Lead author Kumarasamy Thangaraj. 
Mutations in the gene encoding a certain cardiac protein had previously been shown to be associated with cardiomyopathy, which is characterized by weakness in the heart muscle. Kumarasamy Thangaraj from the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad and 24 colleagues spanning nations studied one of these mutations — a 25-base pair deletion — in two populations of Indian individuals with cardiomyopathy.
They find that the deletion is associated with as much as a seven-time increased risk of cardiomyopathy. By assessing 28 unrelated Indian families, the team show that some carriers of the deletion manifest the disease by the third decade of life, and more than 90% of the oldest carriers in each family were affected. The deletion was occasionally observed in Southeast Asians, but was undetectable elsewhere in the world.
The authors show that the frequency of the deletion is significantly higher in southern and western India than in the north, a distribution that correlates with higher rates of heart failure in southern India. Despite being disadvantageous, they suggest that the deletion has risen to such a high frequency in South Asians because it typically has an effect after the age of reproduction.
There are many cases of heart attack, some are genetic and others linked to our lifestyle, but all seemingly complex, hard to pin down, and not yet completely understood. About 20 genes that are implicated in cardiac disease have been identified so far. Of these, Myosin binding protein-C (MYBPC3) is one of the major genes involved in maintaining the structure of cardiac muscle, and regulates cardiac contraction. Mutations in this gene accounts for about 44% of the sudden cardiac arrest.
Scientists have analysed the DNA of 800 cardiac patients reporting to the cardiac Centres at Hyderabad, Madurai, Thirunalveli, Tiruvanandapuram, Kozhikode, Mumbai, Bhubaneswar, Delhi and Chandigargh along with age and ethnically matched 699 normal individuals. They found 25 base pair deletions on the gene, making a heart protein called MYBPC (Mysoin binding protein-C3), was significantly high in cardiac patients compared to the normal individuals.
In addition, they found that if an individual had both copies of this gene defective (homozygous) having 25 base pair deletion, he or she dies at a very early age before reaching 5 years. They have confirmed this by analysing the post-mortem samples with the history of sudden cardiac arrest. But, if the individuals carry the mutation in only one copy of the gene (heterozygous), they live without any symptom of heart problem up to the age of 45; however, beyond 45 years they suffer from a range of effects, including sudden heart attack leading to death. Though the deletion leads to the formation of an abnormal protein, such individuals, therefore, have both abnormal as well as normal proteins.
In young people this abnormal protein is degraded efficiently by cellular machinery called proteasome and thus remain healthy, but as they get older the protein degrading machinery becomes inefficient and leads to build-up of abnormal protein eventually resulting in symptoms of cardiac problem and leading to sudden heart attack.
In order to find out how widespread this mutation is in Indian populations, scientists screened 6273 randomly selected individuals from 107 ethnic populations, including primitive tribes, tribes, castes and sub-castes belonging to all religious groups (Hindu, Sikhs, Muslim, Christian) living across India, and found that about 4% of the individuals studied had this genetic defects (25 base pair deletion in the gene MYBPC3).
Scientists wondered whether this genetic abnormality is restricted to India or is widely distributed all over the world. Therefore, they analysed the DNA of additional 2085 individuals belonging to 70 populations from 26 countries. They found that this genetic defect is present only in the people of the Indian subcontinent (India, Pakistan, Sri Lanka, Indonesia and Malaysia) but not in other countries.
How can such a harmful mutation be so common? "It seems to have originated around 33,000 years ago in India, and spread to Pakistan, Sri Lanka, Malaysia and Indonesia. It has persisted in the population, because its effects usually develop only after people have had children," Thangaraj says.
The lifetime risk of developing heart failure is roughly one in five for a person aged 40 years. "Now that the defect has been identified, there is a new glimmer of hope. It could be detected very early during pregnancy. The foetus having both the copies of defective gene (homozygous) could be aborted through genetic counselling to prevent its spread in the population by prenatal diagnosis," he says.
Carriers of this defect could be identified at a young age by genetic screening and advised to adopt a healthier lifestyle. Thangaraj says eventually new drugs could be developed to enhance the degradation of the abnormal protein and postpone the onset of symptoms. Cardiac stem cell transplant may be used very effectively to expand the lifespan of the individuals who carry the deletion. There is a market of 60 million people waiting for this therapy.
"For us this is most exciting and is a matter of great happiness that we have discovered something which is going to help mankind, particularly people in India, Pakistan, Sri Lanka, Malaysia and Indonesia. The estimated number of people suffering from heart disease is about 60 million, about one per cent of the world population," he adds.
Although the mutation was discovered five years ago in two Indian families with cardiomyopathy, its significance became apparent only after 800 heart patients, 699 healthy controls and 8358 random individuals from different parts of the world were studied.
