Current Pharmacogenomics and Personalized Medicine - Volume 10, Issue 3, 2012

In this paper, we advance the extant health technology innovation frames on global personalized medicine by highlighting the need to rethink genomics medicine in real-life settings – including situations where populations are frequently faced with natural disasters or man-made conflicts. We identify the steps towards building sufficient capacity to effectively harness and integrate genomic medicine and molecular diagnostics in order to benefit global society including those in resource-limited settings and post-war capacity building contexts. Surprisingly, despite a great number of populations currently living in developing countries, including in a state of post-war or conflict resolution context, the public health pharmacogenomics community has largely neglected this crucial dimension in biomedical literature. By exploring the particular case of Sri-Lanka in this paper, we are able to investigate the obstacles commonly faced by low and middle income countries similarly afflicted by crises, natural disasters, conflict and the need for improved, more cost effective health care. Sri Lanka has a relatively strong platform for launching molecular diagnostic technology, including a well networked set of primary, secondary and tertiary care institutions, a small but burgeoning private health and research sector and a strong science base in its universities. Despite this, there has been slow uptake and exploitation of novel molecular diagnostics due to various factors such as a weak regulatory framework and high costs associated with the import of molecular reagents and import and maintenance of equipment. In summary, as a way forward for health technology assessment in resource-limited countries, this paper brings to the fore an integrated discourse on real-life experiences and putative solutions on genomics and molecular diagnostic medicine. For a comprehensive discussion in the nascent field of public health pharmacogenomics, post-war and post-conflict capacity building on biotechnologies such as genomics is essential.

The human microbiota directly and indirectly impacts drug pharmacokinetics and pharmacodynamics, thus affecting treatment outcome and subsequently human health. The Human Microbiome Project (HMP) revived interest in the role of human microbiota in health and disease. Yet, no repository of reported drug-microbe interactions is publicly available, and no attempts have been made to link those interactions to the human microbiome in a structured way. To begin addressing the need for such a crucial and timely resource, we analyzed published experimental data to extract drug-microbe interactions so as to enable the application of emerging HMP knowledge in postgenomics personalized medicine. We hereby report the creation of the PharmacoMicrobiomics Database, which aims to collect, classify, and cross-reference known drug-microbiome interactions and categorize them according to body site and microbial taxonomy. The database is integrated into a web portal that includes a search engine, through which students and scholars can locate drug-microbiome interaction of interest, compiled from and connected to public databases, such as PubMed, PubChem, and Comparative Toxicogenomics. Making these data available is a significant first step towards the prediction of interactions between drugs with similar chemical properties and microbes with similar metabolic abilities. Currently, the PharmacoMicrobiomics Database contains drug-microbiome interactions for more than 60 drugs curated from over 100 research and review articles. Further developments will include the automation of data updating, classification based on drug classes and biochemical pathways, and the participation of the community into data curation and analysis. This work provides a timely and much needed pioneering resource to the global open science community and usefully builds bridges between the rapidly growing fields of pharmacogenomics and human microbiome research. Database URL: http://www.pharmacomicrobiomics.org; Source Code: http://sourceforge.net/projects/ pharmacomicro.

There is marked controversy on the beneficial levels of selenium (Se) to be used as a dietary supplement. The form of supplemented Se and the baseline plasma or serum Se status among supplemented populations are generally considered as crucial factors in this controversy. However, responses to supplemented Se can further vary with other factors, including health status, lifestyle, demographics and genetics. In the present study, the putative supplementation benefits of Se as 200 μg/day selenised yeast for six months were evaluated among a stratified male population from Auckland, New Zealand. Our study considered changes in surrogate biomarkers for cancer including antioxidant selenoenzymes glutathione peroxidase (GPx) and thioredoxin reductase activity (TR) levels, basal and peroxide-induced DNA damage levels. A total of 569 subjects self-reporting a European ancestry signed in for the study and provided answers to a basic demographic, health and lifestyle questionnaire. The effects of Se supplementation on biomarkers showed significant variability based on age, BMI, health status and seleno-genotypes of SELS rs4965373, GPx1 rs1050450, and SEPP1 rs3877899. The data indicate that the benefits of supplementary Se vary significantly across a population, based on demographics, lifestyle, health conditions and seleno-genotypes. As a contrast to “one-size-fits-all” nutritional interventions, these observations collectively inform rational targeting and personalisation of future Se-based dietary supplementation in regards to cancer chemoprevention strategies. This work also represents a way forward in critically understanding Se requirements in populations.

