Current Pharmacogenomics and Personalized Medicine - Volume 10, Issue 1, 2012

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Traditional Chinese Medicine (TCM) is a range of medical practices and health interventions used in China for more than four millennia. While TCM continues to impact healthcare and population health in the Asia-Pacific, it has also received growing attention globally over the last decade. This paper argues that we are currently at a critical junction to accelerate both TCM and its evidence base with the availability of genomics as well as postgenomics technologies such as functional proteomics. On the one hand, TCM stands to benefit from such data-intensive omics technologies, for example, by elucidation of the active molecular substrates of TCM and mechanism of herb-herb and herb-drug interactions often encountered in TCM practice with increasing convergence of traditional and western medicine. On the other hand, TCM offers a rich resource for genomics applications such as novel drug target discovery, molecular ascertainment of hitherto unexplained or understudied clinical and pharmacoepidemiology observations in TCM, and deep phenotyping of health outcomes attendant to use of traditional healthcare prevalent in many parts of the developing countries. Ultimately, genomics can help TCM build a stronger evidence-based practice, and a more versatile range of genomics and personalized medicine applications that are closely attuned to the actual practice of global health, including and beyond developing countries. We conclude with an outlook on the enormous promise anticipated from the integration of TCM with genomics as a new driver for novel molecular-targeted personalized medicine, and the future directions and challenges in this hitherto neglected dimension of postgenomics global personalized medicine.

Some empirical studies and recent developments in pharmacokinetic theory suggest that statistical randomeffects linear models are valuable tools that allow describing simultaneously patient populations as a whole and patients as individuals. This remarkable characteristic indicates that these models may be useful in the development of personalized medicine, which aims at finding treatment regimes that are appropriate for particular patients, not just appropriate for the average patient. In fact, published developments show that random-effects linear models may provide a solid theoretical framework for drug dosage individualization in chronic diseases. In particular, individualized dosages computed with these models by means of an empirical Bayesian approach may produce better results than dosages computed with some methods routinely used in therapeutic drug monitoring. This is further supported by published empirical and theoretical findings that show that random effects linear models may provide accurate representations of phase III and IV steady-state pharmacokinetic data, and may be useful for dosage computations. These models have applications in the design of clinical algorithms for drug dosage individualization in chronic diseases; in the computation of dose correction factors; computation of the minimum number of blood samples from a patient that are necessary for calculating an optimal individualized drug dosage in therapeutic drug monitoring; measure of the clinical importance of clinical, demographic, environmental or genetic covariates; study of drug-drug interactions in clinical settings; the implementation of computational tools for web-site-based evidence farming; design of pharmacogenomic studies; and in the development of a pharmacological theory of dosage individualization.

Pharmacogenomics has long attempted to identify genome-drug interactions and environmental exposures as guideposts for personalized medicine. However, non-drug related environmental factors, too, can interact with the host genome and potentially cause confounding in explaining drug-genome interactions. One such environmental factor that has been bracketed out in the past is the ambient temperature change, and ways in which it can influence genomic plasticity. Indeed, recognition of temperature is an important element of microsensory perception that allows cells to evaluate both their external environment and internal physiological milieu. In this paper, we report the changes in global gene expression three hours after a 30-min cold temperature (10°C) treatment in the human bronchial epithelial cell line BEAS-2B using DNA microarrays. We found 11,276 candidate genes (6,297 with increased, 4,979 with decreased expression) that were differentially expressed after low-temperature treatment of BEAS-2B compared to the untreated control cells (p<0.001). Additionally, up- and down-regulated transcription factor genes were further verified using realtime polymerase chain reaction. We found expression changes in response to cold temperature in transcription factor genes such as ZXDA, ZNF44, ZDHHC13, ZNF423, ZFYVE20, ZNF45, ZC3HAV, ZCCHC5, RUNX1T1, DMRT1, STAT4, EFCAB1 and HSFX1 that can alter the temperature-adaptive responsiveness of the bronchial epithelial cells. In summary, we herein show that a moderately cold temperature induces a genome-wide response in the human bronchial epithelial cell line BEAS-2B, and further discuss its relevance for pharmacogenomics and upstream drug discovery. For example, these observations provide a new crucial putative link between ambient temperature and genomic plasticity that together inform personalized medicine such that future pharmacogenomics biomarker discovery research can better control and account for ever-present dynamic environmental exposures such as ambient temperature. We conclude with the implications of these data in relation to rational drug design for neuropathic and other chronic pain syndromes that are in part moderated by host-ambient temperature interactions.

The health burden resulting from parasitic and infectious diseases such as HIV/AIDS, tuberculosis and malaria, requires that available medication and limited healthcare resources be used optimally. However, due to co-morbidities, patients are often exposed to many drugs concurrently. Most of these drugs are metabolised by similar enzymes which are polymorphic, thus, drug-drug interactions are a constant problem. Quantitative and qualitative differences in drug metabolizing enzyme variants in different populations result in differential drug response. This study investigated the baseline frequencies of genetic variants in key drug metabolizing cytochrome P450 enzymes, CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 in two previously understudied Bantu-speaking populations from Cameroon (N=72) and South Africa (N=163) using PCR-RFLP. Genotype frequencies for CYP1A2 C-163A and CYP3A4 A-392G single nucleotide polymorphisms (SNPs) were significantly different between these two populations (P=0.0004 and 0.0079, respectively). Significant differences were also observed when the two Bantu-speaking populations were each compared to other African populations as well as Caucasian and Asian populations. Importantly, correspondence analysis showed that the two Bantu-speaking African populations were separated from each other and from other African populations based on CYP1A2 C-163A and CYP2A6 G1093A SNPs. The data show that drugs that are substrates for these polymorphic enzymes are likely to have different response profiles among the Bantu-speaking populations and populations of either Caucasian or Asian origin, further emphasizing the need to genetically characterise as many African populations in order to realize personalised medicine. These data further emphasize that linguistically related Bantu-speaking populations are not necessarily genetically homogenous. Finally, we note that our observations also inform future pharmacogeneticguided rational therapeutic drug monitoring to prevent or minimize the risk for adverse drug-drug interactions mediated by these genetically polymorphic pathways.

