Abstract
BackgroundWith a higher throughput and lower cost in sequencing, second generation sequencing technology has immense potential for translation into clinical practice and in the realization of pharmacogenomics based patient care. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the next step in future medicine in line with the vision of personalizing medicine.MethodsGenomic DNA obtained from a 55 years old, self-declared healthy, anonymous male of Malay descent was sequenced. The subject's mother died of lung cancer and the father had a history of schizophrenia and deceased at the age of 65 years old. A systematic, intuitive computational workflow/pipeline integrating custom algorithm in tandem with large datasets of variant annotations and gene functions for genetic variations with pharmacogenomics impact was developed. A comprehensive pathway map of drug transport, metabolism and action was used as a template to map non-synonymous variations with potential functional consequences.Principal FindingsOver 3 million known variations and 100,898 novel variations in the Malay genome were identified. Further in-depth pharmacogenetics analysis revealed a total of 607 unique variants in 563 proteins, with the eventual identification of 4 drug transport genes, 2 drug metabolizing enzyme genes and 33 target genes harboring deleterious SNVs involved in pharmacological pathways, which could have a potential role in clinical settings.ConclusionsThe current study successfully unravels the potential of personal genome sequencing in understanding the functionally relevant variations with potential influence on drug transport, metabolism and differential therapeutic outcomes. These will be essential for realizing personalized medicine through the use of comprehensive computational pipeline for systematic data mining and analysis.
Highlights
Recent advances in nucleotide sequencing technology have made it possible to understand personal genomes at a scale and cost not possible before [1]
The current study successfully unravels the potential of personal genome sequencing in understanding the functionally relevant variations with potential influence on drug transport, metabolism and differential therapeutic outcomes
The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the step in future medicine in line with the vision of personalizing medicine [16]
Summary
Recent advances in nucleotide sequencing technology have made it possible to understand personal genomes at a scale and cost not possible before [1]. These changes in the throughput of genome sequencing will have a consequential impact on the quality of healthcare and genomic services available to individuals and patients alike [2,3]. A number of personal genomes have become publicly available in the recent past [5,6,7,8,9,10,11,12] with several more genomes becoming increasingly available in private databases Global initiatives, such as the 1000 Genomes project [13], have spearheaded the creation of a comprehensive catalogue of the genetic variations found in humans. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the step in future medicine in line with the vision of personalizing medicine
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