Skip to main content
SpringerLink
Log in

Polymorphisms of VEGF, TGFβ1, TGFβR2 and conotruncal heart defects in a Chinese population

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Genetic variants may determine susceptibility of congenital heart disease (CHD). To evaluate the impact of transforming growth factor-β1 (TGFβ1), TGFβ receptor II (TGFβR2) and vascular endothelial growth factor (VEGF) polymorphisms on conotruncal heart defects susceptibility, we genotyped six functional polymorphisms TGFβ1 rs1800469 C>T, TGFβR2 rs3087465 G>A, VEGF −2578C>A, −1498T>C, −634G>C and +936C>T in a hospital based case–control study of 244 conotruncal heart defects cases and 136 non-CHD controls in a Chinese population. Logistic regression analyses revealed that if the TGFβ1 rs1800469 CC homozygote genotype was used as the reference group, subjects carrying the CT variant heterozygote had a significant 0.48-fold decreased risk of conotruncal heart defects [odds ratio (OR) = 0.52; 95 % confidence interval (CI) = 0.30–0.88], subjects carrying the TT variant homozygote had a significant 0.47-fold decreased risk of conotruncal heart defects (OR 0.53; 95 % CI 0.28–1.00). In stratification analyses, the TGFβ1 rs1800469 C>T genotype was associated with a decreased risk for tetralogy of fallot in homozygote comparisons (OR 0.47; 95 % CI 0.22–0.99), a decreased risk for transposition of great artery in the dominant genetic model (OR 0.49; 95 % CI 0.28–0.87) and heterozygote comparisons (OR 0.45; 95 % CI 0.24–0.83). Our findings suggest that TGFβ1 rs1800469 C>T polymorphism was significantly associated with decreased risk of conotruncal heart defects. TGFβR2 rs3087465 G>A, VEGF −2578C>A, −1498T>C, −634G>C and +936C>T polymorphisms may not play a role in the susceptibility of conotruncal heart defects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CI:

Confidential interval

CHD:

Congenital heart disease

EC:

Endocardial cushion

EMT:

Endocardium transform to mesenchyme

LD:

Linkage disequilibrium

OR:

Odds ratio

SNPs:

Single nucleotide polymorphisms

VEGF:

Vascular endothelial growth factor

References

  1. Hoffman JI (1995) Incidence of congenital heart disease: II. Prenatal incidence. Pediatr Cardiol 16:155–165

    Article  CAS  PubMed  Google Scholar 

  2. Zheng XY, Song XM, Chen G, Chen JP, Ji Y, Wu JL, Liu JF, Zhang L, Fan XH (2007) Epidemiology of birth defects in high-prevalence areas of China. Zhonghua Liu Xing Bing Xue Za Zhi 28:5–9

    CAS  PubMed  Google Scholar 

  3. Srivastava D, Olson EN (2000) A genetic blueprint for cardiac development. Nature 407:221–226

    Article  CAS  PubMed  Google Scholar 

  4. Conti E, Grifone N, Sarkozy A, Tandoi C, Marino B, Digilio MC, Mingarelli R, Pizzuti A, Dallapiccola B (2003) DiGeorge subtypes of nonsyndromic conotruncal defects: evidence against a major role of TBX1 gene. Eur J Hum Genet 11:349–351

    Article  CAS  PubMed  Google Scholar 

  5. Armstrong EJ, Bischoff J (2004) Heart valve development: endothelial cell signaling and differentiation. Circ Res 95:459–470

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Vannay A, Vasarhelyi B, Kornyei M, Treszl A, Kozma G, Gyorffy B, Tulassay T, Sulyok E (2006) Single-nucleotide polymorphisms of VEGF gene are associated with risk of congenital valvuloseptal heart defects. Am Heart J 151:878–881

    Article  CAS  PubMed  Google Scholar 

  7. Harrelson Z, Kelly RG, Goldin SN, Gibson-Brown JJ, Bollag RJ, Silver LM, Papaioannou VE (2004) Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development. Development 131:5041–5052

    Article  CAS  PubMed  Google Scholar 

  8. Cambien F, Ricard S, Troesch A, Mallet C, Generenaz L, Evans A, Arveiler D, Luc G, Ruidavets JB, Poirier O (1996) Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l’Infarctus du Myocarde (ECTIM) Study. Hypertension 28:881–887

    Article  CAS  PubMed  Google Scholar 

  9. Silverman ES, Palmer LJ, Subramaniam V, Hallock A, Mathew S, Vallone J, Faffe DS, Shikanai T, Raby BA, Weiss ST, Shore SA (2004) Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma. Am J Respir Crit Care Med 169:214–219

    Article  PubMed  Google Scholar 

  10. Pulleyn LJ, Newton R, Adcock IM, Barnes PJ (2001) TGFbeta1 allele association with asthma severity. Hum Genet 109:623–627

