Guo-Ying Huang

Fudan University, Shanghai, Shanghai Shi, China

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Publications (48)120.7 Total impact

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    ABSTRACT: Several pioneering studies have provided evidence for the introduction of universal pulse oximetry screening for critical congenital heart disease. However, whether the benefits of screening reported in studies from high-income countries would translate with similar success to low-income countries is unknown. We assessed the feasibility and reliability of pulse oximetry plus clinical assessment for detection of major congenital heart disease, especially critical congenital heart disease, in China. We did a pilot study at three hospitals in Shanghai to assess the accuracy of pulse oximetry plus clinical assessment for detection of congenital heart disease. We made a data collection plan before recruitment. We then undertook a large, prospective, and multicentre screening study in which we screened all consecutive newborn babies (aged 6-72 h) born at 18 hospitals in China between Aug 1, 2011, and Nov 30, 2012. Newborn babies with positive screen results (either an abnormal pulse oximetry or abnormal clinical assessment) were referred for echocardiography within 24 h of screening. We identified false-negative results by clinical follow-up and parents' feedback. We calculated sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios for pulse oximetry alone, and in combination with clinical assessment, for detection of major and critical congenital heart disease. In the pilot study, 6785 consecutive newborn babies were screened; 46 of 49 (94%) cases of asymptomatic major congenital heart disease and eight of eight (100%) cases of asymptomatic critical disease were detected by pulse oximetry and clinical assessment. In the prospective multicentre study, we screened 122 738 consecutive newborn babies (120 707 asymptomatic and 2031 symptomatic), and detected congenital heart disease in 1071 (157 critical and 330 major). In asymptomatic newborn babies, the sensitivity of pulse oximetry plus clinical assessment was 93·2% (95% CI 87·9-96·2) for critical congenital heart disease and 90·2% (86·4-93·0) for major disease. The addition of pulse oximetry to clinical assessment improved sensitivity for detection of critical congenital heart disease from 77·4% (95% CI 70·0-83·4) to 93·2% (87·9-96·2). The false-positive rate for detection of critical disease was 2·7% (3298 of 120 392) for clinical assessment alone and 0·3% (394 of 120 561) for pulse oximetry alone. Pulse oximetry plus clinical assessment is feasible and reliable for the detection of major congenital heart disease in newborn babies in China. This simple and accurate combined method should be used in maternity hospitals to screen for congenital heart disease. Key Clinical Research Project sponsored by Ministry of Health, Shanghai Public Health Three-Year Action Plan sponsored by Shanghai Municipal Government, and National Basic Research Project of China.
    The Lancet 04/2014; · 39.06 Impact Factor
  • Lin Yang, Hui-Jun Wang, Guo-Ying Huang, Wen-Hao Zhou
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    ABSTRACT: Congenital malformation is one of the most frequent causes of infant death in western countries and major cities in China. Though genetic screening of newborns remains a hot issue and concern, the mortality rate associated with birth defects has not been significantly reduced over the past 20 years. Many genetic diseases manifest symptoms during the first 28 days of life, but full clinical symptoms might not be evident in newborns. Moreover, genetic aberrations is highly heterogeneous. These complicated factors lead to the establishment of diagnosis based on nonspecific or obscure symptoms. Recently developed array comparative genomic hybridization (CGH) and next generation sequencing (NGS) techniques with efficient high-resolution allow to screening of the entire genome for DNA copy number variants and sequencing respectively. These new and powerful tools can shorten the differential diagnosis process and quicken to movement towards targeted treatment and genetic and prognostic counseling.
    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 11/2013; 15(11):960-964.