Research in the field of pharmacogenetics (PGx) has been growing exponentially over the past decade in a manner that is disproportionate to the rate of its incorporation into clinical practice. That is why efforts to further PGx education in health professional schools have been initiated to reduce the gap that currently exists between research and practice. Because there is a current paucity of information regarding the status of PGx education in low and middle income countries (LMICs) in comparison to high income countries, the aim of our study was to evaluate this important gap using an online survey that we electronically sent to the relevant delegates of the International Union of Basic and Clinical Pharmacology (IUPHAR) “World Pharma 2010” meeting (Copenhagen, July 2010). Respondents from 25 global institutions answered our survey, of which more than half had already incorporated PGx teaching into their curricula. Although PGx was an integral part of the World Pharma 2010 topics, only few PGx abstracts from LMICs were presented when compared to high income countries: 37 abstracts from 18 high income countries compared to 20 from 16 LMICs (Brazil, Chile, Croatia, Cuba, Iran, Lebanon, Montenegro, Romania, Russia, Serbia, Thailand, Trinidad and Tobago, Tunisia, Turkey, and Uganda). PGx education was mainly introduced as part of the already existing pharmacology courses, was dedicated an average of 2-4 hours of teaching, and was mainly delivered through lectures and seminars. Even though these findings are on par with the international guidelines that outline the minimal requirements of PGx education in health professional schools, further strategic planning for PGx education is no doubt crucial which can be informed by our findings reported herein. This research paper presents a discussion and concrete ways forward for teaching PGx for global personalized medicine in LMICS and beyond. To the best of our knowledge, our study provides one of the first empirical insights into the current status of PGx teaching in LMICs.

Organic anion transporting polypeptides (OATP/SLCO) 2B1 and 1B3 mediate the cellular influx of androgens. Very few studies have specifically evaluated genetic variation and androgen transport. The aim of this study was to evaluate if human genetic variation in SLCO2B1 and SLCO1B3 genes are associated with the disposition of testosterone and five of its metabolites before and two days after the administration of a single intramuscular dose (500 mg) of testosterone enanthate in healthy volunteers (N=43). Serum concentration of testosterone and its metabolites were determined by GCMS/LCMS. Two functional polymorphisms in SLCO2B1 (rs12422149) and SLCO1B3 (rs4149117) genes were characterized by allelic discrimination. These SNPs have been hitherto shown to markedly affect the cellular uptake of hormones and hence, they were selected. Individuals homozygous for the SLCO2B1 G-allele displayed lower levels of total testosterone prior to (5.09 ng/ml) and two days after (13.58 ng/ml) testosterone injection, as compared to individuals expressing the A-allele (6.01 ng/ml and 21.88 ng/ml, respectively) (p=0.05 and p=0.002, respectively). Moreover, the concentration of the testosterone metabolites (dihydrotestosterone (DHT), androsterone, 5α-androstane- 3α,17β-diol-17-glucuronide) were significantly lower in subjects with GG genotype at 48 hours post-dose. Individuals homozygous for the SLCO2B1 G allele had a smaller increase in serum testosterone and DHT levels (0.03-fold/kg and 0.02-fold/kg) compared to carriers of the A allele (0.05-fold/kg and 0.03-fold/kg) (p=0.04 and p=0.02, respectively). The SLCO1B3 polymorphism did not show any significant association with serum testosterone levels or the other androgens metabolites investigated. In conclusion, here we report, for the first time to the best of our knowledge, that genetic variation in SLCO2B1 gene impacts the systemic concentrations of testosterone and some of its metabolites, after administration of a single-dose testosterone enanthate. These data also serve as a foundation to examine in the future the role of human genetic variation in SLCO2B1 in relation to testosterone pharmacokinetics, particularly in the context of sports medicine and doping testing or clinical use as a replacement therapy.

