Hostname: page-component-76fb5796d-zzh7m Total loading time: 0 Render date: 2024-04-26T01:08:38.778Z Has data issue: false hasContentIssue false
  • English
  • Français

Association of Cx43 rs2071166 polymorphism with an increased risk for atrial septal defect

Published online by Cambridge University Press:  04 December 2017

Ruoyi Gu ,
Wei Sheng ,
Xiaojing Ma  and
Guoying Huang
Ruoyi Gu
Affiliation:
Children’s Hospital of Fudan University, Shanghai, China
Wei Sheng
Affiliation:
Children’s Hospital of Fudan University, Shanghai, China
Xiaojing Ma
Affiliation:
Children’s Hospital of Fudan University, Shanghai, China Shanghai Key Laboratory of Birth Defects, Shanghai, China
Guoying Huang*
Affiliation:
Children’s Hospital of Fudan University, Shanghai, China Shanghai Key Laboratory of Birth Defects, Shanghai, China
*
Correspondence to: G. Huang, MD, Pediatric Heart Center, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China. Tel: +86-21-64931928; Fax: +86-21-64931928; E-mail: gyhuang@shmu.edu.cn
Get access Rights & Permissions [Opens in a new window]

Abstract

Atrial septal defect is one of the most common CHD. The pathogenesis of atrial septal defect still remains unknown. Cx43 is the most prevalent connexin in the mammalian heart during development. Its genetic variants can cause several CHD. The aim of our study was to investigate the association of genetic variations of the Cx43 with sporadic atrial septal defect. A total of 450 paediatric patients were recruited, including 150 cases with atrial septal defect and 300 healthy controls. The promoter region of Cx43 was analysed by sequencing after polymerase chain reaction. All data were analysed by using the Statistic Package for Social Science 19.0 software. The frequency of the single nucleotide polymorphism rs2071166 was significantly higher in atrial septal defect cases than in healthy controls. The CC genotype at rs2071166 site in Cx43 was correlated with an increased risk for atrial septal defect (p<0.0001, odds ratio=3.891, 95% confidence interval 1.948–7.772) and the C allele was positively correlated with atrial septal defect (p=0.007, odds ratio=1.567, 95% confidence interval 1.129–2.175). In conclusion, our results confirmed that rs2071166 in Cx43 may be relevant with an increased atrial septal defect risk.