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    ABSTRACT: Abnormal expression of connexin 43 (Cx43) has been reported to play an important role in the development of conotrunccal anomalies. However, less is known about the underlying reason for its abnormal expression. MicroRNAs (miRNAs), as an important part of gene expression regulation, have been implicated in some cardiac diseases. This study aimed to investigate the expression of Cx43 and its related miRNAs in patients with tetralogy of Fallot (TOF), and illustrate the potential role of abnormal miRNAs regulation to Cx43 expression in the pathology of TOF. Real-time polymerase chain reaction (PCR) was used to detect the expression of Cx43 and 10 Cx43-related miRNAs in the myocardium from 30 TOF patients and 10 normal controls. Immunohistochemistry was used to detect Cx43 protein expression. Putative miRNA binding sites in the 3'UTR of Cx43 were examined in 200 TOF patients and 200 healthy individuals, using Sanger sequencing, to exclude sequence variations resulting in binding difficulties of miRNAs. Cx43 mRNA and protein expression in the myocardium tissue was significantly increased in TOF patients. The expression of MiR-1 and 206 was significantly decreased in the TOF patients as compared with the controls (P<0.05). No obvious difference was observed in the expression of the other 7 miRNAs between the TOF patients and controls (P>0.05). No meaningful sequence variation was detected in the putative miR1/206 binding sites in the 3'UTR of Cx43. This study indicated that miR-1 and 206 is down-regulated in TOF patients, which may cause an up-regulation of Cx43 protein's synthesis. It provided a clue that miR-1 and 206 might be involved in the pathogenesis of TOF, additional experiments are needed to determine if in fact, miR-1 and 206 contribute substantially to TOF.
    World Journal of Pediatrics 10/2013; · 1.08 Impact Factor
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    ABSTRACT: Tetralogy of Fallot (TOF) is 1 of the most common heart defects in children, and the underlying mechanisms remain largely elusive. MicroRNAs (miRNAs) are a class of regulators of gene expression and are increasingly recognized for their roles in heart development. To identify miRNAs abnormally expressed in TOF, microarrays were used to analyze the miRNA expression profiles of 5 samples of myectomy tissues from right ventricular outflow tract (RVOT) obstruction of infants with nonsyndromic TOF and 3 age-matched normal RVOT tissues. In total, 41 candidate miRNAs were identified. To further validate the microarray results, the 41 miRNAs were detected using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in a larger independent population of tissue samples, including 21 from patients with TOF and 6 from normal controls; it was found that 18 miRNAs were expressed at significantly different levels. Bioinformatic analysis revealed that these miRNAs targeted a network of genes involved in heart development and human congenital heart diseases. Further in vitro studies indicated that upregulation of miR-424/424* promoted proliferation and inhibited migration of primary embryonic mouse cardiomyocytes, whereas miR-222 promoted cardiomyocyte proliferation and reduced the cardiomyogenic differentiation of P19 cells. The 3'UTR (3' untranslated region) luciferase assay revealed that miR-424/424* suppressed the expression of HAS2 and NF1, and their mRNAs were underexpressed in the RVOT myocardial tissues of TOF. Eighteen miRNAs were identified as being deregulated in RVOT myocardial tissues from infants with nonsyndromic TOF, and in vitro experiments indicated that miR-424/424* and miR-222 are involved in cardiomyocyte proliferation and migration and the cardiomyogenic differentiation of P19 cells.
    The Canadian journal of cardiology 10/2013; · 3.12 Impact Factor
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    ABSTRACT: To study the expression of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in children with tetralogy of Fallot (TOF), and to investigate the role of histone acetylation and acetylation-related enzymes in the pathogenesis of TOF. Myocardial tissue samples in the TOF group were obtained from 46 children with TOF who underwent radical operation, and myocardial tissue samples in the control group were obtained from 16 children who suffered accidental deaths and had no cardiac anomalies as shown by autopsy. The acetylation of H3K9, H3K18 and H3K27 was evaluated by immunohistochemistry. The mRNA expression of HATs and HDACs in the myocardium was measured by real-time PCR. The correlation between mRNA expression of HATs and HDACs and histone acetylation was analyzed. Compared with the control group, the TOF group showed significantly increased acetylation of H3K9 (P=0.0165) and significantly decreased acetylation of H3K18 (P=0.0048) and H3K27 (P=0.0084). As to 4 HATs and 6 HDACs, the mRNA expression of EP300 and CBP was significantly higher in the TOF group than in the control group (P=0.025; P=0.017), and there was no significant difference in the mRNA expression of other HATs and HDACs between the two groups. The correlation analysis revealed a positive correlation between H3K9 acetylation and mRNA expression of EP300 (r=0.71, P<0.01) and CBP (r=0.72, P<0.01). Upregulated mRNA expression of EP300 and CBP may be associated with increased H3K9 acetylation, suggesting that EP300 and CBP might affect cardiac development by regulating H3K9 acetylation.
