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Pharmacogenomics and Personalized Medicine: the Plunge Into Next-Generation Sequencing Mia Wadelius1* and Ana AlRevic2

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Pharmacogenomics and Personalized Medicine: the Plunge Into Next-Generation Sequencing Mia Wadelius1* and Ana AlRevic2 Wadelius and Alrevic Genome Medicine 2011, 3:78 http://genomemedicine.com/content/3/12/78 MEETING REPORT Pharmacogenomics and personalized medicine: the plunge into next-generation sequencing Mia Wadelius1* and Ana Alrevic2 Abstract technology has led to a drastic drop in the cost (>10,000-fold) and time (from 10 years to 1 week) needed A report on the 9th Annual Cold Spring Harbor/ to sequence a genome. NGS is now being introduced as a Wellcome Trust meeting ‘Pharmacogenomics and method to personalize medicine. Personalized Medicine’, Hinxton, Cambridge, UK, Yingrui Li (Beijing Genomics Institute, China) des- 29 September to 2 October 2011. cribed the sequencing revolution that has made personal Keywords Consortium, genome-wide association genomes affordable, while it remains difficult and costly study, meta-analysis, next-generation sequencing, to interpret the results. Recent whole genome sequencing pharmacogenomics/pharmacogenetics, public health of individuals at the Beijing Genomics Institute has genomics, P4 medicine. shown an excess of rare deleterious SNPs together with extensive structural variations and novel individual specific sequences with potential functional impact. ese In recent years, pharmacogenomics has moved beyond new genetic variants are likely to explain part of the candidate gene and genome-wide association studies missing heritability seen with previous GWASs. Interest- (GWASs) towards truly personalized genomics. e use ingly, Li reported that more ethnic-specific haplotypes of new biotechnological, mathematical and computa- exist than previously thought and that each defined tional tools has enabled an exponential increase in the population will need its own genome-wide tag SNP array. number of biomarkers for drug safety and efficacy; how- is is a general problem that must be considered when ever, their clinical utility in achieving personalized performing pharmacogenetic GWASs in non-Caucasian therapy remains to be determined. Here we cover current populations. expert opinions concerning emerging pharmacogenomic Steve Scherer (e Hospital for Sick Children, Canada) technologies, international consortia and collaborations shared his enthusiasm over large-scale sequencing efforts including underrepresented populations, development of within the Pharmacogenomics Research Network (PGRN) personalized medicine and clinical relevance of Deep Sequencing Resource (DSR). is network is pharmacogenetic testing. In addition, future directives supported by the National Institutes of Health (NIH), and presented at the meeting are discussed. consists of 14 US research groups. Ongoing projects are: targeted re-sequencing in pharmacogenetic breast cancer Technology-driven research and hypertension studies, platelet RNA sequencing in Since the first Wellcome Trust/Cold Spring Harbor responders and non-responders to clopidogrel, and RNA Labora tory meeting on pharmacogenetics in 2003, the sequencing in tissues of major pharmacologic interest to field has evolved into pharmacogenomics through a shift assess gene expression levels of common splice variants from candidate gene studies to GWASs. Such large-scale in very important pharmacogenes (VIPs). PGRN DSR is studies enable simultaneous detection of >1 million SNPs also developing a gene capture reagent for sequencing of that can be tested for association with drug-related VIPs, such as cytochrome P450 genes and human leuko- outcomes, and verified by replication in separate cohorts. cyte antigen (HLA) genes. Scherer concluded that these e development of next-generation sequencing (NGS) large-scale sequencing projects have the potential to transform medicine, but some important issues, such as the generation of software to present results to physicians *Correspondence: [email protected] 1Department of Medical Sciences, Clinical Pharmacology, Uppsala University, in a coherent manner, remain to be solved. Uppsala University Hospital, entrance 61, SE-751 85 Uppsala, Sweden Full list of author information is available at the end of the article Meta-analyses and consortia e ability of high-throughput genotyping technologies © 2010 BioMed Central Ltd © 2011 BioMed Central Ltd to interrogate millions of markers simultaneously in Wadelius and Alfirevic Genome Medicine 2011, 3:78 Page 2 of 4 http://genomemedicine.com/content/3/12/78 Table 1. Examples of pharmacogenomic networks and consortia presented at the Pharmacogenomics and Personalized Medicine meeting Group Abbreviation Website Presenter(s) Breast Cancer Association Consortium BCAC http://www.srl.cam.ac.uk/consortia/bcac/ Christina Justenhoven Canadian Pharmacogenomics