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

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.

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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.

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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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