Letter | Published:

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

Nature Genetics 41, 187–191 (2009) | Download Citation

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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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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

    • Qasim Ayub
    •  & S Qasim Mehdi

    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.).

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, Ohio 45229, USA.

    • Sakthivel Sadayappan

  3. Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, 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, Massachusetts 02115, USA.

    • Alkes L Price

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

    • Nick Patterson
    •  & David Reich

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

    • David Reich

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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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DOI

https://doi.org/10.1038/ng.309

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