Network for Drug Safety CPNDS http://www.cpnds.ubc.ca/ Michael Hayden, Colin Ross, Ursula Amstutz Clinical Pharmacogenetics Implementation Consortium CPIC http://www.pharmgkb.org/contributors/ Ellen M McDonagh consortia/cpic_profile.jsp Human Heredity and Health in Africa Initiative H3Africa http://h3africa.org/ Collet Dandara Inflammation and the Host Response to Injury Consortium IHRI https://www.gluegrant.org/index.htm Wenzhong Xiao International Cancer Genome Consortium ICGC http://www.icgc.org/ Ultan McDermott International Serious Adverse Events Consortium iSAEC http://www.saeconsortium.org/ Ann Daly International Warfarin Pharmacogenetics Consortium IWPC http://www.pharmgkb.org/contributors/ Stephane Bourgeois consortia/iwpc_profile.jsp Pharmacogenomics Research Network PGRN http://pgrn.org/ Steven Scherer SpiroMeta Consortium - - Ma’en F Obeidat association studies necessitates the use of large sample represented the Breast Cancer Association Consortium, sizes that can be recruited only through collaborations; which is searching for breast cancer susceptibility genes, some studies reported at the meeting included >90,000 as well as studying effects of hormone therapy in relation participants. The trend is therefore to perform meta- to genotypes. One main driver of these networks (except analyses of available GWASs to increase statistical power, the Clinical Pharmacogenetics Implementation Consor- and also to persuade old competitors to work together in tium) is to pool enough samples to enable robust study consortia (Table 1), where primary individualized out- design with high statistical power. come data are pooled with previous or new genotyping data. This is indeed a positive effect brought on by recent Pharmacogenomics in Africa technological developments. African researchers and populations are substantially Several consortia are hosted by the PharmacoGenomics under-represented in most international research net- Knowledge Base (PharmGKB). Among them is the Clinical works. It was therefore a pleasure to hear Collet Dandara Pharmacogenetics Implementation Consortium, which is (University of Cape Town, South Africa) describe the aimed at providing guidance on how to adjust medica- Human Heredity and Health in Africa (H3Africa) initia- tions on the basis of pharmacogenetic test results. tive, which is sponsored by the NIH and the Wellcome Another PharmGKB network is the International War- Trust. Specific issues in African populations are the great farin Pharmacogenetics Consortium, which was intended genetic diversity and the fact that most drugs are initially for the development of a warfarin dose algorithm, developed for non-Africans. Drug safety and efficacy but is now involved in a warfarin GWAS meta-analysis. biomarkers that have already been discovered may not be Two consortia aimed at investigating genetic risk factors appropriate in African populations because of different for adverse drug reactions were presented. First, Ann allele and haplotype frequencies. Recent studies have Daly (Newcastle University, UK) from the International shown that HLA types that confer risk of serious skin Serious Adverse Events Consortium described recent reactions vary between different populations. Hence it is results concerning GWASs and exome sequencing of essential to develop diagnostic and prognostic tools for serious adverse drug reactions affecting the liver. There- all populations. Folefac Aminkeng (University of British after, Michael R Hayden, Colin Ross and Ursula Amstutz Columbia, Canada) described an important project (University of British Columbia, Canada) presented studies aimed at studying the pharmacogenetics of World Health of severe adverse drug reactions in children within the Organization essential medicines in Africa to enable the Canadian Pharmacogenomics Network for Drug Safety. most effective use of available medical resources, and The International Cancer Genome Consortium, which is Marelize Swart (University of Cape Town, South Africa) searching for biomarkers of sensitivity and resistance to illustrated this endeavor by describing pharmacogenetic therapies by exposing 1,000 cancer cell lines to a multi- predictors of response to HIV/AIDS treatment. tude of chemical compounds, was described by Ultan McDermott (Wellcome Trust Sanger Institute, UK). Clinical validity and utility of pharmacogenetic tests Finally, Christina Justenhoven (Dr Margarete Fischer- Numerous pharmacogenetic biomarkers for drug safety Bosch-Institute of Clinical Pharmacology, Germany) and efficacy have been identified over the past few years. Wadelius and Alfirevic Genome Medicine 2011, 3:78 Page 3 of 4 http://genomemedicine.com/content/3/12/78 T1 Bench Bedside T0 T2 Population Knowledge Evidence-based health synthesis recommendation T4 T3 Healthcare systems and prevention programs Figure 1. The genomics translation (T) highway. This model describes the translation
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