The worst luck in the world?

The heart disease mutation carried by 60 million

The worst luck in the world?

Expression and localization of normal (top) and mutant (bottom) MYBPC3 proteins in cultured rat cells. Recombinant adenoviruses that expressed mouse cMyBP-CWT (normal, top) or cMyBP-CΔEx33 (mutant, bottom) forms of MYBPC3 were introduced into rat neonatal cardiomyocytes. Three days after infection, cells were fixed and immunostained with myc-tag antibodies that detect MYBPC3 (left, green) or costained with α-tropomyosin (middle, red). The combined image is shown on the right. Note the regular striated pattern of muscle fibres in the top panels, compared with the disrupted pattern in the bottom panels.

Heart disease is the number one killer in the world and India carries more than its share of this burden. Moreover, the problem is set to rise: it is predicted that by 2010 India's population will suffer approximately 60 per cent of the world's heart disease. Today, an international team of 25 scientists from four countries provides a clue to why this is so: 1 per cent of the world's population carries a mutation almost guaranteed to lead to heart problems and most of these come from the Indian subcontinent, where the mutation reaches a frequency of 4 per cent.

Heart disease has many causes, some carried in our genes and others linked to our lifestyle, but all seemingly complex, hard to pin down and incompletely understood. So the new study published in Nature Genetics is striking for the size and simplicity of the effect it reports.

The mutation, a deletion of 25 letters of genetic code from the heart protein gene MYBPC3, is virtually restricted to people from the Indian subcontinent. But there, Caste and Tribe, Hindu, Muslim, Sikh, Christian and others are all united by this affliction.

The mutation was discovered five years ago in two Indian families with cardiomyopathy, but its significance only became apparent after almost 1500 people from many parts of India, some with heart disease and some without, were studied.

Scientists express this genetic risk as an odds ratio, where 1.2 would be a small effect and 2.0 a large one. For the MYBPC3 mutation, the odds ratio is almost off-scale, a staggering 7.0. Carriers usually show few symptoms until middle age, but after that age most are symptomatic and suffer from a range of effects, at worst sudden cardiac death.

"The mutation leads to the formation of an abnormal protein. Young people can degrade the abnormal protein and remain healthy, but as they get older it builds up and eventually results in the symptoms we see."

Kumarasamy Thangaraj, the study's leader, from the Centre for Cellular and Molecular Biology, Hyderabad, India

The combination of such a large risk with such a high frequency is, fortunately, unique. "How can such a harmful mutation be so common? We might expect such a deleterious change to have 'died out'."

"We think that the mutation arose around 30,000 years ago in India, and has been able to spread because its effects usually develop only after people have had their children. A case of chance genetic drift: simply terribly bad luck for the carriers."

Chris Tyler-Smith from The Wellcome Trust Sanger Institute

"The bad news is that many of these mutation carriers have no warning that they are in danger, but the good news is that we now know the impact of this mutation."

Perundurai S. Dhandapany from Madurai Kamaraj University, Madurai, India

The lifetime risk of developing heart failure is roughly one in five for a person aged 40 years. Now that this mutation has been identified, there is a new glimmer of hope for some of them. The mutation's effects vary a lot from person to person. Carriers could be identified at a young age by genetic screening and adopt a healthier lifestyle.

"This is a genetic finding of great importance. Heart disease is one of the world's leading killers, but now that researchers have identified this common mutation, carried by one in 25 people of Indian origin, we have hope of reducing the burden that the disease causes. This research should lead to better screening to identify those at risk and may ultimately allow the development of new treatments."

Sir Mark Walport, Director of the Wellcome Trust

And perhaps eventually new drugs could be developed to enhance the degradation of the abnormal protein and postpone the onset of symptoms. There is a market of 60 million people waiting.

Notes to Editors
  • A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia.

    Dhandapany PS, Sadayappan S, Xue Y, Powell GT, Rani DS et al.

    Nature genetics 2009;41;2;187-91

Odds Ratio

the ratio of the odds of an event occurring in one group to the odds of it occurring in another group.


This work was supported by the Wellcome Trust; the Council for Scientific and Industrial Research, India; the Indian Council of Medical Research; the Postgraduate Institute of Medical Education & Research, Chandigarh; the American Heart Association and a Burroughs Wellcome Career Development Award in the Biomedical Sciences.

Participating Centres
  • Department of Biochemistry, Madurai Kamaraj University, Madurai 625 021, India
  • Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  • Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  • Centre for Cellular and Molecular Biology, Hyderabad, India
  • Department of Genetics, Osmania University, Hyderabad, India
  • Post Graduate Institute of Medical Education and Research, Chandigarh, India
  • Faculty of Biological Sciences, Institute of Integrative and Comparative Biology, University of Leeds, Leeds, UK
  • Department of Cardiology, Sri Chitra Tirunal Institute of Medical Sciences and Technology, Trivandrum, India
  • Department of Pathology (Cardiovascular & Thoracic Division), Seth GS Medical College and KEM Hospital, Mumbai, India
  • Department of Cardio-Thoracic Surgery, Rajaji Government Hospital and Madurai Medical College, Madurai, India
  • Cardiology Unit, CARE Hospital, The Institute of Medical Sciences, Hyderabad, India
  • Department of Cardiac Surgery, Nizams Institute of Medical Sciences, Hyderabad, India
  • Institute of Biotechnology and Genetic Engineering (KIBGE), University of Karachi, Karachi 75270, Pakistan
  • Department of Anthropology, University of Oxford, Oxford, UK
  • Harvard School of Public Health, Boston, Massachusetts, USA
  • Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  • Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

Scientists analysed the DNA of 800 patients at cardiac centres in Hyderabad, Madurai, Thirunalveli, Tiruvanandapuram, Kozhikode, Mumbai, Bhubaneswar, Delhi and Chandigargh.

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