Current Pharmacogenomics and Personalized Medicine - Volume 11, Issue 3, 2013

Pharmacogenomic technologies can potentially be beneficial to patients and healthcare providers alike. Decision-makers allocating finite healthcare budgets require robust and timely evidence to support the cost-effectiveness of pharmacogenomic technologies. This paper describes the use of the quality adjusted life year (QALY) to inform decision-making drawing on the examples of National Institute for Health and Care Excellence (NICE) technology appraisals of pharmacogenomic technologies in the UK. Importantly, the paper explains two theoretical viewpoints that underpin the two main types of economic analysis: cost benefit analysis and cost-effectiveness analysis. The advantages and disadvantages of QALYs are discussed together with potential options for moving beyond the QALY such as the use of the capability approach and willingness to pay methods. However, the paper concludes that most health economists, as providers of information for societal decision-making, are probably not yet ready to depart from the QALY to inform resource allocation in the context of pharmacogenomic technologies.

Genome sequencing technology is the basis of personalized genomic medicine and expansion of this technology will likely lead to widespread personalized medicine. Innovation in the highly competitive biotechnology industry is leading to a substantial decline in the price of whole genome sequencing, which will increase access to this technology. Also, the US National Institutes of Health recently invested $25 million in newborn genome sequencing, which will substantially increase the number of newborns and thereby parents with genome sequence data, albeit in research studies. These concurrent events are likely to stimulate an era of personalized medicine that begins at birth. This era has come faster than expected by scientists, policymakers, ethicists, and clinicians. In order for newborn genome sequencing to proceed in a manner that maximizes its benefits, countries need to consider key ethical, social, and legal implications of this technology, which are likely to affect its uptake and impact on their societies – namely patent protection of DNA, reimbursement, genetic discrimination, and equitable distribution of the technology. In this article, the authors review these challenges and assess whether countries are prepared to address them. With an adequate understanding of these issues, policymakers worldwide—advised by experts and their citizenry—can develop welldesigned policies that increase the societal benefits of newborn genome sequencing and limit any potential harm to their societies.

Dual antiplatelet therapy with aspirin and clopidogrel is a standard care to reduce the risk of recurrent cardiovascular events in patients with acute coronary syndrome (ACS). The dual treatment has demonstrated substantial benefit in patients undergoing percutaneous coronary intervention (PCI) and stent implantation. Despite adequate treatment, major adverse cardiovascular events (MACE) occur in about 10% of patients on dual antiplatelet therapy. Genetic variants in CYP2C19 gene have been associated with residual platelet reactivity on-clopidogrel treatment and adverse outcomes in high risk vascular patients. The introduction of pharmacogenetic tests, in addition to platelet function test, could provide the clinician with an additional tool to make decisions on differentiated therapeutic strategies, tailored antiplatelet therapy, modeled on the individual characteristics of the patients, amplifying the concept of “personalized medicine”. The use of genetic test for the identification of CYP2C19*2 and other polymorphisms involved in the pharmacogenetics of clopidogrel could thus be useful to improve the risk stratification of patients, guide clinicians in the choice for alternative antiplatelet therapy, and therapeutic management of patients, and consequently to reduce the occurrence of MACE in patients with ACS. Rapid point of care genetic tests would be desirable to allow cardiologists and primary care physicians to obtain a rapid genetic profile of patients under treatment and integrate this information in an accurate predictive algorithm to achieve truly antiplatelet personalized care. This expert review provides an analysis of the currently available biotechnologies for clopidogrel pharmacogenetics testing and what we can anticipate in the near future for personalized medicine.

