Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 10, Issue 4, 2012

Although personalized medicine is not a new concept, recent advances in OMICS technologies and highthroughput discovery of biomarkers have taken this goal to greater heights as well as challenges, particularly from the perspective of globalized post-genomics science. The crucial question is to what extent developing countries can participate in this nascent healthcare facet in the 21st century? In Iran, this issue is even more challenging due to several cross-cutting factors such as inadequate financial and skilled human resources and importantly, sanctions on the import of a wide array of technologies that have seriously affected advanced proteomic instruments such as mass spectrometry. Apart from these barriers, another drawback is the inadequate incorporation of high-throughput data into cancer clinical settings. The available instruments in Iran are essentially limited to the level of two-dimensional gel electrophoresis equipment. However, opportunity still exists for collaboration with proteomic centers equipped with mass spectrometry abroad while local scientists contributing to proteomics study conception, design and implementation. In this article, we discuss the current OMICS data-intensive research conducted in Iran, with a view to “proteomics-in-oncology”, considering in parallel the effects of international sanctions on the ongoing research in the country. The lessons learned have broad importance to inform the global personalized medicine scientific community on the ways in which postgenomics science is presently making strides in resource-limited settings.

This feature article provides an overview of the nascent field of pharmacoproteomics, its definitions and role in personalized medicine, and the specifications of pharmacoproteomics in developing countries. The “ideal world view” is outlined on the opportunities for pharmacoproteomics in the developing countries, for example, research in the fields of neglected tropical diseases and the potential merger of traditional holistic eastern medicine approaches and the practice of personalized medicine. An innovation analysis is performed on the distribution of pharmacoproteomics publications across the countries, and the types of publications (original research versus reviews). Pharmacoproteomics publications in the developing countries are analyzed in further detail, revealing the lower percentage of original research and higher percentage of reviews illustrating both the intention to develop pharmacoproteomics and the limitations in resources and access to the high-end proteomics instrumentation.

Predicting individual response to drug therapy has long been a goal of personalized medicine in every therapeutic area. The mapping of the human genome and subsequent advancements in genetic technology had raised the public expectation that personalized drug therapy would come sooner than later. However, with barriers and logistical challenges existing at multiple levels, achieving this goal remains years away. Knowledge gap in healthcare professionals has always been cited as a significant barrier in clinical implementation of pharmacogenomics. Yet, to overcome the spectrum of challenges and for personalized medicine to succeed, there needs to be a rethinking of expanding the educational scope to include all stakeholders within the personalized medicine innovation ecosystem, rather than “narrowly” focusing on simply educating current and future health practitioners. Personalized medicine can only be achieved with all stakeholders in the field, under the rubric of a vision of a “knowledge ecosystem”, working together, and occasionally accepting a paradigm change in their current approaches to implementation. If postgenomics personalized medicine is to embrace systems pharmacology as a core tenet, it seems essential that such broader vision should be extended to field of education as well.

CYP2D6 is involved in the metabolism of antidepressants drugs and of the endogenous neurotransmitter serotonin. We have previously shown an increased number of CYP2D6 active alleles, indicative of higher enzyme hydroxylation capacity, among patients with eating disorders. From a population genetic heterogeneity standpoint, there is a need to extend this line of inquiry to populations hitherto understudied. Moreover, because environmental factors do vary regionally, genetic/pharmacogenetic studies need to be broadened in different populations. In this study, we tested the role of CYP2D6 activity variation in a sample of women with regard to their risk of eating disorder symptoms from Havana, Cuba. Subjects, recruited from university students and staff with no prior history of psychopathology or psychotropic treatment, completed the Eating Disorder Inventory (EDI) (N=159). Subjects' CYP2D6 genotypes and phenotypic activity (debrisoquine metabolic ratio, MR) were determined. All subjects were at low-risk for “EDI-global”, “drive for thinness” or “body dissatisfaction” but 47.7% were at moderate-risk for “EDI-bulimia” in this sample. This moderate risk group for bulimia symptoms displayed a higher number of phenotypically ultrarapid (MR<0.1), and a lower number of poor metabolizers (MR>12.6), compared to the “EDI-Bulimia” low-risk group in the sample (p<0.01). To the best of our knowledge, this is the first study regarding this phenotype, which lends further support to prior observations on an association between CYP2D6 activity and risk of eating disorders.

Alterations in serotonin availability, levels and function have been shown to affect drug consumption patterns, behavior and responses to treatment. Despite the existence of health burdens related to drug dependence in resourcelimited settings outside the realm of developed countries, there have been relatively few public health pharmacogenetics studies focusing on drug dependence in developing countries outside Europe and North America. This study examines the influence of SLC6A4 gene polymorphisms (5-HTTLPR and rs25531) on clinical and biological outcomes of drug dependence in patients of Arab descent in a sample from Jordan. PCR-RFLP based genotyping of the 5-HTTLPR gene variants (LL/LS/SS) and rs25531 marker polymorphisms (A/G) was performed in 192 drug dependent patients of Arab descent. These patients were undergoing an 8-week pharmacological and behavioral inpatient treatment program. In treatment, end of treatment and follow-up outcome measures included changes in drug consumption and alcohol intake, urine drug screen, alcohol breath test, days in treatment, counselling and self-help group sessions and completion rate. Patients were stratified according to receptor polymorphism using a bi-allelic (Group A: LL versus Group B: SS and LS genotype) and a tri-allelic approach (Group A': LA/LA versus Group B': non-LA/LA genotype). Bonferroni corrections were applied for multiple comparisons. There were no significant differences between genotype subgroups regarding severity of drug dependence, psychiatric status, past history, medications (p> 0.1). However, the frequency of drug use, reduction in heroin consumption and alcohol intake and responsiveness to treatment were significantly different for the LL, LS and SS genotypes (p< 0.05). In addition, assuming a dominant effect of S(Group A versus Group B), a significant difference in the age of first drug use was observed (p< 0.05). Notably, patients with the LL genotype were younger when they first used drugs. Group A' compared to Group B' showed a significant difference in age of first use, drug use frequency and detoxification with higher averages in patients who were carrying the LA allele (p < 0.05). To the best of our knowledge, this is the first study of serotonin transporter polymorphisms (5-HTTLPR and rs25531) and the clinical and biological outcomes of drug dependence in patients of Arab origin. We conclude with a discussion of these findings with a view to the emerging nascent field of “public health pharmacogenetics”, and personalized medicine diagnostics for rational treatment of drug dependence as seen through the lens of global postgenomics science.

