Skip to main content
SpringerLink
Log in

Association of growth/differentiation factor 1 gene polymorphisms with the risk of congenital heart disease in the Chinese Han population

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

There is evidence suggesting that genetic variants of Nodal signaling may be associated with risk of congenital heart diseases (CHDs), in which several polymorphisms, such as Nodal rs1904589, have been considered to be implicated in the accumulation of the genetic burden of CHD risk with interacting genes. We hypothesized that genetic variants of GDF1, a protein that heterodimerizes with Nodal, may be related to increased CHD susceptibility. In this study, four tagSNPs of GDF1 were genotyped in 310 non-syndromic CHD patients and 320 healthy controls by using PCR-based DHPLC and RFLP. The results showed no statistically significant differences in genotype and allele frequencies between CHDs and controls with any of the analyzed variants of GDF1. However, a weak statistical association existed between GDF1 rs4808870 and conotruncal defects (CTDs) (uncorrected P = 0.027). Further stratified analysis for subtype revealed the SNP AA genotype and A allele have statistical significance in pulmonary atresia (PA) (corrected P = 1.01 × 10−3 and 0.015, respectively), especially in pulmonary atresia with intact ventricular septum (PA + IVS) (corrected P = 1.67 × 10−3 and 0.034, respectively). Furthermore, two haplotypes, TGGT and CAGT, were found to be significantly associated with increased CHD susceptibility (corrected P = 3.20 × 10−3 and 2.73 × 10−7, respectively). In summary, our results provide evidence that genetic variations of the Nodal-like factor, GDF1 may be associated with CHD risk, and these variations contribute at least in part to the development of some subtypes of CTD in the Chinese Han population.

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

Similar content being viewed by others

References

  1. Hoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39:1890–1900

    Article  PubMed  Google Scholar 

  2. van der Bom T, Zomer AC, Zwinderman AH, Meijboom FJ, Bouma BJ, Mulder BJ (2011) The changing epidemiology of congenital heart disease. Nat Rev Cardiol 8:50–60

    Article  PubMed  Google Scholar 

  3. Srivastava D (2006) Making or breaking the heart: from lineage determination to morphogenesis. Cell 126:1037–1048

    Article  PubMed  CAS  Google Scholar 

  4. Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313:1922–1927

    Article  PubMed  CAS  Google Scholar 

  5. Bisgrove BW, Essner JJ, Yost HJ (2000) Multiple pathways in the midline regulate concordant brain, heart and gut left–right asymmetry. Development 127:3567–3579

    PubMed  CAS  Google Scholar 

  6. Branford WW, Essner JJ, Yost HJ (2000) Regulation of gut and heart left–right asymmetry by context-dependent interactions between xenopus lefty and BMP4 signaling. Dev Biol 223:291–306

    Article  PubMed  CAS  Google Scholar 

  7. Whitman M, Mercola M (2001) TGF-beta superfamily signaling and left–right asymmetry. Sci STKE 2001(64):re1

    Article  PubMed  CAS  Google Scholar 

  8. Hanafusa H, Masuyama N, Kusakabe M, Shibuya H, Nishida E (2000) The TGF-beta family member derrière is involved in regulation of the establishment of left–right asymmetry. EMBO Rep 1:32–39

    Article  PubMed  CAS  Google Scholar 

  9. Kathiriya IS, Srivastava D (2000) Left–right asymmetry and cardiac looping: implications for cardiac development and congenital heart disease. Am J Med Genet 97:271–279

    Article  PubMed  CAS  Google Scholar 

  10. Arthur HM, Bamforth SD (2011) TGFβ signaling and congenital heart disease: insights from mouse studies. Birth Defects Res A Clin Mol Teratol 91:423–434

    Article  PubMed  CAS  Google Scholar 

  11. Schier AF (2009) Nodal morphogens. Cold Spring Harb Perspect Biol 1:a003459

    Article  PubMed  Google Scholar 

  12. Schier AF, Shen MM (2000) Nodal signalling in vertebrate development. Nature 403:385–389

    Article  PubMed  CAS  Google Scholar 

  13. Shen MM (2007) Nodal signaling: developmental roles and regulation. Development 134:1023–1034

    Article  PubMed  CAS  Google Scholar 

  14. Baker K, Holtzman NG, Burdine RD (2008) Direct and indirect roles for Nodal signaling in two axis conversions during asymmetric morphogenesis of the zebrafish heart. Proc Natl Acad Sci U S A 105:13924–13929

    Article  PubMed  CAS  Google Scholar 

  15. Goldmuntz E, Bamford R, Karkera JD, dela Cruz J, Roessler E, Muenke M (2002) CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. Am J Hum Genet 70:776–780

