Hyderabad, India - A heritable 25-base-pair (bp) deletion from the gene coding for cardiac myosin-binding protein C (MYBPC3) is associated with cardiomyopathy and risk for heart failure in South Asian populations, according to a new study published online January 18, 2009 in Nature Genetics [1]. Defective cardiac-myosin binding protein C, a component of filaments in cardiac muscle cells, results in distorted sarcomeres—the smallest functional units of muscle.
Various MYBPC3 mutations have been associated in several world populations with cardiac disease; however, the 25-bp deletion occurs in approximately 4% of individuals in the Indian subcontinent. Carriers of this deletion demonstrate an increased risk for heart failure, which is exacerbated by ventricular arrhythmia, increased age, high blood pressure, and environmental factors.
Senior author Dr Kumarasamy Thangaraj (Centre for Cellular and Molecular Biology, Hyderabad, India) points out that the high incidence of heart disease among South Asians has been blamed largely on lifestyle factors; this new finding suggests genetics may also play a major role.
An initial study screened DNA from Indian individuals diagnosed with cardiomyopathies. A 25-bp deletion found in patients with hypertrophic cardiomyopathy was investigated further in two study groups. Group 1 included cardiomyopathy patients (33 postmortem; n=354) and healthy control patients (n=238). The 25-bp deletion was identified in 49 patients with cardiomyopathy (13.8%) but in only seven control patients (2.9%). In two of the three homozygous cases, death from cardiomyopathies occurred before three years of age. Among control patients, none of the seven carriers was homozygous for the deletion.
Interestingly, a few normal individuals have shown homozygous deletions. Thangaraj noted, "The homozygous individuals are [from] the random samples, whose clinical conditions are not known. They live in rural areas, and their lifestyle is entirely different from those [who] live in cities. That could be the main reason.
"More important, we did not find homozygous deletions in any of the . . . well-characterized controls," Thangaraj emphasized. "Further, it is possible that other genetic factors or modifier genes could also play an important role. It is really difficult to pin down the difference in the onset of the disease in a heterogeneous population like Indians."
Interestingly, the deletion is found most frequently in southern and western India, where heart failure is known to be more prevalent: 386 to 422 cardiac deaths per 100 000 people in southern India vs 76 to 99 cardiac deaths per 100 000 people in northern and northeastern India.
In light of India's ethnic diversity, the investigators also screened 107 diverse populations throughout the country. The 25-bp deletion was found in 2% to 8% of individuals in all major populations of India but was not present in northeast Indians, recent African immigrants, or peoples of the Andaman Islands.
Lead author Dr Perundurai S Dhandapany (Madurai Kamaraj University, India) pointed out that the presence of the deletion in most Indian populations strongly indicates that it arose before the caste system, which would have limited transmission of a genetic characteristic between people of different castes.
The clinical importance of this study lies in the recognition that the 25-bp deletion conveys increased risk for heart failure throughout the life of carriers. "We believe . . . MYBPC3 mutations in cardiomyopathy patients act through accumulation of altered proteins as a part of the disease's pathogenesis," explained Dhandapany.
"However, the research output on this hypothesis is still in its rudimentary stage, and preventing the accumulation of altered protein is one . . . strategy in MYBPC3-mutated patients. But future work should clarify this issue with [an] animal model of the deletion. 'Prevention is better than cure'—so genetic counseling can be employed for such patients, giving particular emphasis on lifestyle," Dhandapany concluded.