Pharmacogenomics for Understanding Complex Genomics Aspects of Stroke

Stroke, a leading cause of death worldwide including in Indonesia, has a heritable component and gene discovery efforts have identified an expanding number of known single-gene disorders associated with stroke and have linked common variants at approximately 35 genetic loci to stroke risk. In fact, Mendelian stroke causes ~7% of ischaemic strokes and identifying the genetic abnormalities in Mendelian strokes is important as it would facilitate therapeutic management and genetic counseling. A causal relationship with risk factors has been demonstrated and genome-wide polygenic scores can help identify high-risk individuals before the emergence of vascular risk factors. But, there remain challenges for integration of genetics into precision medicine, integration with other omics data, uncovering the genetic factors that govern stroke recurrence and stroke outcome, and translating genetic discoveries to novel therapies.

In light of the complexity associated with understanding the genomics aspects of stroke, and whilst building a biobank of relevant samples that can be used to study these complex aspects of the disease, our project will focus on establishing proof of concept for applying a pharmacogenomics approach to improve treatment outcome.

Our first focus will be clopidogrel. This is an anti-platelet drug widely used to treat stroke patients. This drug must be converted to an active metabolite to have its anti-platelet effects, and polymorphisms in the CYP2C19 gene have been linked with varying degrees of clopidogrel responsiveness.Genomic variants in the CYP2C19 gene are associated with variable enzyme activities affecting drug metabolism and hence, patients with reduced or increased enzymatic function have increased risk of bleeding and therefore their treatment regime should be adjusted. Our first project will aim to develop the capacity to test for the genomic variants of CYP2C19 (and other genes associated with clopidogrel pharmacogenomics) at the National Brain Center Hospital and demonstrate that this test can be used to improve treatment outcome for our stroke patients.

Vision

Our vision is to make genomics an integral part of stroke patient care with an initial focus on building pharmacogenomics testing capacity in-house.

Disease Target

Stroke

Outcome

Novel insights into pathogenesis, biomarkers, & drug discovery of stroke