    Article  PubMed  CAS  Google Scholar 

  16. Roessler E, Ouspenskaia MV, Karkera JD, Vélez JI, Kantipong A, Lacbawan F, Bowers P, Belmont JW, Towbin JA, Goldmuntz E, Feldman B, Muenke M (2008) Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am J Hum Genet 83:18–29

    Article  PubMed  CAS  Google Scholar 

  17. Lopes Floro K, Artap ST, Preis JI, Fatkin D, Chapman G, Furtado MB, Harvey RP, Hamada H, Sparrow DB, Dunwoodie SL (2011) Loss of Cited2 causes congenital heart disease by perturbing left–right patterning of the body axis. Hum Mol Genet 20:1097–1110

    Article  PubMed  CAS  Google Scholar 

  18. Hyatt BA, Yost HJ (1998) The left–right coordinator: the role of Vg1 in organizing left–right axis formation. Cell 93:37–46

    Article  PubMed  CAS  Google Scholar 

  19. Rankin CT, Bunton T, Lawler AM, Lee SJ (2000) Regulation of left–right patterning in mice by growth/differentiation factor-1. Nat Genet 24:262–265

    Article  PubMed  CAS  Google Scholar 

  20. Andersson O, Reissmann E, Jörnvall H, Ibáñez CF (2006) Synergistic interaction between Gdf1 and Nodal during anterior axis development. Dev Biol 293:370–381

    Article  PubMed  CAS  Google Scholar 

  21. Tanaka C, Sakuma R, Nakamura T, Hamada H, Saijoh Y (2007) Long-range action of Nodal requires interaction with GDF1. Genes Dev 21:3272–3782

    Article  PubMed  CAS  Google Scholar 

  22. Karkera JD, Lee JS, Roessler E, Banerjee-Basu S, Ouspenskaia MV, Mez J, Goldmuntz E, Bowers P, Towbin J, Belmont JW, Baxevanis AD, Schier AF, Muenke M (2007) Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans. Am J Hum Genet 81:987–994

    Article  PubMed  CAS  Google Scholar 

  23. Kaasinen E, Aittomäki K, Eronen M, Vahteristo P, Karhu A, Mecklin JP, Kajantie E, Aaltonen LA, Lehtonen R (2010) Recessively inherited right atrial isomerism caused by mutations in growth/differentiation factor 1 (GDF1). Hum Mol Genet 19:2747–2753

    Article  PubMed  CAS  Google Scholar 

  24. De Luca A, Sarkozy A, Ferese R, Consoli F, Lepri F, Dentici ML, Vergara P, De Zorzi A, Versacci P, Digilio MC, Marino B, Dallapiccola B (2010) New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot and double outlet right ventricle. Clin Genet 80:184–190

    Article  PubMed  Google Scholar 

  25. De Luca A, Sarkozy A, Consoli F, Ferese R, Guida V, Dentici ML, Mingarelli R, Bellacchio E, Tuo G, Limongelli G, Digilio MC, Marino B, Dallapiccola B (2010) Familial transposition of the great arteries caused by multiple mutations in laterality genes. Heart 96:673–677

    Article  PubMed  Google Scholar 

  26. Roessler E, Pei W, Ouspenskaia MV, Karkera JD, Veléz JI, Banerjee-Basu S, Gibney G, Lupo PJ, Mitchell LE, Towbin JA, Bowers P, Belmont JW, Goldmuntz E, Baxevanis AD, Feldman B, Muenke M (2009) Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly. Mol Genet Metab 98:225–234

    Article  PubMed  CAS  Google Scholar 

  27. Johns M, Paulus-Thomas J (1989) Purification of human genomic DNA from whole venous blood using proteinase K treatment followed by phenol–chloroform extraction. Annal Bio chem 180:276–278

    Article  CAS  Google Scholar 

  28. Gross E, Arnold N, Goette J, Schwarz-Boeger U, Kiechle M (1999) A comparison of BRCA1 mutation analysis by direct sequencing, SSCP and DHPLC. Hum Genet 105:72–78

    Article  PubMed  CAS  Google Scholar 

  29. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I (2001) Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125:279–284

    Article  PubMed  CAS  Google Scholar 

  30. Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15:97–98

    Article  PubMed  CAS  Google Scholar 

  31. Joziasse IC, van de Smagt JJ, Smith K, Bakkers J, Sieswerda GJ, Mulder BJ, Doevendans PA (2008) Genes in congenital heart disease: atrioventricular valve formation. Basic Res Cardiol 103:216–227

