Systematic Pharmacogenomics Analysis of a Malay Whole Genome: Proof of Concept for Personalized Medicine

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.

Content Analysis of Informed Consent for Whole Genome Sequencing Offered by Direct-to-Consumer Genetic Testing Companies

“…To date, the use of genomic sequencing approaches has proved to be useful in both the research context and clinical context; for instance, in providing molecular diagnoses for Mendelian disorders [Yang et al, 2013], for disorders with complex phenotypic presentations such as intellectual disabilities, or neurological diseases [de Ligt et al, 2012;Martin et al, 2014], potentially enabling targeted therapeutic strategies in some cases [Salleh et al, 2013]. WGS can also be used for disease risk predictions [Heo et al, 2013], preconceptional carrier testing [Chrystoja and Diamandis, 2014], and prenatal testing [Carss et al, 2014].…”

Pharmacogenetic Landscape of Clopidogrel in North Indians Suggest Distinct Interpopulation Differences in Allele Frequencies

“…Among various potential factors that regulate interindividual variability of clopidogrel response, genetic polymorphisms in genes (ABCB1, CYP3A4, CYP3A5, CYP2C9, CYP2C19, PON1 and P2RY12) involved in drug metabolism play a crucial role. However, under resource limited and time critical situations the screening for the variants is not practical in routine clinical settings, while genome-scale approaches towards elucidating pharmacogenomics profiles of individuals are enormously costly [4].…”

“…future science group exome-sequencing studies, whole-genome sequencing and in-depth ana lysis of pharmacogenomics markers have the potential to identify novel rare variants with significant odds ratios in these populations [4,32]. Furthermore, genotype datasets available from cross-sectional studies in an ethnically stratified population would provide a valuable resource to create a retrospective high resolution map of pharmacogenetic variants, which could potentially be useful in predicting clopidogrel dosing.…”

Pharmacogenomics for Precision Medicine in the Era of Collaborative Co-creation and Crowdsourcing

“…The initial years have seen sequencing of a number of individual genomes from different countries, populations, and ethnic groups. These include genomes from China [16], Japan [17], Korea [18], India [19], Sri Lanka [20], and Malaysia [21]. The 1000 Genome initiative includes 13 population groups in Phase I and additional 7 population groups in Phase II.…”