Skip to main content

Advertisement

SpringerLink
Log in

Phenotype-Specific Association of Single-Nucleotide Polymorphisms with Heart Failure and Preserved Ejection Fraction: a Genome-Wide Association Analysis of the Cardiovascular Health Study

  • Original Article
  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Little is known about genetics of heart failure with preserved ejection fraction (HFpEF) in part because of the many comorbidities in this population. To identify single-nucleotide polymorphisms (SNPs) associated with HFpEF, we analyzed phenotypic and genotypic data from the Cardiovascular Health Study, which profiled patients using a 50,000 SNP array. Results were explored using novel SNP- and gene-centric tools. We performed analyses to determine whether some SNPs were relevant only in certain phenotypes. Among 3804 patients, 7 clinical factors and 9 SNPs were significantly associated with HFpEF; the most notable of which was rs6996224, a SNP associated with transforming growth factor-beta receptor 3. Most SNPs were associated with HFpEF only in the absence of a clinical predictor. Significant SNPs represented genes involved in myocyte proliferation, transforming growth factor-beta/erbB signaling, and extracellular matrix formation. These findings suggest that genetic factors may be more important in some phenotypes than others.

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

AF:

Atrial fibrillation

BMI:

Body mass index

CAD:

Coronary artery disease

CHS:

Cardiovascular Health Study

CKD:

Chronic kidney disease

COPD:

Chronic obstructive pulmonary disease

DM:

Diabetes mellitus

GWA:

Genome-wide association

HFpEF:

Heart failure with preserved ejection fraction

IBC:

ITMAT-Broad-CARe

HTN:

Hypertension

OR:

Odds ratio

SNP:

Single-nucleotide polymorphism

TGF:

Transforming growth factor

References

  1. Senni, M., Paulus, W. J., Gavazzi, A., Fraser, A. G., Díez, J., Solomon, S. D., Smiseth, O. A., Guazzi, M., Lam, C. S., et al. (2014). New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes. European Heart Journal, 35(40), 2797–2815.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Shah, S. J., Katz, D. H., & Deo, R. C. (2014). Phenotypic spectrum of heart failure with preserved ejection fraction. Heart Failure Clinics, 10(3), 407–418.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Vazir, A., & Solomon, S. D. (2014). Management strategies for heart failure with preserved ejection fraction. Heart Failure Clinics, 10(4), 591–598.

    Article  PubMed  Google Scholar 

  4. Borlaug, B. A., & Paulus, W. J. (2011). Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. European Heart Journal, 32(6), 670–679.

    Article  PubMed  Google Scholar 

  5. Kao, D. P., Lewsey, J. D., Anand, I. S., Massie, B. M., Zile, M. R., Carson, P. E., McKelvie, R. S., Komajda, M., McMurray, J. J., & Lindenfeld, J. (2015). Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment response. European Journal of Heart Failure, 17(9), 925–935.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Shah, S. J., Katz, D. H., Selvaraj, S., Burke, M. A., Yancy, C. W., Gheorghiade, M., Bonow, R. O., Huang, C. C., & Deo, R. C. (2015). Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation, 131(3), 269–279.

    Article  PubMed  Google Scholar 

  7. Fried, L. P., Borhani, N. O., Enright, P., Furberg, C. D., Gardin, J. M., Kronmal, R. A., Kuller, L. H., Manolio, T. A., Mittelmark, M. B., & Newman, A. (1991). The cardiovascular health study: design and rationale. Annals of Epidemiology, 1(3), 263–276.

    Article  CAS  PubMed  Google Scholar 

  8. Mailman, M. D., Feolo, M., Jin, Y., Kimura, M., Tryka, K., Bagoutdinov, R., Hao, L., Kiang, A., Paschall, J., et al. (2007). The NCBI dbGaP database of genotypes and phenotypes. Nature Genetics, 39(10), 1181–1186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gardin, J. M., Wong, N. D., Bommer, W., Klopfenstein, H. S., Smith, V. E., Tabatznik, B., Siscovick, D., Lobodzinski, S., Anton-Culver, H., & Manolio, T. A. (1992). Echocardiographic design of a multicenter investigation of free-living elderly subjects: the cardiovascular health study. Journal of the American Society of Echocardiography, 5(1), 63–72.

    Article  CAS  PubMed  Google Scholar 

  10. Ives, D. G., Fitzpatrick, A. L., Bild, D. E., Psaty, B. M., Kuller, L. H., Crowley, P. M., Cruise, R. G., & Theroux, S. (1995). Surveillance and ascertainment of cardiovascular events. The cardiovascular health study. Annals of Epidemiology, 5(4), 278–285.