Keywords

Cx43single nucleotide polymorphismatrial septal defect
Type
Original Articles
Information
Cardiology in the Young , Volume 28 , Issue 3 , March 2018 , pp. 397 - 402
Check for updates
Copyright
© Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Greenway, SC, McLeod, R, Hume, S, et al. Exome sequencing identifies a novel variant in ACTC1 associated with familial atrial septal defect. Can J Cardiol 2014; 30: 181–187.CrossRefGoogle ScholarPubMed
2. Garg, V, Kathiriya, IS, Barnes, R, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 2003; 424: 443–447.CrossRefGoogle ScholarPubMed
3. Stanczak, P, Witecka, J, Szydlo, A, et al. Mutations in mammalian tolloid-like 1 gene detected in adult patients with ASD. Eur J Hum Genet 2009; 17: 344–351.CrossRefGoogle ScholarPubMed
4. Lin, X, Huo, Z, Liu, X, et al. A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect. J Hum Genet 2010; 55: 662–667.CrossRefGoogle ScholarPubMed
5. Schott, JJ, Benson, DW, Basson, CT, et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 1998; 281: 108–111.CrossRefGoogle ScholarPubMed
6. Salameh, A, Blanke, K, Daehnert, I. Role of connexins in human congenital heart disease: the chicken and egg problem. Front Pharmacol 2013; 4: 70.CrossRefGoogle ScholarPubMed
7. Ewart, JL, Cohen, MF, Meyer, RA, et al. Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene. Development 1997; 124: 1281–1292.CrossRefGoogle ScholarPubMed
8. Huang, GY, Cooper, ES, Waldo, K, Kirby, ML, Gilula, NB, Lo, CW. Gap junction-mediated cell-cell communication modulates mouse neural crest migration. J Cell Biol 1998; 143: 1725–1734.CrossRefGoogle ScholarPubMed
9. Huang, GY, Wessels, A, Smith, BR, Linask, KK, Ewart, JL, Lo, CW. Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development. Dev Biol 1998; 198: 32–44.CrossRefGoogle ScholarPubMed
10. Paznekas, WA, Boyadjiev, SA, Shapiro, RE, et al. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 2003; 72: 408–418.CrossRefGoogle ScholarPubMed
11. Schulz, R, Gorge, PM, Gorbe, A, Ferdinandy, P, Lampe, PD, Leybaert, L. Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection. Pharmacol Ther 2015; 153: 90–106.CrossRefGoogle ScholarPubMed
12. Severs, NJ, Bruce, AF, Dupont, E, Rothery, S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 2008; 80: 9–19.CrossRefGoogle ScholarPubMed
13. Dasgupta, C, Martinez, AM, Zuppan, CW, Shah, MM, Bailey, LL, Fletcher, WH. Identification of connexin43 (alpha1) gap junction gene mutations in patients with hypoplastic left heart syndrome by denaturing gradient gel electrophoresis (DGGE). Mutation Res 2001; 479: 173–186.CrossRefGoogle ScholarPubMed
14. Britz-Cunningham, SH, Shah, MM, Zuppan, CW, Fletcher, WH. Mutations of the Connexin43 gap-junction gene in patients with heart malformations and defects of laterality. New Engl J Med 1995; 332: 1323–1329.CrossRefGoogle ScholarPubMed
15. Wu, Y, Ma, XJ, Wang, HJ, et al. Expression of Cx43-related microRNAs in patients with tetralogy of Fallot. World J Pediatr 2014; 10: 138–144.CrossRefGoogle ScholarPubMed
16. http:// browser.1000genomes.org/.Google Scholar
17. http://www.ensembl.org/.Google Scholar
18. Gu, R, Xu, J, Lin, Y, et al. Liganded retinoic acid X receptor alpha represses connexin 43 through a potential retinoic acid response element in the promoter region. Pediatric Res 2016; 80: 159–168.CrossRefGoogle ScholarPubMed
19. Huang, GY, Xie, LJ, Linask, KL, et al. Evaluating the role of connexin43 in congenital heart disease: screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models. J Cardiovasc Dis Res 2011; 2: 206–212.CrossRefGoogle ScholarPubMed
20. Paznekas, WA, Karczeski, B, Vermeer, S, et al. GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. Hum Mutat 2009; 30: 724–733.CrossRefGoogle Scholar
21. Chen, P, Xie, LJ, Huang, GY, Zhao, XQ, Chang, C. Mutations of connexin43 in fetuses with congenital heart malformations. Chin Med J 2005; 118: 971–976.Google ScholarPubMed
22. De Luca, A, Sarkozy, A, Consoli, F, et al. Exclusion of Cx43 gene mutation as a major cause of criss-cross heart anomaly in man. Int J Cardiol 2010; 144: 300–302.CrossRefGoogle Scholar
23. Penman Splitt, M, Tsai, MY, Burn, J, Goodship, JA. Absence of mutations in the regulatory domain of the gap junction protein connexin 43 in patients with visceroatrial heterotaxy. Heart 1997; 77: 369–370.CrossRefGoogle Scholar
24. Debrus, S, Tuffery, S, Matsuoka, R, et al. Lack of evidence for connexin 43 gene mutations in human autosomal recessive lateralization defects. J Mol Cell Cardiol 1997; 29: 1423–1431.CrossRefGoogle ScholarPubMed
25. Cao, Y, Wang, J, Wei, C, et al. Genetic variations of NKX2-5 in sporadic atrial septal defect and ventricular septal defect in Chinese Yunnan population. Gene 2015.CrossRefGoogle Scholar
26. Huang, Q. Genetic study of complex diseases in the post-GWAS era. J Genet Genomics 2015; 42: 87–98.CrossRefGoogle ScholarPubMed
27. Muntean, I, Toganel, R, Benedek, T. Genetics of congenital heart disease: past and present. Biochemical Genet 2017; 55: 105–123.CrossRefGoogle ScholarPubMed
28. Junker, R, Kotthoff, S, Vielhaber, H, et al. Infant methylenetetrahydrofolate reductase 677TT genotype is a risk factor for congenital heart disease. Cardiovasc Res 2001; 51: 251–254.CrossRefGoogle ScholarPubMed
29. Xie, J, Yi, L, Xu, ZF, et al. VEGF C-634G polymorphism is associated with protection from isolated ventricular septal defect: case-control and TDT studies. Eur J Hum Genet 2007; 15: 1246–1251.CrossRefGoogle ScholarPubMed
30. Rossaak, JI, Van Rij, AM, Jones, GT, Harris, EL. Association of the 4G/5G polymorphism in the promoter region of plasminogen activator inhibitor-1 with abdominal aortic aneurysms. J Vascular Surgery 2000; 31: 1026–1032.CrossRefGoogle ScholarPubMed
31. Loukanov, T, Hoss, K, Tonchev, P, et al. Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) and acute pulmonary hypertension post cardiopulmonary bypass in children with congenital cardiac diseases. Cardiol Young 2011; 21: 161–169.CrossRefGoogle ScholarPubMed
32. Lambrechts, D, Devriendt, K, Driscoll, DA, et al. Low expression VEGF haplotype increases the risk for tetralogy of Fallot: a family based association study. J Med Genet 2005; 42: 519–522.CrossRefGoogle ScholarPubMed
33. Li, X, Liu, CL, Li, XX, Li, QC, Ma, LM, Liu, GL. VEGF gene polymorphisms are associated with risk of tetralogy of Fallot. Med Sci Monit 2015; 21: 3474–3482.CrossRefGoogle ScholarPubMed
34. Wang, W, Hou, Z, Wang, C, Wei, C, Li, Y, Jiang, L. Association between 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and congenital heart disease: a meta-analysis. Meta Gene 2013; 1: 109–125.CrossRefGoogle Scholar
35. Harismendy, O, Notani, D, Song, X, et al. 9p21 DNA variants associated with coronary artery disease impair interferon-gamma signalling response. Nature 2011; 470: 264–268.CrossRefGoogle ScholarPubMed
36. Musunuru, K, Strong, A, Frank-Kamenetsky, M, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 2010; 466: 714–719.CrossRefGoogle ScholarPubMed
37. Lubbe, SJ, Pittman, AM, Olver, B, et al. The 14q22.2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4. Oncogene 2012; 31: 3777–3784.CrossRefGoogle ScholarPubMed
38. Kolcz, J, Drukala, J, Bzowska, M, Rajwa, B, Korohoda, W, Malec, E. The expression of connexin 43 in children with tetralogy of Fallot. Cell Mol Biol Lett 2005; 10: 287–303.Google ScholarPubMed