Background: With a higher throughput and lower cost in sequencing, second generation sequencing technology has immense potential for translation into clinical practice and in the realisation of pharmacogenomics based patient care. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetic and pharmacodynamic responses towards drugs would be the next step in future medicine in line with the vision of personalizing medicine.
Methods: Genomic DNA was obtained from a middle aged, self-declared healthy, anonymous male of Malay descent whose mother died of lung cancer and father had a history of Schizophrenia and deceased at the age of 65. 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.
Principle findings: Over 3 million known variations and 100,898 novel variations in the Malay genome were identified. Further in-depth pharmacogenetic analysis revealed a total of 607 unique variants in 563 proteins, with the eventual identification of 4 drug transport genes, 2 drug metabolising enzyme genes and 33 target genes harbouring deleterious SNVs involved in pharmacological pathways, which could have a potential role in clinical settings.
Conclusions: 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 realising personalised medicine through the use of comprehensive computational pipeline for systematic data mining and analysis.
Salleh MZ*, Teh LK, Lee LS, Ismet RI, Patowary A, Joshi K, Pasha A, Ahmed AZ, Janor MH, Hamzah AS, Adam I, Yusoff K, Hoh BP, Hatta FM, Ismail MI, Scaria V*, Sivasubbu S*
Systematic Pharmacogenomics analysis of a Malay whole genome : Proof of concept for Personalised Medicine.
PLoS ONE (2013) Accepted
Datasets and Scripts
Datsets and scripts pertaining to the first Malaysian Genome is available online [here]