‘’Such a study may provide robust genomic markers for risk prediction, disease progression’’

In a major research project, Apollo Hospitals Educational and research Foundation (AHERF) has found out that there is possibility of a connection between the risk factors for coronary diseases and the human genes among Indians. Dr Ranjit Roy Chaudhary, Chairman-Task Force for Research, AHERF gives an understanding of the study conducted and its benefits, in an interaction with Raelene Kambli

What are the genetic factors responsible for increasing incidence of myocardial infarction (MI)?

Dr Ranjit Roy Chaudhary

Cardiovascular diseases (CVD) have a complex, multi-factorial aetiology and the presence of ‘metabolic syndrome’ (MS) more than doubles the risk of CVDs. The features of MS include an abnormal lipid profile, high blood pressure, presence of diabetes and other features that increase the chance of blood clotting or inflammation. Many of the features of the MS, such as diabetes and lipid abnormalities themselves have a strong genetic component.

What was the rationale behind this study?

The rationale was to find out why Indians are more susceptible for CVDs at a younger age. No study in India has been conducted to measure a whole genome sequel in patients. This study, done for the first time in India, aimed to demonstrate if it works. In the recent times, India is witnessing a rapid increase in non-communicable diseases (NCDs) like coronary artery disease, diabetes, hypertension and cancer. This increase in NCDs over the last decade is a matter of great concern.

It is widely accepted that myocardial infarction (MI) occurs a decade earlier in Indians as compared to other ethnicities. Any possible diagnostic tests for predicting susceptibility to CVDs would be very useful in introducing life style changes and enhancing abilities to manage this forthcoming epidemic. Hence, it is difficult to identify the contribution of genetic risk for MI per se, especially for the early events seen in our population.

To date, seven genome-wide association studies have been conducted in the area of CAD/MI, identifying thirteen genomic regions. Of these, only three studies have been exclusively dedicated to MI. Only one major Asian Indian population cohort study had been conducted in this area.

Therefore in a context where India has become the capital of cardiovascular disease, the assessment of risk for MI is challenging and there is a lack of studies exclusively focused on young Indians. Hence, the study undertaken by AHERF has the potential to contribute to answering critical questions which may potentially lead to genomic biomarkers and disease progression enabling new management algorithms.

AHERF used a state-of-the-art technology platform, to perform genomic data analysis for detecting genome specific signatures and associations in a small exploratory study. The study involved recruitment of younger patients who are under the age of 50 years at the time of a definite MI event. In order to provide a high contrast and enhance the possibility of finding genes underlying MI susceptibility, control population was chosen from among those who were a decade older, without any history of MI, diabetes or hypertension. Both patients and controls were recruited from Chennai, Delhi, Hyderabad and Ahmedabad. A total of 109 MI patients (92 male) and 101 controls (76 male), fulfilling inclusion and exclusion criteria were recruited for the study. The mean age of the patients was 42.3 for males and 42.6 for females while it was 63 years and 52 years respectively for the controls.

All the blood samples from the four centres were sent to Institute for Genomics and Integrative Biology (IGIB), New Delhi, for performing the genomic analysis. Unbiased and agnostic choice of 1.14 million genomic markers was made and DNA sample of each individual was genotyped for these markers in National Institute for Biomedical Genomics (NIBMG) using the Human Omni 1 Quad v1.0 DNA Bead Chip. This was the most complete genome-profiling platform that was available at the time of the study. It may be pointed out that IGIB, a CSIR Institution and NIBMG, a DBT Institution, are two of the leading centres for genetic research in the country.

Statistical Quality control analysis performed at NIBMG, revealed exceptionally high quality data. Except for a few number of patients excluded as a result of poor data quality, most markers could be included in the final analysis. Data on 941882 genetic markers on each of 189 individuals (patients and controls) were included for analysis. Although patients/controls were recruited from multiple locations, only three individuals turned out to be genetically variable from the remaining individuals. This is of importance, as genetic heterogeneity is usually neutralised in a larger population. However, in a small cohort like the present study, it would compound results. After making all essential adjustments and corrections, 941882 SNPs were analysed in a total of 189 individuals.

How did you conduct this study? What were the findings?

The study involved analysing the 10 genetic markers, showed the highest significant association with MI. These are located on chromosomes 10 (4), 4 (4), 2 and 20 (1 each) and some of these SNPs (markers) are located close to known markers for various CVD risk factors such as obesity.

What was the cost of conducting this study?

This ambitious project was funded internally by Apollo Hospitals and conducted by AHERF over a period of 16 months. Apollo Hospitals spent almost Rs 1.5 crores to fund this project.

How will this study help to control the growing incidence of MI?

The encouraging results of this pilot study stimulate us to believe that the genetic factors contributing to the high incidence of MI at a younger age in Indians can be possibly screened out if a large or full-scale prospective study is undertaken. Such a study may also provide robust genomic markers for risk prediction, disease progression etc., which can then lead to development of new management algorithms. Such new management algorithms may lead to preventive healthcare programmes which may help in decreasing the incidence of MI. such study also helps in early diagnosis and preventions.

Will you be presenting this study at any national or international meeting?

There is potential to analyse the available data further and post the same, AHERF alongwith its collaborators may be in a position to decide the next steps.

Are there any specific plans in the pipeline in relation with the study?

AHERF is in the process of looking for potential collaborators who would be interested in conducting a full scale prospective study to assess the feasibility of moving towards biomarker development.

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