    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 10/2013; 15(10):817-821.
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    ABSTRACT: To characterize the clinical and angiographic features in children with renovascular hypertension. Clinical data of 14 children (7 male, 7 female; age 0.8-14 years, mean 8.7 years), who were diagnosed with renovascular hypertension by renal angiography in our institute from January 2005 to December 2012 were collected and retrospectively analyzed. The mean blood pressure at the diagnosis was 187/127 mm Hg. Chief complaints of symptomatic patients were headache (29%, 4/14), hypertensive encephalopathy (36%, 5/14), signs of congestive heart failure (14%, 2/14) and hematemesis (7%, 1/14). Renovascular hypertension was found incidentally in 14% (2/14) of patients who were asymptomatic. Conventional renal angiography elucidated the anatomical distribution of lesions in the renal arterial system. It was found that 14% (2/14) of patients had bilateral disease, 50% (7/14) had single stenosis at main or accessory renal artery, while multiple stenoses was seen in 43% (6/14) of children, with involvement of segmental renal artery and small interlobar or arcuate vessels. Compared with catheter angiography, 50% (7/14) of patients with renovascular hypertension, especially intrarenal arterial disease, were missed on computed tomography angiography or magnetic resonance angiography. It is mandatory to emphasize blood pressure measurement in pediatric clinical practice for early recognition of renovascular hypertension. As children with renovascular hypertension display involvement of multiple arteries, including in smaller intrarenal arteries, digital subtraction angiography is the only method that can reliably diagnose pediatric renovascular hypertension.
    Zhonghua er ke za zhi. Chinese journal of pediatrics 08/2013; 51(8):621-4.
  • Lan He, Fang Liu, Guo-Ying Huang
    Chinese medical journal 08/2013; 126(16):3192. · 0.90 Impact Factor
  • Xiao-Jing Ma, Guo-Ying Huang
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    ABSTRACT: Life-threatening critical congenital heart disease (cCHD) is often not detected in the neonatal period. Unrecognized cCHD results in high morbidity and mortality rates. As a non-invasive, convenient, quick and accurate measuring method, pulse oximetry is considered to be a promising strategy to screen for cCHD in neonates. This article is a review on the neonatal pulse oximetry screening for cCHD. Articles on neonatal pulse oximetry screening for cCHD were accessed from PubMed, using keywords including congenital heart defects, neonatal screening and oximetry. Original articles and critical reviews selected were relevant to the review's theme. The factors in the course of implementation, including threshold for positive pulse-oximetry screening results, the pulse oximeters used, timing of the screening, and the measuring position, influence the accuracy of the screening. It is recommended that the screening is completed on the second day of life, before hospital discharge. Motion-tolerant pulse oximeters, which can also be applied to measure the saturation in low-perfusion conditions, should be used. The probe should be put on both the right hand and on one foot. Thresholds of < 95% in either limb or a difference of > 3% between the limbs as a positive result may be appropriate. It should be emphasized that pulse-oximetry screening cannot be used as the only way to detect cCHD, clinical examination is also important in this situation. Cost-benefit analysis in the United Kingdom revealed it was plausible to use pulse oximetry as an adjunct to clinical examination. However, it is still controversial as to whether pulse oximetry can be used as a routine screening method for cCHD in neonates. Neonatal pulse oximetry screening improves detection of cCHD. Further studies should be carried out before it becomes one of the routine newborn screening programs.
    Chinese medical journal 07/2013; 126(14):2736-40. · 0.90 Impact Factor
  • Jun Xu, Hui-Jun Wang, Guo-Ying Huang
    Zhonghua er ke za zhi. Chinese journal of pediatrics 07/2013; 51(7):552-554.
