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Association Between ISL1 Variants and Susceptibility to Ventricular Septal Defect in a Chinese Cohort

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Abstract

Aim

It has previously been reported that ISLET1 (ISL1) plays a fundamental role in cardiac morphogenesis. This study investigated the possible association between variants in the ISL LIM homeobox 1 (ISL1) gene and congenital ventricular septal defect (VSD) in a Chinese cohort.

Methods

A total of 512 congenital VSD patients and 612 unrelated age- and sex-matched healthy control subjects were enrolled in this study. Genotypes for three variants in ISL1 (rs3762977, IVS1+17C>T, and rs1017) were determined.

Results

We found that the rs3762977 and IVS+17C>T variants were closely associated with the risk of developing VSD. Carriers of the GG genotype of rs3762977 and the TT genotype of IVS+17C>T were less likely to have VSD, whereas variants in rs1701 did not affect the VSD risk. The haplotypes rs3762977G-rs1017A-IVS+17T and rs3762977G-rs1017T-IVS+17T represented a protective effect against VSD. None of these ISL1 variants showed any association with VSD type according to defect location and VSD severity according to defect size.

Conclusion

These findings suggest that ISL1 genetic polymorphisms are associated with occurrence of VSD, thus they may be useful as molecular markers for prediction of VSD.

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References

  1. Rachko M, Safi AM, Chadow HL, Lyon AF, Gunsburg D, Rafii SE. Ventricular septal defect and left ventricular aneurysm: late occurrence as complications of an acute myocardial infarction. Jpn Heart J. 2000;41(6):773–9.

    Article  PubMed  CAS  Google Scholar 

  2. King ME, de Moor M. Ventricular septal defect. Curr Treat Options Cardiovasc Med. 1999;1(4):311–22.

    Article  PubMed  Google Scholar 

  3. Bruneau BG. The developmental genetics of congenital heart disease. Nature. 2008;451(7181):943–8.

    Article  PubMed  CAS  Google Scholar 

  4. Toscano A, Anaclerio S, Digilio MC, Giannotti A, Fariello G, Dallapiccola B, Marino B. Ventricular septal defect and deletion of chromosome 22q11: anatomical types and aortic arch anomalies. Eur J Pediatr. 2002;161(2):116–7.

    Article  PubMed  CAS  Google Scholar 

  5. Liu CX, Shen AD, Li XF, Jiao WW, Bai S, Yuan F, Guan XL, Zhang XG, Zhang GR, Li ZZ. Association of TBX5 gene polymorphism with ventricular septal defect in the Chinese Han population. Chin Med J (Engl). 2009;122(1):30–4.

    CAS  Google Scholar 

  6. Mitsiadis TA, Angeli I, James C, Lendahl U, Sharpe PT. Role of Islet1 in the patterning of murine dentition. Development. 2003;130(18):4451–60.

    Article  PubMed  CAS  Google Scholar 

  7. Lin L, Cui L, Zhou W, Dufort D, Zhang X, Cai CL, Bu L, Yang L, Martin J, Kemler R, et al. Beta-catenin directly regulates Islet1 expression in cardiovascular progenitors and is required for multiple aspects of cardiogenesis. Proc Natl Acad Sci USA. 2007;104(22):9313–8.

    Article  PubMed  CAS  Google Scholar 

  8. Nathan E, Monovich A, Tirosh-Finkel L, Harrelson Z, Rousso T, Rinon A, Harel I, Evans SM, Tzahor E. The contribution of Islet1-expressing splanchnic mesoderm cells to distinct branchiomeric muscles reveals significant heterogeneity in head muscle development. Development. 2008;135(4):647–57.

    Article  PubMed  CAS  Google Scholar 

  9. Golzio C, Havis E, Daubas P, Nuel G, Babarit C, Munnich A, Vekemans M, Zaffran S, Lyonnet S, Etchevers HC. ISL1 directly regulates FGF10 transcription during human cardiac outflow formation. PLoS One. 2012;7(1):e30677.

    Article  PubMed  CAS  Google Scholar 

  10. Kang J, Nathan E, Xu SM, Tzahor E, Black BL. Isl1 is a direct transcriptional target of Forkhead transcription factors in second-heart-field-derived mesoderm. Dev Biol. 2009;334(2):513–22.

    Article  PubMed  CAS  Google Scholar 

  11. Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S. ISL1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003;5(6):877–89.

    Article  PubMed  CAS  Google Scholar 

  12. Stevens KN, Hakonarson H, Kim CE, Doevendans PA, Koeleman BP, Mital S, Raue J, Glessner JT, Coles JG, Moreno V, et al. Common variation in ISL1 confers genetic susceptibility for human congenital heart disease. PLoS One. 2010;5(5):e10855.

    Article  PubMed  Google Scholar 

  13. Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15(2):97–8.

    Article  PubMed  CAS  Google Scholar 

  14. Koshiba-Takeuchi K, Mori AD, Kaynak BL, Cebra-Thomas J, Sukonnik T, Georges RO, Latham S, Beck L, Henkelman RM, Black BL, et al. Reptilian heart development and the molecular basis of cardiac chamber evolution. Nature. 2009;461(7260):95–8.

    Article  PubMed  CAS  Google Scholar 

  15. Lin L, Bu L, Cai CL, Zhang X, Evans S. ISL1 is upstream of sonic hedgehog in a pathway required for cardiac morphogenesis. Dev Biol. 2006;295(2):756–63.

    Article  PubMed  CAS  Google Scholar 

  16. Kwon C, Qian L, Cheng P, Nigam V, Arnold J, Srivastava D. A regulatory pathway involving Notch1/beta-catenin/ISL1 determines cardiac progenitor cell fate. Nat Cell Biol. 2009;11(8):951–7.

    Article  PubMed  CAS  Google Scholar 

  17. Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, Chien KR. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature. 2009;460(7251):113–7.

    Article  PubMed  CAS  Google Scholar 

  18. Moretti A, Bellin M, Jung CB, Thies TM, Takashima Y, Bernshausen A, Schiemann M, Fischer S, Moosmang S, Smith AG, et al. Mouse and human induced pluripotent stem cells as a source for multipotent ISL1+ cardiovascular progenitors. FASEB J. 2010;24(3):700–11.

    Article  PubMed  CAS  Google Scholar 

  19. Xue L, Wang X, Xu J, Xu X, Liu X, Hu Z, Shen H, Chen Y. ISL1 common variant rs1017 is not associated with susceptibility to congenital heart disease in a Chinese population. Genet Test Mol Biomarkers. 2012;16(7):679–83.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank Dr. Sun Jun for his guidance in determining ISL1 genetic polymorphisms and Dr. Xuwei Hou for his help in statistics analyses. No sources of funding were used to conduct this study or to prepare this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this article.

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Authors and Affiliations

  1. Cardiac Surgery Department, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu, Nangang District, Harbin, Heilongjiang, China

    Jilu Lang & Weichen Tian

  2. Department of Oncology, Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

    Xian Sun

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  1. Jilu Lang
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  2. Weichen Tian
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  3. Xian Sun
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Correspondence to Jilu Lang.

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Lang, J., Tian, W. & Sun, X. Association Between ISL1 Variants and Susceptibility to Ventricular Septal Defect in a Chinese Cohort. Mol Diagn Ther 17, 101–106 (2013). https://doi.org/10.1007/s40291-013-0033-8

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  • DOI: https://doi.org/10.1007/s40291-013-0033-8

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