    Article  PubMed  CAS  Google Scholar 

  32. Chiquet BT, Lidral AC, Stal S, Mulliken JB, Moreno LM, Arcos-Burgos M, Valencia-Ramirez C, Blanton SH, Hecht JT (2007) CRISPLD2: a novel NSCLP candidate gene. Hum Mol Genet 16:2241–2248

    Article  PubMed  CAS  Google Scholar 

  33. Waldo KL, Kumiski DH, Wallis KT, Stadt HA, Hutson MR, Platt DH, Kirby ML (2001) Conotruncal myocardium arises from a secondary heart field. Development 128:3179–3188

    PubMed  CAS  Google Scholar 

  34. Ward C, Stadt H, Hutson M, Kirby ML (2005) Ablation of the secondary heart field leads to tetralogy of Fallot and pulmonary atresia. Dev Biol 284:72–83

    Article  PubMed  CAS  Google Scholar 

  35. Leong FT, Freeman LJ, Keavney BD (2009) Fresh fields and pathways new: recent genetic insights into cardiac malformation. Heart 95:442–447

    Article  PubMed  CAS  Google Scholar 

  36. Stoller JZ, Epstein JA (2005) Cardiac neural crest. Semin Cell Dev Biol 16:704–715

    Article  PubMed  CAS  Google Scholar 

  37. Nowotschin S, Liao J, Gage PJ, Epstein JA, Campione M, Morrow BE (2006) Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Development 133:1565–1573

    Article  PubMed  CAS  Google Scholar 

  38. Mohapatra B, Casey B, Li H, Ho-Dawson T, Smith L, Fernbach SD, Molinari L, Niesh SR, Jefferies JL, Craigen WJ, Towbin JA, Belmont JW, Ware SM (2009) Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Gene 18:861–871

    CAS  Google Scholar 

  39. Gruber PJ, Epstein JA (2004) Development gone awry: congenital heart disease. Circ Res 94:273–283

    Article  PubMed  CAS  Google Scholar 

  40. Bentham J, Bhattacharya S (2008) Genetic mechanisms controlling cardiovascular development. Ann N Y Acad Sci 1123:10–19

    Article  PubMed  CAS  Google Scholar 

  41. Stevens KN, Hakonarson H, Kim CE, Doevendans PA, Koeleman BP, Mital S, Raue J, Glessner JT, Coles JG, Moreno V, Granger A, Gruber SB, Gruber PJ (2010) Common variation in ISL1 confers genetic susceptibility for human congenital heart disease. PLoS ONE 26:e10855

    Article  Google Scholar 

  42. Lozano-Velasco E, Chinchilla A, Martínez-Fernández S, Hernández-Torres F, Navarro F, Lyons GE, Franco D, Aránega AE (2011) Pitx2c modulates cardiac-specific transcription factors networks in differentiating cardiomyocytes from murine embryonic stem cells. Cells Tissues Organs 194:349–362

    Article  PubMed  CAS  Google Scholar 

  43. Snarr BS, O’Neal JL, Chintalapudi MR, Wirrig EE, Phelps AL, Kubalak SW, Wessels A (2007) Isl1 expression at the venous pole identifies a novel role for the second heart field in cardiac development. Circ Res 101:971–974

    Article  PubMed  CAS  Google Scholar 

  44. He MA, Zhang X, Wang J, Cheng L, Zhou L, Zeng H, Wang F, Chen Y, Xu Z, Wei Q, Hu FB, Wu T (2008) Genetic variation in heat shock protein 60 gene and coronary heart disease in China: tagging-SNP haplotype analysis in a case-control study. Cell Stress Chaperones 13:231–238

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We express our appreciation to the original DNA donors who made this study possible.

Conflict of interest

The authors state that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, P. R. China

    Xiaowei Sun, Peiqiang Li, Hua Wu, Ming Yu & Xiaodong Xie

  2. Pediatric Heart Center Fuwai Cardiovascular Hospital, Peking Union Medical College, Beijing, 100037, P. R. China

    Ying Meng

  3. Department of Cardiac Surgery, People’s Hospital of Gansu Province, Lanzhou, 730000, Gansu, P. R. China

    Tao You

Authors
  1. Xiaowei Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tao You
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peiqiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaodong Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaodong Xie.

Additional information

Xiaowei Sun and Ying Meng contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 3845 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, X., Meng, Y., You, T. et al. Association of growth/differentiation factor 1 gene polymorphisms with the risk of congenital heart disease in the Chinese Han population. Mol Biol Rep 40, 1291–1299 (2013). https://doi.org/10.1007/s11033-012-2172-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-012-2172-0

Keywords

Search

Navigation