  • Xi-Hong Hu, Mi-Er Pa, Quan-Li Shen, Guo-Ying Huang
    Chinese medical journal 07/2013; 126(14):2790-2. · 0.90 Impact Factor
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    ABSTRACT: Elevated homocysteine levels are known to be a risk factor for congenital heart disease (CHD), but the mechanism underlying this effect is unknown. During early embryonic development, homocysteine removal is dictated exclusively by the MTR activity. To examine the role of MTR in CHD risk, we identified genetic variants in MTR and investigated the mechanisms that affect its expression levels and that increase the risk of CHD in Chinese populations. The association between regulatory variants of the MTR gene and CHD was examined in three independent case-control studies in a total of 2340 patients with CHD and 2270 controls. The functional consequences of these variants were demonstrated using dual-luciferase assays, real-time polymerase chain reaction (PCR), electrophoretic mobility shift assays, surface plasma resonance, chromatin immunoprecipitation, and bisulfite sequencing, as well as by a group of predicted microRNAs using a gene reporter system. Two regulatory variants of MTR, -186T>G and +905G>A, were associated with an increased risk of CHD in both the separate and combined case-control studies (-186GG P = 1.32 × 10(-9); +905AA P = 6.35 × 10(-14)). Compared with the major allele, the -186G allele exhibited significantly lower promoter activity, decreased hnRNA and mRNA levels, reduced transcription factor binding affinity, and a more highly methylated promoter. The +905A allele exhibited a statistically stronger binding affinity to functional microRNAs that down regulate MTR expression at the translational level. Both of the minor alleles were correlated with elevated plasma homocysteine concentrations, indicating a genetic component for hyperhomocysteinaemia. Regulatory variants of the MTR gene increase CHD risk by reducing MTR expression and inducing the homocysteine accumulation and elevation.
    European Heart Journal 06/2013; · 14.10 Impact Factor
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    ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are endogenous noncoding RNAs of approximately 22 nucleotides in length that mediate post-transcriptional gene silencing by annealing to sequences in the 3'-untranslated region of target mRNAs. METHODS: In this study, we analyzed 25 candidate miRNAs selected based on microarray data for cardiac tissue from individuals with congenital heart defects (CHDs) and from healthy control tissue. RESULTS: This study identified specific changes in the miR-1-1 and miR-181c levels in human cardiac samples from individuals with ventricular septal defects (VSDs) relative to the levels in healthy control tissue. Increased levels of GJA1 and SOX9 were associated with the decreased expression of miR-1-1 in VSD patients, and increased miR-181c expression was correlated with downregulated BMPR2 levels. In addition, the results revealed that miR-1-1 and miR-181c directly regulate the expression of these predicted targets. CONCLUSIONS: miR-1-1 and miR-181c are associated with the pathogenesis of VSDs.
    International journal of cardiology 01/2013; · 6.18 Impact Factor
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    ABSTRACT: Several studies have suggested a difference in clinical features of intellectual ability and psychiatric illness in the Prader-Willi syndrome (PWS) with the 15q11-q13 paternal deletion and maternal uniparental disomy (mUPD). Our objective was to appraise evidence on this association through a meta-analysis. The electronic records PubMed and EMBASE from 1956 to 2012 were extracted for meta-analysis. Meta-analyses were performed by using fixed effect model. Mean difference, odds ratio, and 95% confidence interval were calculated. We retrieved a total of 744 PWS cases from 13 studies. These include 423 cases with paternal 15q11-q13 deletions and 318 cases of mUPD. Compare to the PWS cases with mUPD, PWS patients with the paternal 15q11-q13 deletion associated with significantly lower full scale IQ (FSIQ) [mean difference (MD), -2.69; 95%CI, -4.86 to -0.52; p=0.02] and verbal IQ (VIQ) (MD, -7.5; 95%CI, -9.75 to -5.26; p<0.00001) but higher performance IQ (PIQ) (MD, 4.02; 95%CI, 1.13 to 6.91; p=0.006). In contrast, PWS patients with mUPD are associated with significantly higher risk of psychiatric illness [odds rate (OR), 0.14; 95%CI, 0.08 to 0.23; p<0.00001] and higher risk of bipolar disorder (OR, 0.04; 95%CI, 0.01 to 0.23; p=0.0002). Significant different clinical features of cognitive development and psychiatric illness are associated with PWS with different molecular defects. These findings provide support for evidence based practice to evaluate and manage the PWS syndrome with different molecular defects.