Although the harmful health effects of smoking are well-known, roughly fifth of mankind is still smoking. Because quitting smoking is difficult mainly due to the addictive effect of nicotine, several attempts have been made to ease this in the smoking cessation process. These attempts have been complicated by existence of a substantial variability in the nicotine addiction and relapse times, shown to be attributable to both environmental and genetic factors. The new emerging means like personalized medicine are hoped to help in overcoming the obstacles caused by the inherited factors in the treatment of tobacco dependence. The personalized treatment of smokers would be cost-effective, safe from gratuitous medicine taking and would improve the success rate of long term abstinence, which all can be enabled by the means of genetic studies. The impact of genetic factors on individual response to smoking cessation treatments has therefore been of great interest during the recent years. The focus of these studies has been on relationship between candidate gene polymorphisms and individual differences in smoking behavior and ability to quit smoking, especially considering the impact of multiple genetic variants of some smoking-related pathway on both nicotine dependence and individual response to smoking cessation treatments. This expert review summarizes the present knowledge on the genetic factors in smoking addiction and the potential of this knowledge to advance the future smoking cessation actions.

Personalized medicine applies knowledge about the patient’s individual characteristics in relation to health and intervention outcomes, including treatment response and adverse side-effects, to develop a tailored treatment plan. For women with breast cancer, personalized medicine has substantially improved the rate of survival, however, a high proportion of these women report multiple, co-occurring psychoneurological symptoms over the treatment trajectory that adversely affect their quality of life. In a subset of these women, co-occurring symptoms referred to as symptoms clusters, can persist long after treatment has ended. Over the past decade, research from the field of nursing and other health sciences has specifically examined the potential underlying mechanisms of the psychoneurological symptom cluster in women with breast cancer. Recent findings suggest that epigenetic and genomic factors contribute to inter-individual variability in the experience of psychoneurological symptoms during and after breast cancer treatment. While nursing research has been underrepresented in the field of personalized medicine, these studies represent a shared goal; that is, to improve patient outcomes by considering the individual’s risk of short- and long-term adverse symptoms. The aim of this paper is to introduce a conceptual model of the individual variations that influence psychoneurological symptoms in women with breast cancer, including perceived stress, hypothalamic-pituitary adrenocortical axis dysfunction, inflammation, as well as epigenetic and genomic factors. The proposed concepts will help bring nursing research and personalized medicine together, in hopes that this hitherto neglected and understudied area of biomedical research convergence may ultimately lead to the development of more targeted clinical nursing strategies in breast cancer patients with psychoneurological symptoms.

Abacavir hypersensitivity reaction (ABC-HSR) is associated with the presence of HLA-B* 57:01 allele. Alternative tests for ABC-HSR associated allele determination are needed where sequence-based HLA typing is not available, particularly in resource-limited settings or developing countries. This study focused on the development and evaluation of two HLA-B* 57:01 tagging SNPs (single nucleotide polymorphism) HCP5 (HLA complex P5) rs2395029 and TNF (tumor necrosis factor) rs3093726 genotyping assays. Two hundred and thirteen purified genomic DNA samples were used to evaluate the performance characteristics of a HLA-B* 57:01 screening method based on allele-specific polymerase chain reaction (AS-PCR) with melting curve analysis. HCP5 rs2395029 and TNF rs3093726 were also genotyped using simple probe real-time PCR assay. All samples were successfully genotyped wherein AS-PCR genotyping provided 100% sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) when compared with specific HLA-B status by sequencing based assay. When comparing the AS-PCR screening method with the HCP5 rs2395029 and TNF rs3093726 genotyping method, the former had 100% sensitivity, 100% specificity, 100% PPV and 100% NPV using a simple probe; while the latter one had 95.24% sensitivity, 100% specificity, 100% PPV and 99.48% NPV, respectively. In conclusion, our study lends support on a molecular tool for pharmacogenetic screening in resource-limited settings. Thus, serious drug hypersensitivity associated with ABC may potentially be reduced in Thailand by further evaluation of the proposed assay in clinical practice.

