomic DNA from right ventricular tissue samples was obtained from 32 patients with TOF and 15 control subjects. Sequenom MassARRAY platform was performed to examine the methylation levels of LINE-1, NKX2-5, HAND1 and TBX20. Mann–Whitney U test was used to compare differences in methylation levels between two groups.ResultsThe methylation level of LINE-1 was significantly lower in patients with TOF, with a median of 57.95% (interquartile range [IQR]: 56.10%–60.04%), as opposed to 59.70% in controls (IQR: 59.00%–61.30%; P = 0.0021). The highest LINE-1 methylation level was 61.3%. The risk of TOF increased in subjects with the lowest methylation levels (less than or equal to 59.0%; OR = 14.7, 95% CI: 1.8–117.7, P = 0.014) and in those with medium methylation levels (59.0%–61.3%; OR = 2.0, 95% CI: 0.3–14.2, P = 0.65). An ROC curve analysis showed a relatively high accuracy of using the LINE-1 methylation level in predicting the presence of TOF (AUC = 0.78, 95% CI: 0.65–0.91; P = 0.002). The association of the LINE-1 methylation level with TOF was only observed in males (P = 0.006) and not in females (P = 0.25). Neither age nor gender was found to be associated with the LINE-1 methylation level in patients or controls. Higher methylation levels of NKX2-5 and HAND1 and lower methylation levels of TBX20 were also observed in patients with TOF than in controls. No association was found between the methylation levels of NKX2-5, HAND1 and TBX 20 with the LINE-1 methylation level.ConclusionsLower LINE-1 methylation levels are associated with increased risk of TOF and may provide important clues for the development of TOF.

show abstract

Structural Abnormalities of the Pulmonary Trunk in Tetralogy of Fallot and Potential Clinical Implications

Cited by 50 publications

References 34 publications

Association of promoter methylation statuses of congenital heart defect candidate genes with Tetralogy of Fallot

Association of promoter methylation statuses of congenital heart defect candidate genes with Tetralogy of Fallot

DNA methylation status of NKX2-5, GATA4 and HAND1in patients with tetralogy of fallot

LINE-1 methylation status and its association with tetralogy of fallot in infants

Contact Info

Product

Resources

About