21 June 2017
Qatar exome study: An advancement in precision medicine
Published online 24 September 2016
Scientists look at Qataris' exome sequences to anticipate response to two common blood-thinners.
Scientists have used information from the whole-exome sequencing of 100 Qataris to create a comprehensive map of pharmacogenetic variants associated with two anticoagulants.
The study, by a team from the Delhi-based CSIR Institute of Genomics and Integrative Biology, will be the first that tries to anticipate the reaction of a Qatari patient to a medication based on his or her genetic makeup. The study will appear in Pharmacogenomics.
The work is in the field of pharmacogenetics, a relatively new research realm which rose from advances in genomics, and which studies inherited genetic differences in metabolic pathways that can affect an individual's response to drugs.
In this study, the scientists look at warfarin and clopidogrel, two most widely prescribed oral anticoagulants among Arab patients.
Given the genetic variety that exists in this Gulf state, where the population can be traced to African, Persian-South Asian or Bedouin ancestries, administered dosage levels of these drugs should vary significantly to improve efficacy and reduce side-effects.
Vinod Scaria, an Indian researcher specializing in precision medicine, and his research team, based their work on exome data originally collected by Weill Cornell Medical College researchers in Qatar and New York1. Their field of study combines factors such as an individual's genetic makeup, environment, age, lifestyle and diet, and other medication, to enable precise diagnosis, treatment and management of a disease.
"The lack of genetic data from Arab populations was a major impediment all these years."
The potential for drugs to be ineffective or to cause harm has not been adequately studied for Arab populations because pharmaceutical clinical trials and dosing algorithms of a large majority of drugs are predominantly derived from European Caucasian populations.
In Qatar, cardiovascular diseases are the number one cause of mortality and in 2012, WHO attributed some 400 deaths to ischaemic heart disease – a condition that can be eased or prevented by warfarin and clopidogrel. The drugs prevent clots forming or help break them down in blood vessels. They are typically prescribed for patients with a disrupted blood flow to the heart or brain, or those who have undergone an angioplasty.
Since these medicines increase the time it takes for blood clots to form, haemorrhage or excessive bleeding can occur.
"Warfarin is a widely used blood-thinner all over the world, and if you are not taking enough, then you have an increased risk for clot, if you give too much you have an increased risk for bleeding which can be life-threatening and fatal," says Ronald Crystal, chairman of Genetic Medicine at Weill Cornell Medical College, which provided the original data-sets that Scaria and his team used independently. "So getting the dose right is important."
Scaria says that, for years, there was a lack of genetic data from Arab populations. “The data from Qatar exomes provided the ability to be able to analyze the genetic variants and their frequencies in order to create the pharmacogenetic map," he explains.
The availability of whole exome sequences allowed the CSIR to study many variants together, at a population level. "Studies like Dr. Scaria's is exactly why we have been studying the Qatari genome," comments Crystal.
According to co-researcher Ambily Sivadas, the cyctochrome (CYP) genes are those that determine the metabolism of drugs.
“A small percentage of Qatari individuals have two non-functional copies (homozygous) of CYP2C9*2 variation, which significantly reduces the metabolism of warfarin and necessitates a lower dose of the medicine, while a vast majority of people had a variant in CYP4F2 which necessitate a higher dose,” he explains.
Around 70% of people with the CYP2C9*2 variant, and half of those who had the CYP4F2 variant were of Bedouin ancestry. Given the small sample of the population studied, the scientists, who looked into Qataris of Bedouin, African and Persian-South Asian descents, were surprised by the significant differences between those three distinct subpopulations.
They also found very low occurrence of clopidogrel resistance associated with variant CYP2C19*3 in the population, suggesting that clopidogrel would be quite effective among Qataris.
“Genetic testing would provide an opportunity to avoid adverse events by modulating the dose or in some cases, swap it with a compatible alternative medication. It would thus enable precision at an individual level and a better outcome for the treatment regimen,” says Scaria.
An earlier version of this article stated that Vinod Scaria is affiliated to Weill Cornell Medical College in Qatar, which is not correct. He and his team used a dataset produced by researchers at Weill Cornell Medical College.
- Rodriguez-Flores, J.L. et al. Indigenous Arabs are descendants of the earliest split from ancient Eurasian populations. Genome Research http://dx.doi.org/10.1101/gr.191478.115 (2016)