Visceral leishmaniasis is a vector borne parasitic infection caused by Leishmania donovani or Leishmania infantum, mostly in poorer sections of the population in endemic areas. More than 90% of the cases occur in just six countries, namely, Bangladesh, Brazil, Ethiopia, India, Nepal and Sudan. In the Indian subcontinent where the disease is caused by infection with L. donovani, man is the only host. Hence, the key to eradication of this disease is the proper treatment of the cases and the prevention of spread. Moreover, untreated visceral leishmaniasis is always fatal. The diagnosis of the infection involves invasive procedures. Adverse drug reactions for existing drugs are severe and drug resistance is an increasing problem. There is an urgent need for an early diagnosis of this infection. Equally important is the discovery of effective treatment methods with less or no side effects. The advent of genomics and proteomics has bestowed us with powerful theoretical and experimental tools. These have opened us vistas, which we previously thought as practically impossible to explore. We know now that there are many host alleles, which can attenuate the severity of the disease. Patients carrying these alleles must have different treatment mode than the other patients. Identification of these patients is within the realms of proteomics. Serum immune proteomics have identified many antigens, which can serve as future vaccination candidates. Proteomics reveals the differential protein expression in the infected serum. Genomics differentiates the host and pathogen genes. Both of these “Omics” approaches are complementary. Their strength is that these tools identify the global differential expression enabling disease markers as well as the individual variations enabling personalized medicine. Genomics and proteomics, therefore, have much to offer for advancement of the juxtaposed goals in therapeutics and diagnostics (i.e., theranostics) for visceral leishmaniasis, and neglected diseases of importance for global public health.

Particulate matter (PM) air pollution exerts significant adverse health effects in global populations, particularly in developing countries with extensive air pollution. Understanding of the mechanisms of PM-induced health effects including the risk for cardiovascular diseases remains limited. In addition to the direct cellular physiological responses such as mitochondrial dysfunction and oxidative stress, PM mediates remarkable dysregulation of gene expression, especially in cardiovascular tissues. The PM-mediated gene dysregulation is likely to be a complex mechanism affected by various genetic and non-genetic factors. Notably, PM is known to alter epigenetic markers (e.g., DNA methylation and histone modifications), which may contribute to air pollution-mediated health consequences including the risk for cardiovascular diseases. Notably, epigenetic changes induced by ambient PM exposure have emerged to play a critical role in gene regulation. Though the underlying mechanism(s) are not completely clear, the available evidence suggests that the modulated activities of DNA methyltransferase (DNMT), histone acetylase (HAT) and histone deacetylase (HDAC) may contribute to the epigenetic changes induced by PM or PM-related chemicals. By employing genome-wide epigenomic and systems biology approaches, PM toxicogenomics could conceivably progress greatly with the potential identification of individual epigenetic loci associated with dysregulated gene expression after PM exposure, as well the interactions between epigenetic pathways and PM. Furthermore, novel therapeutic targets based on epigenetic markers could be identified through future epigenomic studies on PM-mediated cardiopulmonary toxicities. These considerations collectively inform the future population health applications of genomics in both developing and developed countries while benefiting global personalized medicine at the same time.

Warfarin is an oral anticoagulant used worldwide for prevention and treatment of thromboembolic disorders. Marked inter-individual responses to warfarin have been a mainstay challenge to optimal prescription of warfarin. More recently, clinical pharmacogenomics studies of warfarin have categorized patients into low- and high-dose groups, in part by associating warfarin dosing with patients' genomic variation. It is expected that post-genomics methodologies such as pharmacoproteomics, by analyzing differentially expressed proteins, will provide additional insights on mechanisms of warfarin dosage variations. As thromboembolic disorders are vastly prevalent in both the developed and the resourcelimited countries, warfarin studies in western countries should be complemented by those in the Asia-Pacific region so as to account for global variations in the human genome and proteome, not to mention the diverse regional differences in environmental exposures. This paper offers an introduction to personalized warfarin dosing, followed by current advances in warfarin pharmacoproteomics. Furthermore, the biotechnology associated with pharmacoproteomics is discussed, as well as a brief summary of approaches to warfarin therapy in the Asia-pacific region. Finally, trends on recent miniaturization of pharmacoproteomics and other “-omics” applications in pharmacology are offered as a future outlook in this nascent field of post-genomics medicine and personalized therapeutics.