Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 12, Issue 2, 2014

The interest in personalized medicine, together with the search for good genetic biomarkers that predict the individual response to drugs, has increased during the last decades. Several decades have passed since the first description in the 1950’s of variability in the clinical response of patients but still today the use of pharmacogenetics in clinical practice is not a reality worldwide. This is particularly far from happening in developing countries, where the cost of genetic testing is higher than the cost of food or treatment for common diseases. Pharmacogenetics in Africa has focused almost entirely on the description of frequencies of known genetic variants in enzymes related with drug metabolism. The Zanzibar islands are one of the areas where such genotypic information is available. Cytochrome P450 2C8 (CYP2C8) genetic variability was described in the Zanzibar population in 2005, in a study that raised for the first time the hypothesis that the genetic variation of the CYP2C8 gene could be connected with the interindividual variability observed in the clinic outcome of malaria patients treated with amodiaquine. Moreover, this study also raised the possibility that slow metabolizers (CYP2C8*2 and 2C8*3 carriers) of amodiaquine could be more prone to develop side effects after treatment. Other studies followed that addressed these specific aspects in malaria chemotheraphy, but general pharmacogenetic studies were also performed in other African countries. The information available today can be used to help health authorities and agencies to establish guidelines that will increase the awareness for toxicity or efficacy issues in drug administration at a regional or national scale. With the development of affordable genotyping methods this reality could change in developing countries and pharmacogenetics could be used in clinical practice to provide individual therapy, leading to better treatment of patients.

Blood pressure responses to antihypertensive drugs vary widely between individuals. Certain phenotypic factors may predict some drug responses such as plasma renin activity (PRA) as an indicator of activation of the reninangiotensin- aldosterone system. Higher PRA levels may predict better average responses to angiotensin converting enzyme inhibitors, angiotensin receptor blockers or β-blockers. Conversely, high salt intake or salt sensitivity may predict a better response to diuretics and calcium channel blockers. Genetic factors influencing the pharmacokinetics of specific drugs through enzymes or transporters or the pharmacodynamics of drug classes through receptors or pathways involved in the mechanism of drug action can also affect blood pressure responses, but the effects of most candidate genes are limited. Furthermore, the need to choose the most effective first-line antihypertensive agent becomes less critical with the awareness that most hypertensive patients will require a combination of drugs and drug combinations with complementary modes of action should help to overcome the major mechanisms driving hypertension. However, there may be situations where genotypes in pathways that may not be directly related to the blood pressure lowering effect may predict cardiovascular benefits with certain drugs. Currently, there are probably no genetic factors which dictate the use of a particular antihypertensive drug, except in some of the rare monogenic causes of hypertension. With the rapid expansion of pharmacogenetic knowledge, this situation is likely to change and specific targeted treatments may be selected based on combined genetic and phenotypic factors for individualizing long-term therapy for hypertension.

In this manuscript, we review the literature on the nutrigenetics and pharmacogenetics of vitamin D pathways, with a focus on genes involved in the pharmacokinetic and pharmacodynamic pathways of vitamin D as they have been major research targets. These include: VDR, CYP2R1, CYP27B1, DHCR7/NADSYN1, GC and CYP24A1. So far only 2 genome wide associations studies evaluated the potential role of genetic polymorphisms in the variability in 25 hydroxy vitamin D (25(OH)D) levels. Most of the evidence is based on the candidate gene approach with some conflicting results when it comes to effect size and associating disease outcome with 25(OH)D levels and genetic polymorphisms. Moreover, very little has been done to look at the effect of significant polymorphisms on the response to vitamin D supplementation. Further research is needed on larger population samples of different ethnicities to resolve some of the controversies. In addition, emerging technologies such as next generation sequencing may be a better genotyping alternative in order to detect rare but potentially important genetic variants. Functional studies are also needed to better understand the association results. This includes coupling genotyping data with gene expression studies as well as epigenetic evaluations.