    PLoS ONE 01/2013; 8(8):e72640. · 3.73 Impact Factor
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    ABSTRACT: Homocysteine is an independent risk factor for various cardiovascular diseases. There are two ways to remove homocysteine from embryonic cardiac cells: remethylation to form methionine or transsulfuration to form cysteine. Cystathionine β-synthase (CBS) catalyzes the first step of homocysteine transsulfuration as a rate-limiting enzyme. In this study, we identified a functional variant -4673C>G (rs2850144) in the CBS gene promoter region that significantly reduces the susceptibility to congenital heart disease (CHD) in a Han Chinese population consisting of 2 340 CHD patients and 2 270 controls. Individuals carrying the heterozygous CG and homozygous GG genotypes had a 15% (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75-0.96, P = 0.011) and 40% (OR = 0.60, 95% CI = 0.49-0.73, P = 1.78 × 10(-7)) reduced risk to develop CHD than the wild-type CC genotype carriers in the combined samples, respectively. Additional stratified analyses demonstrated that CBS -4673C>G is significantly related to septation defects and conotruncal defects. In vivo detection of CBS mRNA levels in human cardiac tissues and in vitro luciferase assays consistently showed that the minor G allele significantly increased CBS transcription. A functional analysis revealed that both the attenuated transcription suppressor SP1 binding affinity and the CBS promoter hypomethylation specifically linked with the minor G allele contributed to the remarkably upregulated CBS expression. Consequently, the carriers with genetically increased CBS expression would benefit from the protection due to the low homocysteine levels maintained by CBS in certain cells during the critical heart development stages. These results shed light on unexpected role of CBS and highlight the importance of homocysteine removal in cardiac development.Cell Research advance online publication 18 September 2012; doi:10.1038/cr.2012.135.
    Cell Research 09/2012; · 10.53 Impact Factor
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    ABSTRACT: Epicardium-derived cells (EPDCs) can migrate into the myocardium, giving rise to several types of cell which are indispensable to compact myocardium and inducing normal myocardial development. Subepicardium accumulates bone morphogenetic proteins (Bmps), which can release into myocardium further. It has been shown that reduced Bmp-mediated signaling in a novel neural crest derivative in the epicardium reduced the cardiomyocyte proliferative activity in the developing myocardium. Furthermore, studies have demonstrated that cardiomyocytes can develop in proepicardial organ (PEO) explant cultures after stimulation with bone morphogenetic protein (Bmp2). We present a hypothesis that Bmp2 regulates the interaction between EPDCs and cardiomyocyte in the developing outflow tract (OFT). Our previous empirical data also shows that Bmp2 is expressed in the myocardial cell in the OFT at embryonic day (E) 14.5 in wild-type mice, and expression of Bmp2 in Cx43α1 knockout (KO) OFT was delayed for 1day. Further validation of this hypothesis will provide additional insight of the molecular mechanism of myocardium maturation.
    Medical Hypotheses 05/2012; 79(2):174-7. · 1.18 Impact Factor
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    ABSTRACT: Transforming growth factor β2 (TGFβ2) plays an essential role in cardiac morphogenesis. However, the prevalence of TGFβ2 mutations in congenital heart disease (CHAD) and the correlation between the TGFβ2 genotype and the CHAD phenotype have not been studied extensively. The aim of this study was to examine DNA sequence changes in the TGFβ2 gene in sporadic patients with tetralogy of Fallot (TOF), and to observe whether TGFβ2 is the susceptibility gene for TOF. A cohort of 100 pediatric patients with TOF was recruited to the study; 200 healthy children were used as controls. PCR and genotyping were conducted for the detection of DNA changes in TGFβ2. The exons and the 5' untranslated region (5'UTR) sequences of the TGFβ2 gene were amplified. No mutations were identified in the coding region in any of the TOF patients. However, three single nucleotide changes, including 9126 A>AC, 9353 A>AG and 9040_9043 del CTTC, in the 5'UTR were found. There were no significant differences in allelic frequencies and genotype frequencies of position 9126 and 9353 between the TOF group and the control group. On the contrary, a significant difference was identified in the allelic frequencies (χ(2)=17.469, P<0.001) of position 9040_9043 in the 5'UTR between the TOF group and the control group. Our results suggest that TGFβ2 may be a potential candidate gene of TOF. SNPs at position 9040_9043 del CTTC in the 5'UTR of TGFβ2 may be associated with susceptibility to TOF. The CTTC allele may be the susceptibility allele for TOF. However, the exact effect of these sequence changes requires further study using functional experiments.
