A couple of years after successfully mapping the genetic variants associated with differential responses to two widely used drugs — warfarin (an anti-coagulant drug) and clopidogrel (an antiplatelet drug) — in 2,000 people from Delhi, Harayana, Uttar Pradesh, Bihar and Punjab, Dr. Vinod Scaria and Ambily Sivadas studied the pharmacogenetic markers in a cosmopolitan population of Malays (southeast Asian Malays).
Dr. Scaria is from the Delhi-based Institute of Genomics and Integrative Biology and Sivadas is a Research Scholar at IGIB. The results of the study were published recently in The Pharmacogenomics Journal.
The duo used the recently released whole genome sequences of 100 South East Asian Malay individuals from Singapore Sequencing Malay Project for the study. Using this data, they checked if the pharmacogenetic markers in the Malay population were similar or different from those seen in the rest of the world and looked for percentage of people who had these markers. Differences in the markers and how frequently they were seen in a population will result in differences in drug response in the population.
Genetic variation in absorption and metabolism of the drug can affect the concentration of the drug and in turn the effect of the drug. Also, genetic variation in the drug target can change the effect of the drug. For instance, they found potential deleterious effects in the gene VKORC1, which is the enzymatic target of the commonly used anticoagulant, warfarin. The genetic variation in the gene meant that in the SE Asian Malay population the amount of warfarin required for the desired effect is lower than the rest of the world.
“In the case of India, different populations have different frequencies of the marker connected with warfarin metabolism. Therefore, it is important to capture the sub-population data within India to optimise drug dosing,” said Sivadas. “In general, the Asian population requires a lower warfarin dose to achieve stable anticoagulation.”
Similarly, as a result of predominance of polymorphism in the gene GRIK4, the response to antidepressants was found to be very good. “We can predict higher success in treatment outcomes with antidepressant medications in SE Asian Malays,” he said. “But additional validations would be required for this to be considered definitive.”
Compared with other East Asian populations, the SE Asian Malays were found to be poor metabolisers of an antihypertensive drug debrisoquine. So the drug dosage should be lower to avoid toxicity.
“The real impact of the study is that this information could lead to a change in dosage of a certain drug for a particular population to achieve the same effect. And in future, the dosages can be modified before undertaking any clinical trial in this population,” they noted.
This information is particularly useful as dosages of most of the drugs in the market are based on information derived from clinical trials carried out on Caucasians. “Asian subpopulations including Indians and Malays are still not sufficiently represented in comprehensive pharmacogenomic research and drug development and so the efficacy of the drugs in these minority populations is not known,” he said. The varied response to drugs both by Indians and SE Asian Malays compared with Caucasians would mean that future trials have to necessarily include a few volunteers from these countries to know the precise dosing.
The earlier study carried out in India revealed significant differences in the percentage of people in the five States who had the markers for the drug warfarin and clopidogrel. “Given the ethno-linguistic diversity represented by India, these studies further emphasize the need to profile more Indian subpopulations in order to build a comprehensive pharmacogenetic map for the entire Indian subcontinent,” Dr. Scaria stressed. “We are very keen on creating such comprehensive pharmacogenetic maps for all known drugs in use for the Indian populations which will immensely benefit safe drug dosing in our populations, provided we have adequate funding.”
While the Indian studies were limited by the availability of low-resolution genotype microarray datasets which allows one to profile only a set of known common variants, the latest study on Malays used the more powerful whole genome sequencing. Whole genome sequencing helps in identifying the common genetic variants when performed for a population as well as the very rare and personal variants that are found unique to an individual.
The SE Asian Malay study has helped build one of the most comprehensive pharmacogenetic maps including 227 common and 466 rare potentially functional variants in 437 genes in the population.