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A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia

Nature Genetics volume 41, pages 187–191 (2009)Cite this article

Abstract

Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown1. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3–13), P = 2 × 10−6; replication study OR = 8.59 (3.19–25.05), P = 3 × 10−8; combined OR = 6.99 (3.68–13.57), P = 4 × 10−11) and that disrupts cardiomyocyte structure in vitro. Its prevalence was found to be high (∼4%) in populations of Indian subcontinental ancestry. The finding of a common risk factor implicated in South Asian subjects with cardiomyopathy will help in identifying and counseling individuals predisposed to cardiac diseases in this region.

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Figure 1: Morphology and histopathology of heart, and cardiac transcript analysis of individuals with the 25-bp deletion.
Figure 2: Expression and localization of cMyBP-CWT and cMyBP-CΔEx33 proteins in neonatal rat cardiomyocytes.
Figure 3: Global distribution of MYBPC3 deletion in indigenous populations.

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Acknowledgements

We thank all participants for making this study possible. We acknowledge the help of G.S. Selvam, C. Rajamanickam, R. Srinivasan, V. Madhavan, S. Madhavan, A.G. Reddy, A. Vanniarajan, P. Govindaraj, B.D. Gelb and Q. Long. P.S.D. was supported by Council of Scientific and Industrial Research – Senior Research Fellowship (CSIR-SRF) and P.N. by Department of Biotechnology (DBT). K.T. was supported by Council of Scientific and Industrial Research (CSIR) - Raman Research Fellowship and Y.X., G.T.P., Q.A., S.Q.M. and C.T.-S. were supported by The Wellcome Trust. T.S.R. received an Senior Research Fellowship (SRF) from Indian Council of Medical Research (ICMR), M.K. and A.B. were supported by Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh. S.S. received a post-doctoral training grant from the American Heart Association, Ohio Valley Affiliate, USA. D.R. is supported by a Burroughs Wellcome Career Development Award in the Biomedical Sciences.

Author information

Author notes

  1. Qasim Ayub & S Qasim Mehdi

    Present address: Present addresses: Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK (Q.A.) and Centre for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation, Karachi 74200, Pakistan (S.Q.M.).,

Authors and Affiliations

  1. Department of Biochemistry, Madurai Kamaraj University, Madurai, 625 021, India

    Perundurai S Dhandapany

  2. Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, 45229, Ohio, USA

    Sakthivel Sadayappan

  3. Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, Cambridgeshire, UK

    Yali Xue, Gareth T Powell & Chris Tyler-Smith

  4. Centre for Cellular and Molecular Biology, Hyderabad, 500 007, India

    Deepa Selvi Rani, Lalji Singh & Kumarasamy Thangaraj

  5. Department of Genetics, Osmania University, Hyderabad, 500 007, India

    Prathiba Nallari

  6. Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India

    Taranjit Singh Rai, Madhu Khullar & Ajay Bahl

  7. Faculty of Biological Sciences, Institute of Integrative and Comparative Biology, University of Leeds, Leeds, LS2 9JT, UK

    Pedro Soares & Martin B Richards

  8. Department of Cardiology, Sri Chitra Tirunal Institute of Medical Sciences and Technology, Thiruvananthapuram, 695 011, India

    Jagan Mohan Tharkan

  9. Department of Pathology (Cardiovascular & Thoracic Division), Seth GS Medical College and KEM Hospital, Mumbai, 400 012, India

    Pradeep Vaideeswar

  10. Department of Cardio-Thoracic Surgery, Rajaji Government Hospital and Madurai Medical College, Madurai, 625020, India

    Andiappan Rathinavel

  11. Cardiology Unit, CARE Hospital, Hyderabad, 500 001, India

    Calambur Narasimhan

  12. Department of Cardiac Surgery, Nizams Institute of Medical Sciences, Hyderabad, 500 082, India

    Dharma Rakshak Ayapati

  13. Institute of Biotechnology and Genetic Engineering (KIBGE), University of Karachi, Karachi, 75270, Pakistan

    Qasim Ayub & S Qasim Mehdi

  14. Department of Anthropology, University of Oxford, Oxford, OX1 2JD, UK

    Stephen Oppenheimer

  15. Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Alkes L Price

  16. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Nick Patterson & David Reich

  17. Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    David Reich

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  1. Perundurai S Dhandapany
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Contributions

P.S.D., C.T.-S. and K.T. designed the study. A.B., J.M.T., P.V., A.R., C.N. and D.R.A. helped in recruitment of cardiomyopathy cases and controls. P.S.D., P.N., T.S.R., M.K. and D.S.R. screened the subject samples. P.S.D., S.S., Y.X., G.T.P., D.S.R. and K.T. performed the major experiments including genotyping, functional studies and sequencing. K.T., L.S., C.T.-S. and D.R. provided reagents for the study. K.T., C.T.-S., L.S., Q.A., S.Q.M., P.S., S.O., A.L.P., N.P. and M.B.R. helped in collecting and genotyping the various population samples. P.S.D. and K.T. drafted the manuscript with the help of C.T.-S. and D.R.

Corresponding author

Correspondence to Kumarasamy Thangaraj.

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Supplementary Figures 1–8, Supplementary Tables 1–9, Supplementary Methods and Supplementary Note (PDF 3620 kb)

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Dhandapany, P., Sadayappan, S., Xue, Y. et al. A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia. Nat Genet 41, 187–191 (2009). https://doi.org/10.1038/ng.309

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