While many would argue that personalised medicine has a long history, the era of modern deployment dates only to hormone-receptor guided tamoxifen therapy and growth-factor receptor guided Herceptin therapy in the 1990s and has been rather sporadic in the intervening years. From this uneven beginning, global adoption remains modest, with wide variations in availability of testing and associated therapy. Indeed, while over 120 U.S. Food and Drug Administration (FDA)-approved drugs have pharmacogenomics information in their labelling, most such labelling is informational, and there are today only 6 distinct “companion” markers cleared by FDA as in vitro companion diagnostic tests mandated for the safe and effective use of the corresponding therapy (HER2, CKIT, EGFR, KRAS, BRAF, ALK). Approval and availability of such companion tests with a 1:1 therapeutic relationship is only the beginning, however. “High value” diagnostic tests with indirect relationships to therapeutics and next generation multi-omic tests with higher predictive precision have even lower availability in global markets. Scientific and regulatory hurdles are only part of the underlying challenge. In an increasingly constrained global healthcare environment, heath-technology assessment and deployment models assume equal significance, and various models have emerged across the US and EU to accelerate market access. Some recent trends and best practices include use of adaptive clinical trial designs, pragmatic application of regulations, new Health Technology Assessment and reimbursement models, and emergent quality assurance practices. This article will review some of these prevailing global best practices for the deployment of personalised medicine, extract some general learnings, and draw some inferences for global markets, including emerging regions.

The increase in mean corpuscular volume (MCV) is the hematological parameter that better correlates with clinical improvement in sickle cell patients taking Hydroxycarbamide (HU). The mechanism by which HU increases erythrocyte MCV is still unclear. It could be due to megaloblastic changes in the bone marrow cells by the action of HU. To test our hypothesis, morphological, morphometric and cytometric analyses in bone marrow (BM) and peripheral blood (PB) cells of sickle cell patients were performed. Bone marrow smears showed signs of megaloblastic change, such as megaloblasts, red cells with open chromatin nuclei, hypersegmented neutrophils, giant metamyelocytes, and hypersegmented megakaryocytic nuclei. Morphometry showed a significant increase in cell surface area of blood cells in the HU group. In conclusion, we showed for the first time that HU causes megaloblastic change of the bone marrow cells of sickle cell patients and increases the MCV and the cell surface area, mechanisms that may reduce the polymerization of HbS molecules and the adhesive phenotype of sickle erythrocytes. This finding may shed light on the mechanisms of action of HU in sickle cell disease, helping in the search of new drugs and more personalized treatment for these patients.

Despite the rapid development of pharmacogenetic testing and the frequencies of medication related emergencies increasing, pharmacogentic testing is not yet implemented extensively in clinical practice. Several studies document that polymorphic Cytochrome P450 isoenzymes CYP2C9, CYP2C19 and CYP2D6 are responsible for the metabolism of many clinically important drugs and xenobiotics. These polymorphisms contribute to inter-individual and interethnic variation in drug metabolism which may lead to differences in drug response, suggesting that common dose regimen will not always equivocate to efficacious dosing. The CYP2D6*2, CYP2D6*4 and CYP2D6*10 variants were studied in four Indian populations (Gujarati, Punjabi, Bengali and Koya tribe). Genotypes at individual alleles were identified using Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) method. Differences in frequencies of CYP2D6 genotypes/ alleles were compared at regional and global level. CYP2D6*2 variant frequency was highest among Gujarati population (47%) Gujarati and Punjabi populations showed high levels of CYP2D6*4 (13% and 24% respectively), whilst high levels of CYP2D6*10 were found in Bengali and Koya populations (21% and 12% respectively). At genotypic level, CYP2D6 *4/*4 genotype was absent in all study populations, resulting in the absence of the PM (poor metaboliser) phenotype in these samples. Overall there are significant differences among Indian populations at this locus. Overall observed allele frequency spectrum fits well into other Indian and European populations. There are significant differences in CYP2D6 allele and genotype frequencies in 4 populations leading to differential estimates of EM and IM. These results suggest the importance of delivering pharmacotherapeutic regimes for patients on the basis of their genetic profile.