    Experimental and therapeutic medicine 05/2012; 3(5):878-880. · 0.34 Impact Factor
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    ABSTRACT: Clinical research indicates that periconceptional administration of folic acid can reduce the occurrence of congenital cardiac septal defects (CCSDs). The vital roles of folate exhibits in three ways: the unique methyl donor for DNA expression regulation, the de novo biosynthesis of purine and pyrimidine for DNA construction, and the serum homocysteine removal. Thymidylate synthase (TYMS) is the solo catalysis enzyme for the de novo synthesis of dTMP, which is the essential precursor of DNA biosynthesis and repair process. To examine the role of TYMS in Congenital Cardiac Septal Defects (CCSDs) risk, we investigated whether genetic polymorphisms in the TYMS gene associated with the CCSDs in a Han Chinese population. Polymorphisms in the noncoding region of TYMS were identified via direct sequencing in 32 unrelated individuals composed of half CCSDs and half control subjects. Nine SNPs and two insertion/deletion polymorphisms were genotyped from two independent case-control studies involving a total of 529 CCSDs patients and 876 healthy control participants. The associations were examined by both single polymorphism and haplotype tests using logistic regression. We found that TYMS polymorphisms were not related to the altered CCSDs risk, and even to the changed risk of VSDs subgroup, when tested in both studied groups separately or in combination. In the haplotype analysis, there were no haplotypes significantly associated with risks for CCSDs either. Our results show no association between common genetic polymorphisms of the regulatory region of the TYMS gene and CCSDs in the Han Chinese population.
    PLoS ONE 01/2012; 7(2):e31644. · 3.73 Impact Factor
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    ABSTRACT: Homocysteine is known to be an independent risk factor for congenital heart disease (CHD). Methionine synthase reductase (MTRR) is essential for the adequate remethylation of homocysteine, which is the dominant pathway for homocysteine removal during early embryonic development. Here, we report that the c.56+781 A>C (rs326119) variant of intron-1 of MTRR significantly increases the risk of CHD in the Han Chinese population. In 3 independent case-control studies involving a total of 2340 CHD patients and 2270 healthy control participants from different geographic areas, we observed that patients carrying the heterozygous AC and homozygous CC genotype had a 1.40-fold (odds ratio=1.40; P=2.32×10(-7)) and 1.84-fold (odds ratio=1.84; P=2.3×10(-11)) increased risk, respectively, of developing CHD than those carrying the wild-type AA genotype. Both in vivo quantitative real-time polymerase chain reaction analysis of MTRR mRNA in cardiac tissue samples from CHD patients and in vitro luciferase assays in transfected cells demonstrated that the c.56+781 C allele profoundly decreased MTRR transcription. Further analysis demonstrated that the c.56+781 C allele manifested reduced CCAAT/enhancer binding protein-α binding affinity. In addition, healthy individuals with the homozygous CC genotype had significantly elevated levels of plasma homocysteine compared with the wild-type AA carriers. We have demonstrated that the MTRR c.56+781 A>C variant is an important genetic marker for increased CHD risk because this variant results in functionally reduced MTRR expression at the transcriptional level. Our results accentuate the significance of functional single-nucleotide polymorphisms in noncoding regions of the homocysteine/folate metabolism pathway core genes for their potential contributions to the origin of CHD.