The cytochrome P450 (CYP450) enzymes play a key role for interindividual variability in drug response. No comprehensive pharmacogenetic data are yet available for the Rwandan population in regards to single nucleotide polymorphisms in CYP450s of major importance for personalized medicine. This study investigated the genotype and allele frequencies with respect to relevant SNPs for CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 genes in Rwandan subjects (n=80). Results were compared with data from South African and Cameroonian populations using Pearson’s Χ 2 and Fisher’s Exact statistical tests. Genetic variation was observed in 11 out of the 13 SNPs in the above CYP450 genes. There were significant differences in the distribution of the allelic variants when the Rwandan sample was compared to the Cameroonian and the South African groups, with respect to CYP2A6 1093G>A SNP (P=0.0033 and 0.019, respectively) and CYP3A4 -392A>G SNP (P=0.0001 and 0.0084, respectively). The distribution of the CYP1A2 -163C>A SNP differed between the Rwandans and the South Africans (P=0.0001), and CYP3A5 6986A>G SNP between the Rwandan and the Cameroonian subjects (P=0.017). The polymorphisms CYP2B6 516G>T and 785A>G did not show significant differences (P>0.05) between the Rwandans, Cameroonians and South Africans in the distribution of the 516T and the 785G variants. This is the first study evaluating the allele and genotype frequencies of these key CYP450 genes in Rwandan subjects. The results demonstrate the need to further characterize individual African populations with respect to genetic variations in order for personalized medicine to be realized among Africans. These data will also help illuminate the future planning of pharmacodynamic studies aimed at associations of these pharmacogenetic variants with drug safety and efficacy in Rwanda.

Sex-dependent and population differences in the activities of cytochrome P450 enzymes affect the metabolism of many xenobiotics, including drugs. The proton pump inhibitor omeprazole is widely prescribed in many countries that call for population studies of its disposition. Omeprazole is metabolized by CYP2C19 and CYP3A4, resulting in the formation of 5-hydroxyomeprazole and omeprazole sulfone, respectively. This study examined the sex-differences in CYP2C19-, and CYP3A4-mediated metabolism of omeprazole in an understudied population in Turkey. Data were obtained from 107 healthy unrelated subjects (51 females and 56 males; heterozygous and homozygous extensive metabolizers (EMs) in regard to CYP2C19) from a recent study on the relationship between CYP2C19 genotype and phenotype, using a single oral dose of 60 mg R,S-omeprazole. The differences in plasma concentrations of racemic omeprazole, its R- and S-enantiomers, 5-hydroxyomeprazole, and omeprazole sulfone as well as the metabolic ratios of omeprazole and its enantiomers were compared between females and males. We also examined the parameters mentioned above in homozygous EM (CYP2C19*1/*1) subjects (n=90). No significant differences of metabolic ratios (MRs) (omeprazole/5-hydroxyomeprazole (O/OHO), omeprazole/omeprazole sulfone (O/OS), omeprazole plus 5-hydroxyomeprazole/ omeprazole sulfone (O+OHO/OS), omeprazole plus omeprazole sulfone/5-hydroxyomeprazole (O+OS/OHO), and the same ratios for its S-, and R- enantiomers) were found between females and males in the homozygous EM group, except a trend for difference of the O+OS/OHO (P=0.061), RO+OS/OHO (P=0.047) and SO+OS/OHO (P=0.072) MRs, which was higher in females. In the heterozygous plus homozygous EMs with regard to CYP2C19, the MR of O+OS/OHO (P=0.059) was borderline higher in females, while the O+OHO/OS (P=0.009) MR was higher in males. Similar results were found for MRs of R-, and S-omeprazole (RO+OS/OHO, P=0.040; SO+OS/OHO P=0.018; RO+OHO/OS, P=0.005; SO+OHO/OS, P=0.007). There are sex-related differences in the MRs of omeprazole and its R-, and S- enantiomers, also suggesting that females have a higher CYP3A4, but a slightly lower CYP2C19 activity compared to males in healthy Turkish subjects.