Janus Kinases (JAKs) and Signal Transducer and Activator of Transcription proteins (STATs) are central mediators of cytokine and growth factor signaling pathways that are constitutively active in several cancers and play an important role in cancer progression. Glioblastoma multiforme (GBM; WHO grade IV) is the most commonly occurring brain tumor with very poor prognosis, limited options of treatment and a median survival of 12 to 16 months. The objective of this study was to investigate the transcriptional expression of JAK/STAT candidate genes, their regulators and interactors in post-surgical GBM tissue specimens and normal/non-neoplastic brain, using the global expression data in gliomas from two data series (GSE10878 and GSE19728) obtained from GEO datasets. The raw dataset was analyzed using GeneSpring GX11 software and expression data were obtained for JAK/STAT and other pertinent functionally related genes in GBM and normal tissue. Prior to the microarray data analysis, we built a comprehensive JAK/STAT interactome that brought into perspective all of the associated molecules in relation to cancer pathophysiology. This report represents for the first time, to the best of our knowledge, the transcriptional analysis for almost all the candidate genes, regulators as well as potential interactors of JAK/STAT pathway in GBM from two GEO datasets. Several key genes of the interactome, namely- STAT3, STAT4, STAT5A, STAT5B, TYK2, AKT2, SOCS1, SOCS3, SOCS6, PIAS1, PIAS2, PTPN6 and HIF1A were determined to be differentially expressed in GBM tumor tissues as compared to normal/nonneoplastic brain. Expression of STAT3, STAT4, SOCS3 and PDK1 in GBM tumor tissues with respect to normal brain was validated by qRT-PCR analysis of RNA preparations from tumor biopsies. We found an association of the transcript levels of a few of these genes with favorable prognosis of glioblastoma patients, which may potentially form a basis for future application of JAK/STAT interactome as a target of personalized medicine.

The field of personalized medicine is currently broadening in scope in at least three crucial dimensions. First, while genetics/genomics individual variability is an important aspect of personalized medicine, it is clear that environmental, nutritional, lifestyle and social risk factors play a crucial role for suboptimal therapeutics or disease susceptibility. Second, personalized medicine can inform not only drug therapy but also preventative medicine such that public health interventions that mitigate or prevent disease risks are also customized at an individual and subpopulation level. Third, personalized medicine is now truly global in scope demanding scholarship and innovation analysis beyond the developed countries. In this paper, we critically bring together these three emerging and broader strands of personalized medicine by focusing on prevention of prostate cancer in the developing world. Although prostate cancer prevalence used to be lower in developing countries in the past, this situation is beginning to change rapidly as people living in the developing world transition to a lifestyle more similar to that found in affluent countries. This transition to decreased physical activity, burgeoning overweight/obesity levels, changing nutritional habits, and greater consumption of tobacco, leads to an increased prevalence of non-communicable diseases. There are indications that these changes may also lead to an increase in prostate cancer in low and middle income countries (LMICs). We outline the risk factors associated with prostate cancer, some of the changes that are taking place in LMICs, the reasons behind these changes and the need for personalized or rationally targeted preventative interventions against prostate cancer in LMICs and globally.

In order for the promise of personalised medicine to be realized, a thorough understanding and description of the genetic variants that affect drugs side effects and therapeutic response must be realized for all populations in the world. Although certain populations can have the patterns of genetic variation imputed or extrapolated from other related populations, African populations are too heterogeneous to extrapolate genetic information from one population to the other without missing additional variants of pharmacogenetics relevance. In these early days of 2012, Africa has become the ‘epicenter’ of genomics research investments with the Human Heredity and Health in Africa (H3Africa) Initiative that is accelerating the study of genomics and environmental determinants of common diseases in the African continent. This paper focuses on the status of genomics/pharmacogenomics research in Malawi. The Republic of Malawi is located in Southeast of Africa and its population is made up of eight major native ethnic groups (Chewa or Nyanja, Tumbuka, Yao, Lhomwe, Sena, Tonga, Ngoni and Ngonde) as well as Asians and Europeans. We herein identify a series of gene-centric knowledge gaps that need to be addressed urgently to advance population pharmacogenomics in Malawi. We also underscore the need for research attention and investment in personalized genomics for this African country. The genetic data obtained from the few previous studies show that frequencies of polymorphism in different genes among Malawians are not similar to other African populations, indicating again the need for population specific genomics research across Africa, if the goal of global personalized medicine is going to be achieved equitably for all populations of the world.

The reader will find below the list of expert reviewers who dedicated their time and expertise to the peer-review process of the Journal over the past year. Rigorous, objective and timely peer-review is crucial to sustain the high publication standards of the CPPM. I am glad to take this opportunity to thank the CPPM editors and the reviewers for their availability, promptness and valuable comments that support the editorial goals of addressing the complexities and nuances of pharmacogenomics and personalized medicine for a global readership. If I have failed to acknowledge the efforts of anyone who has reviewed manuscripts in the past year, I apologize. I recognize that great research and truly groundbreaking scholarship may originate anywhere around the globe and in any language. I am always on the look out for qualified expert reviewers and innovative authors with original ideas. Please do not hesitate to write to me about your ideas and manuscripts for rigorous independent peer review.....