Personalized medicine has been defined as the tailoring of medical treatment based on individual patient characteristics. In practice, personalized medicine generally involves the stratifying of patient populations based on biomarkers, most frequently genetic in nature. This results in patient subpopulations likely to show differential responses to drug therapy in terms of efficacy and toxicity. While the potential for personalized medicine to positively impact on drug discovery and therapeutics has been widely hyped, clinical uptake has been markedly limited. Over the recent years, a number of potential barriers to the more widespread uptake of personalized medicine have been identified. These include technical, economic and social factors. One such barrier is the need for the significant up-skilling of health professionals in order to harness the potential of personalized medicine and ensure adequate information flow to consumers. Pharmacists are ideally positioned to be active participants in personalized medicine but to date, their role has been minimal. While the reasons are multifactorial, we argue that there is a clear need for significant reforming of current pharmacy curricula. Here we review progress in worldwide pharmaceutical education and practice relevant to global personalized medicine and public health pharmacogenomics and highlight salient points for future consideration.

Novel diagnostics R&D in public health and personalized medicine hold great promise as tools to speed up the translation of results from bench to bedside for selecting and optimizing treatment and health outcomes for each person. Although the integration of individualized medicine into clinical decision making is still evolving, accumulating evidence reveals that genetic and genomic information could help predict clinical drug response and adverse drug reactions for drugs in patients with certain diseases. This article first gives a brief overview of selected diagnostics R&D studies in Taiwan for antipsychotic treatments, antidepressant responsiveness, sibutramine therapy, chronic hepatitis C therapy, and other various treatments of significance for public health in Taiwan, with consideration of genetic and genomic variants. For example, the interactions of two insulin-induced gene (INSIG) biomarkers, designated INSIG1 and INSIG2, were found to be associated with metabolic syndrome in schizophrenic patients treated with antipsychotics. Recent advances in pharmacogenomics and personalized medicine studies conducted in Taiwanese populations and attendant novel computational approaches are highlighted here, with a view to public and population health in the country and the Asia- Pacific region where there are extensive investments in genomics and postgenomics diagnostics R&D. Finally, we address a discussion of future directions and some of the most pressing computational challenges in data-intensive life sciences owing to the combinatorial explosion of ever larger data sets. Anticipating and addressing these emerging issues in public health genomics are of great relevance not only for Taiwan but also for the Asia-Pacific and global health.

It is increasingly common for patients to use western medications concurrently with Traditional Chinese Medicine or other herbal medicines. Indeed, it is estimated that one-third of people in developed countries are using alternative therapies including herbal medicines. Metabolism of drugs/herbs takes place to a large extent in the liver and small intestine via various drug-metabolizing enzymes. Therefore, the concurrent use of western and herbal medicines has potential for drug-herb interactions at these biological locations. There are several hepatic metabolic enzymes and drug transporters that have been documented to be involved in the herb-drug interactions. These include the cytochrome P450 (CYP450) enzymes that contribute to metabolism of various drugs, food constituents, and herbs, and the ATPbinding cassette (ABC) transporters, particularly P-glycoprotein (P-gp), and solute carrier (SLC) transporters. Pharmacogenetic variance in CYP450s and drug transporters in humans and animals may lead to pharmacokinetic and pharmacodynamics changes of target substrates which could be drugs and/or herbal medicines. This paper presents a synthesis of the emerging evidence on the role of pharmacogenetics in the mechanism of the salient herb-drug interactions, and why the time has come to consider integrating this new strand of postgenomics knowledge to clinical and public health practice.