    Article  CAS  PubMed  Google Scholar 

  11. Gottdiener, J. S., McClelland, R. L., Marshall, R., Shemanski, L., Furberg, C. D., Kitzman, D. W., Cushman, M., Polak, J., Gardin, J. M., et al. (2002). Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The cardiovascular health study. Annals of Internal Medicine, 137(8), 631–639.

    Article  PubMed  Google Scholar 

  12. Mentz, R. J., Kelly, J. P., von Lueder, T. G., Voors, A. A., Lam, C. S., Cowie, M. R., Kjeldsen, K., Jankowska, E. A., Atar, D., et al. (2014). Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. Journal of the American College of Cardiology, 64(21), 2281–2293.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Levey, A. S., Stevens, L. A., Schmid, C. H., Zhang, Y. L., Castro, A. F., Feldman, H. I., Kusek, J. W., Eggers, P., Van Lente, F., & Greene, T. (2009). A new equation to estimate glomerular filtration rate. Annals of Internal Medicine, 150(9), 604–612.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Keating, B. J., Tischfield, S., Murray, S. S., Bhangale, T., Price, T. S., Glessner, J. T., Galver, L., Barrett, J. C., Grant, S. F., et al. (2008). Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PloS One, 3(10), e3583.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chang, C. C., Chow, C. C., Tellier, L. C., Vattikuti, S., Purcell, S. M., & Lee, J. J. (2015). Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience, 4, 7.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., Maller, J., Sklar, P., de Bakker, P. I., et al. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics, 81(3), 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sherry, S. T., Ward, M. H., Kholodov, M., Baker, J., Phan, L., Smigielski, E. M., & Sirotkin, K. (2001). dbSNP: the NCBI database of genetic variation. Nucleic Acids Research, 29(1), 308–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. International HapMap Consortium. (2003). The international HapMap project. Nature, 426(6968), 789–796.

    Article  Google Scholar 

  19. Whirl-Carrillo, M., McDonagh, E. M., Hebert, J. M., Gong, L., Sangkuhl, K., Thorn, C. F., Altman, R. B., & Klein, T. E. (2012). Pharmacogenomics knowledge for personalized medicine. Clinical Pharmacology and Therapeutics, 92(4), 414–417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Leach, S. M., Tipney, H., Feng, W., Baumgartner, W. A., Kasliwal, P., Schuyler, R. P., Williams, T., Spritz, R. A., & Hunter, L. (2009). Biomedical discovery acceleration, with applications to craniofacial development. PLoS Computational Biology, 5(3), e1000215.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Vehlow, C., Kao, D. P., Bristow, M. R., Hunter, L. E., Weiskopf, D., & Görg, C. (2015). Visual analysis of biological data-knowledge networks. BMC Bioinformatics, 16(1), 135.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., & Ideker, T. (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Research, 13(11), 2498–2504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ho, J. E., Lyass, A., Lee, D. S., Vasan, R. S., Kannel, W. B., Larson, M. G., & Levy, D. (2012). Predictors of new-onset heart failure: differences in preserved versus reduced ejection fraction. Circulation Heart Failure, 6(2), 279–286.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Huang, D. A. W., Sherman, B. T., & Lempicki, R. A. (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols, 4(1), 44–57.

    Article  CAS  Google Scholar 

  25. Gene Ontology Consortium. (2015). Gene ontology consortium: going forward. Nucleic Acids Research, 43(Database issue), D1049–D1056.

    Article  Google Scholar 

  26. Kanehisa, M., & Goto, S. (2000). KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Research, 28(1), 27–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huntgeburth, M., Tiemann, K., Shahverdyan, R., Schlüter, K. D., Schreckenberg, R., Gross, M. L., Mödersheim, S., Caglayan, E., Müller-Ehmsen, J., et al. (2011). Transforming growth factor β1 oppositely regulates the hypertrophic and contractile response to β-adrenergic stimulation in the heart. PloS One, 6(11), e26628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lou, J., Zhao, D., Zhang, L. L., Song, S. Y., Li, Y. C., Sun, F., Ding, X. Q., Yu, C. J., Li, Y. Y., et al. (2016). Type III transforming growth factor-β receptor drives cardiac hypertrophy through β-arrestin2-dependent activation of calmodulin-dependent protein kinase II. Hypertension, 68(3), 654–666.

    Article  CAS  PubMed  Google Scholar 

  29. Deten, A., Hölzl, A., Leicht, M., Barth, W., & Zimmer, H. G. (2001). Changes in extracellular matrix and in transforming growth factor beta isoforms after coronary artery ligation in rats. Journal of Molecular and Cellular Cardiology, 33(6), 1191–1207.

    Article  CAS  PubMed  Google Scholar 

  30. Chu, W., Li, X., Li, C., Wan, L., Shi, H., Song, X., Liu, X., Chen, X., Zhang, C., et al. (2011). TGFBR3, a potential negative regulator of TGF-β signaling, protects cardiac fibroblasts from hypoxia-induced apoptosis. Journal of Cellular Physiology, 226(10), 2586–2594.