    Circulation 12/2011; 125(3):482-90. · 15.20 Impact Factor
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    ABSTRACT: GJA1 gene encodes a gap junction protein known as connexin 43 (Cx43). Cx43 is abundantly expressed in the ventricular myocardium and in cardiac neural crest cells. Cx43 is proposed to play an important role in human congenital heart disease, as GJA1 knock-out mice die neonatally from outflow tract obstruction. In addition, patients with visceroatrial heterotaxia or hypoplastic left heart syndrome were reported to have point mutations in GJA1 at residues that affect protein kinase phosphorylation and gating of the gap junction channel. However, as these clinical findings were not replicated in subsequent studies, the question remains about the contribution of GJA1 mutations in human congenital heart disease (CHD). We analyzed the GJA1 coding sequence in 300 patients with CHD from two clinical centers, focusing on outflow tract anomalies. This included 152 with Tetralogy of Fallot from over 200 patients exhibiting outflow tract anomalies, as well as other structural heart defects including atrioventricular septal defects and other valvar anomalies. Our sequencing analysis revealed only two silent nucleotide substitutions in 8 patients. To further assess the possible role of Cx43 in CHD, we also generated two knock-in mouse models with point mutations at serine residues subject to protein kinase C or casein kinase phosphorylation, sites that are known to regulate gating and trafficking of Cx43, respectively. Both heterozygous and homozygous knock-in mice were long term viable and did not exhibit overt CHD. The combined clinical and knock-in mouse mutant studies indicate GJA1 mutation is not likely a major contributor to CHD, especially those involving outflow tract anomalies.
    Journal of cardiovascular disease research 10/2011; 2(4):206-12.
  • Ying Zhang, Wei-Cheng Chen, Guo-Ying Huang
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    ABSTRACT: To investigate the mechanism of myocardialization of proximal outflow tract septum and its effect on the conotruncal anomaly in mice. The C(57)/BL(6) mice of embryonic day (E) 11.5 - 16.5 were selected. The phenotypes of connexin 43 (Cx43) homozygotes (Cx43(-/-)), heterozygotes (Cx43(+/-)) and wild-types (Cx43(+/+)) were genetically typed by polymerase chain reaction (PCR). Bone morphogenetic protein receptor 2 (Bmpr2) and α-sarcomeric acti (α-SCA) were detected by immunohistochemistry. The expression of α-SCA in the proximal outflow tract (OFT) septum was delayed obviously in Cx43(-/-) predominantly at E13.5 and E14.5. From E11.5 to E13.5, the expression of Bmpr2 was detected in cardiac atrium and epicardium of Cx43(+/+) fetal heart. And Bmpr2 was slightly expressed in ventricular muscle of Cx43(+/+) fetal heart. And it was expressed slightly only in cardiac atrium and epicardium of Cx43(+/-) and Cx43(-/-) fetal heart. From E14.5 to E16.5, its expression was detected obviously in cardiac atrium, epicardium, endocardium, trabeculum, ventricular muscle and OFT septum of Cx43(+/+) fetal heart. At E14.5, its expression was detected obviously in cardiac atrium, epicardium, endocardium and trabeculum of Cx43(+/-) and Cx43(-/-) fetal heart while none in ventricular muscle and OFT septum. At E15.5 and E16.5, its expression was detected obviously in cardiac atrium, epicardium, endocardium, trabeculum, ventricular muscle and OFT septum of Cx43(+/-) and Cx43(-/-) fetal heart. Its expression was also detected obviously in OFT septum of Cx43(+/-) and Cx43(-/-) fetal heart with incomplete myocardialization. Cx43KO embryonic mice exhibit delayed myocardialization. As compared with the Cx43(+/+), the expression of Bmpr2 in proximal OFT septum was delayed obviously in Cx43(+/-) and Cx43(-/-) mice. And the expression of Bmpr2 is abnormal in OFT septum of Cx43(+/-) and Cx43(-/-) fetal heart. Bmpr2 may be involved in the interaction between epicardium and myocardium. It may be a critical mechanism in the maturation process of cardiac muscles.
    Zhonghua yi xue za zhi 08/2011; 91(31):2211-5.