    Article  CAS  PubMed  Google Scholar 

  11. Kim YJ, Lee HS, Im JP, Min BH, Kim HD, Jeong JB, Yoon JH, Kim CY, Kim MS, Kim JY, Jung JH, Kim LH, Park BL, Shin HD (2003) Association of transforming growth factor-beta1 gene polymorphisms with a hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection. Exp Mol Med 35:196–202

    Article  CAS  PubMed  Google Scholar 

  12. Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spector TD (1999) Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 8:93–97

    Article  CAS  PubMed  Google Scholar 

  13. Meng J, Thongngarm T, Nakajima M, Yamashita N, Ohta K, Bates CA, Grunwald GK, Rosenwasser LJ (2005) Association of transforming growth factor-beta1 single nucleotide polymorphism C-509T with allergy and immunological activities. Int Arch Allergy Immunol 138:151–160

    Article  CAS  PubMed  Google Scholar 

  14. Massague J, Blain SW, Lo RS (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103:295–309

    Article  CAS  PubMed  Google Scholar 

  15. Massague J (1996) TGFbeta signaling: receptors, transducers, and Mad proteins. Cell 85:947–950

    Article  CAS  PubMed  Google Scholar 

  16. Markowitz S (2000) TGF-beta receptors and DNA repair genes, coupled targets in a pathway of human colon carcinogenesis. Biochim Biophys Acta 1470:M13–M20

    CAS  PubMed  Google Scholar 

  17. Mizuguchi T, Collod-Beroud G, Akiyama T, Abifadel M, Harada N, Morisaki T, Allard D, Varret M, Claustres M, Morisaki H, Ihara M, Kinoshita A, Yoshiura K, Junien C, Kajii T, Jondeau G, Ohta T, Kishino T, Furukawa Y, Nakamura Y, Niikawa N, Boileau C, Matsumoto N (2004) Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36:855–860

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC (2006) Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355:788–798

    Article  CAS  PubMed  Google Scholar 

  19. Pannu H, Fadulu VT, Chang J, Lafont A, Hasham SN, Sparks E, Giampietro PF, Zaleski C, Estrera AL, Safi HJ, Shete S, Willing MC, Raman CS, Milewicz DM (2005) Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 112:513–520

    Article  CAS  PubMed  Google Scholar 

  20. Singh KK, Rommel K, Mishra A, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M (2006) TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat 27:770–777

    Article  CAS  PubMed  Google Scholar 

  21. Seijo ER, Song H, Lynch MA, Jennings R, Qong X, Lazaridis E, Muro-Cacho C, Weghorst CM, Munoz-Antonia T (2001) Identification of genetic alterations in the TGFbeta type II receptor gene promoter. Mutat Res 483:19–26

    Article  CAS  PubMed  Google Scholar 

  22. Dor Y, Camenisch TD, Itin A, Fishman GI, McDonald JA, Carmeliet P, Keshet E (2001) A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects. Development 128:1531–1538

    CAS  PubMed  Google Scholar 

  23. Miquerol L, Gertsenstein M, Harpal K, Rossant J, Nagy A (1999) Multiple developmental roles of VEGF suggested by a LacZ-tagged allele. Dev Biol 212:307–322

    Article  CAS  PubMed  Google Scholar 

  24. Vincenti V, Cassano C, Rocchi M, Persico G (1996) Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 93:1493–1495

    Article  CAS  PubMed  Google Scholar 

  25. Brogan IJ, Khan N, Isaac K, Hutchinson JA, Pravica V, Hutchinson IV (1999) Novel polymorphisms in the promoter and 5′ UTR regions of the human vascular endothelial growth factor gene. Hum Immunol 60:1245–1249

    Article  CAS  PubMed  Google Scholar 

  26. Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE (2000) Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine 12:1232–1235

    Article  CAS  PubMed  Google Scholar 

  27. Gong D, Gu H, Zhang Y, Gong J, Nie Y, Wang J, Zhang H, Liu R, Hu S, Zhang H (2012) Methylenetetrahydrofolate reductase C677T and reduced folate carrier 80 G>A polymorphisms are associated with an increased risk of conotruncal heart defects. Clin Chem Lab Med 50:1455–1461

    Article  CAS  PubMed  Google Scholar 

  28. Gu H, Gong J, Qiu W, Cao H, Xu J, Chen S, Chen Y (2011) Association of a tandem repeat polymorphism in NFATc1 with increased risk of perimembranous ventricular septal defect in a Chinese population. Biochem Genet 49:592–600

    Article  CAS  PubMed  Google Scholar 

  29. Kruithof BP, Duim SN, Moerkamp AT, Goumans MJ (2012) TGFbeta and BMP signaling in cardiac cushion formation: lessons from mice and chicken. Differentiation 84:89–102