    Article  CAS  PubMed  Google Scholar 

  31. Sun, F., Duan, W., Zhang, Y., Zhang, L., Qile, M., Liu, Z., Qiu, F., Zhao, D., Lu, Y., & Chu, W. (2015). Simvastatin alleviates cardiac fibrosis induced by infarction via up-regulation of TGF-β receptor III expression. British Journal of Pharmacology, 172(15), 3779–3792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hermida, N., López, B., González, A., Dotor, J., Lasarte, J. J., Sarobe, P., Borrás-Cuesta, F., & Díez, J. (2009). A synthetic peptide from transforming growth factor-beta1 type III receptor prevents myocardial fibrosis in spontaneously hypertensive rats. Cardiovascular Research, 81(3), 601–609.

    Article  CAS  PubMed  Google Scholar 

  33. Hu, B. C., Li, L., Sun, R. H., Gao, P. J., Zhu, D. L., Wang, J. G., & Chu, S. L. (2010). The association between transforming growth factor beta3 polymorphisms and left ventricular structure in hypertensive subjects. Clinica Chimica Acta, 411(7–8), 558–562.

    Article  CAS  Google Scholar 

  34. Mujumdar, V. S., & Tyagi, S. C. (1999). Temporal regulation of extracellular matrix components in transition from compensatory hypertrophy to decompensatory heart failure. Journal of Hypertension, 17(2), 261–270.

    Article  CAS  PubMed  Google Scholar 

  35. Mizuno, T., Yau, T. M., Weisel, R. D., Kiani, C. G., & Li, R. K. (2005). Elastin stabilizes an infarct and preserves ventricular function. Circulation, 112(9 Suppl), I81–I88.

    PubMed  Google Scholar 

  36. Liu, X., Gu, X., Li, Z., Li, X., Li, H., Chang, J., Chen, P., Jin, J., Xi, B., et al. (2006). Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy. Journal of the American College of Cardiology, 48(7), 1438–1447.

    Article  CAS  PubMed  Google Scholar 

  37. Lemmens, K., Doggen, K., & De Keulenaer, G. W. (2007). Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation, 116(8), 954–960.

    Article  CAS  PubMed  Google Scholar 

  38. Gui, C., Zhu, L., Hu, M., Lei, L., & Long, Q. (2012). Neuregulin-1/ErbB signaling is impaired in the rat model of diabetic cardiomyopathy. Cardiovascular Pathology, 21(5), 414–420.

  39. Biernacka, A., Cavalera, M., Wang, J., Russo, I., Shinde, A., Kong, P., Gonzalez-Quesada, C., Rai, V., Dobaczewski, M., Lee, D., Wang, X., & Frangogiannis, N. (2015). Smad3 signaling promostes fibrosis while preserving cardiac and aortic geometry in obese diabetic mice. Circulation Heart Failure, 8(4), 788–798.

  40. Falcão-Pires, I., & Leite-Moreira, A. (2012). Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Failure Reviews 17(3), 325–344.

  41. Paulus, W. J., & Tschöpe, C. (2013). A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. Journal of the American College of Cardiology, 62(4), 263–271.

    Article  PubMed  Google Scholar 

  42. Glezeva, N., & Baugh, J. A. (2014). Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target. Heart Failure Reviews, 19(5), 681–694.

    Article  CAS  PubMed  Google Scholar 

  43. Buglioni, A., & Burnett, J. C. (2015). Pathophysiology and the cardiorenal connection in heart failure. Circulating hormones: biomarkers or mediators. Clinica Chimica Acta, 443, 3–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank William Baumgartner for his role in creating the gene-centric knowledge networks for this analysis.

Author information

Authors and Affiliations

  1. University of Colorado School of Medicine, 12700 E 19th Ave Campus Box B-139, Aurora, CO, 80045, USA

    David P. Kao, Laura M. Stevens, Michael A. Hinterberg & Carsten Görg

Authors
  1. David P. Kao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura M. Stevens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael A. Hinterberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carsten Görg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David P. Kao.

Ethics declarations

Sources of Funding

This work was supported the American Heart Association Cardiovascular Phenome-Genome Study Award 15CVGPSD27090024.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Associate Editor Sanjiv Shah oversaw the review of this article

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kao, D.P., Stevens, L.M., Hinterberg, M.A. et al. Phenotype-Specific Association of Single-Nucleotide Polymorphisms with Heart Failure and Preserved Ejection Fraction: a Genome-Wide Association Analysis of the Cardiovascular Health Study. J. of Cardiovasc. Trans. Res. 10, 285–294 (2017). https://doi.org/10.1007/s12265-017-9729-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-017-9729-1

Keywords

Search

Navigation