    Article  CAS  PubMed  Google Scholar 

  30. Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791

    Article  CAS  PubMed  Google Scholar 

  31. Pardali K, Moustakas A (2007) Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 1775:21–62

    CAS  PubMed  Google Scholar 

  32. Magdoud K, Granados Herbepin V, Messaoudi S, Hizem S, Bouafia N, Almawi WY, Mahjoub T, Touraine R (2013) Genetic variation in TGFB1 gene and risk of idiopathic recurrent pregnancy loss. Mol Hum Reprod 19:438–443

    Google Scholar 

  33. van Eerde AM, Duran K, van Riel E, de Kovel CG, Koeleman BP, Knoers NV, Renkema KY, van der Horst HJ, Bokenkamp A, van Hagen JM, van den Berg LH, Wolffenbuttel KP, van den Hoek J, Feitz WF, de Jong TP, Giltay JC, Wijmenga C (2012) Genes in the ureteric budding pathway: association study on vesico-ureteral reflux patients. PLoS ONE 7:e31327

    Article  PubMed Central  PubMed  Google Scholar 

  34. Yang XX, Li FX, Wu YS, Wu D, Tan JY, Li M (2011) Association of TGF-beta1, IL-4 and IL-13 gene polymerphisms with asthma in a Chinese population. Asian Pac J Allergy Immunol 29:273–277

    CAS  PubMed  Google Scholar 

  35. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380:435–439

    Article  CAS  PubMed  Google Scholar 

  36. Miquerol L, Langille BL, Nagy A (2000) Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 127:3941–3946

    CAS  PubMed  Google Scholar 

  37. van den Akker NM, Molin DG, Peters PP, Maas S, Wisse LJ, van Brempt R, van Munsteren CJ, Bartelings MM, Poelmann RE, Carmeliet P, Gittenberger-de Groot AC (2007) Tetralogy of fallot and alterations in vascular endothelial growth factor-A signaling and notch signaling in mouse embryos solely expressing the VEGF120 isoform. Circ Res 100:842–849

    Article  PubMed  Google Scholar 

  38. Xie J, Yi L, Xu ZF, Mo XM, Hu YL, Wang DJ, Ren HZ, Han B, Wang Y, Yang C, Zhao YL, Shi DQ, Jiang YZ, Shen L, Qiao D, Chen SL, Yu BJ (2007) VEGF C-634G polymorphism is associated with protection from isolated ventricular septal defect: case-control and TDT studies. Eur J Hum Genet 15:1246–1251

    Article  CAS  PubMed  Google Scholar 

  39. Griffin HR, Hall DH, Topf A, Eden J, Stuart AG, Parsons J, Peart I, Deanfield JE, O’Sullivan J, Babu-Narayan SV, Gatzoulis MA, Bu’lock FA, Bhattacharya S, Bentham J, Farrall M, Granados Riveron J, Brook JD, Burn J, Cordell HJ, Goodship JA, Keavney B (2009) Genetic variation in VEGF does not contribute significantly to the risk of congenital cardiovascular malformation. PLoS ONE 4:e4978

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Major National Basic Research Program in the People’s Republic of China (Program 973, 2010CB529508), the National Natural Science Foundation of China (30900630), China Postdoctoral Science Special Foundation (2012T50066, 2012M510353), Peking Union Medical College Postdoctoral Foundation (2011-XH6), the Jiangsu Province Health Department Program Grant (H201046) and the Jiangsu Province Natural Science Foundation (BK2009207, BK2009209).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital & Cardiovascular Institute, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China

    Enshi Wang, Zhenhua Wang, Shenghua Liu, Haiyong Gu, Dingxu Gong, Kun Hua, Yu Nie, Jue Wang, Haoran Wang, Shengshou Hu & Hao Zhang

  2. Department of Cardiothoracic Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212000, China

    Haiyong Gu

  3. Division of Cardiology, Department of Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China

    Jie Gong

  4. Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical College, Wenzhou, China

    YuJian Zhang

  5. Central Laboratory, Affiliated Hospital of Nanjing Medical University, Changzhou Second People’s Hospital, Changzhou, 213003, China

    Hui Zhang & Ruiping Liu

  6. Research Center for Cardiovascular Regenerative Medicine, Fuwai Hospital, 167 Beilishilu Street, Beijing, 100037, China

    Shengshou Hu

Authors
  1. Enshi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhenhua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shenghua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haiyong Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dingxu Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kun Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Haoran Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jie Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. YuJian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ruiping Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shengshou Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hao Zhang.

Additional information

Enshi Wang and Zhenhua Wang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, E., Wang, Z., Liu, S. et al. Polymorphisms of VEGF, TGFβ1, TGFβR2 and conotruncal heart defects in a Chinese population. Mol Biol Rep 41, 1763–1770 (2014). https://doi.org/10.1007/s11033-014-3025-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-014-3025-9

Keywords

Search

Navigation