Current Pharmacogenomics and Personalized Medicine - Volume 11, Issue 2, 2013

In 1996, the US-based biotechnology company Myriad Genetics began offering genetic diagnostic tests for mutations in the genes BRCA1 and BRCA2, which are linked to hereditary breast and ovarian cancer. Since that time, Myriad has been a forerunner in the field of personalized medicine through the use of effective commercialization strategies which have been emulated by other commercial biotechnology companies. Myriad’s strategies include patent acquisition and active enforcement, direct-to-consumer advertising, diversification, and trade secrets. These business models have raised substantial ethical controversy and criticism, often related to the company’s focus on market dominance and the potential conflict between private sector profitability and the promotion of public health. However, these strategies have enabled Myriad to survive the economic challenges that have affected the biotechnology sector and to become financially successful in the field of personalized medicine. Our critical assessment of the legal, economic and ethical aspects of Myriad’s practices over this period allows the identification of the company’s more effective business models. It also discusses of the consequences of implementing economically viable models without first carrying out broader reflection on the socio-cultural, ethical and political contexts in which they would apply.

The dopaminergic system has an important role in the rewarding properties of nicotine. Gene polymorphisms of DRD2 and DβH that regulate dopamine neurotransmission or metabolism could influence smoking behavior. Additionally, the ability of a 5-HT2CR agonist to block mesolimbic dopamine activation produced by nicotine at the level of ventral tegmental area, suggests a possible interaction between dopaminergic and serotonergic systems in smoking initiation. In the present study, DRD2 TaqIA and DβH -1021C>T polymorphisms and their interactions with 5-HT2CR - 759C>T and -697G>C and 5HTTLPR S/L polymorphisms of serotonergic system were analyzed in 166 smoking initiators (SI) and 244 non-initiators (NI) of Greek origin, using PCR-RFLP method. No differences were found in genotype distributions of DRDR2 TaqIA and DβH -1021C>T polymorphisms between SI and NI. Also, we found no interaction of DRD2 TaqIA and DβH -1021C>T with smoking initiation. When DRD2 TaqIA polymorphism was combined with 5- HT2CR -759C>T and -697G>C polymorphisms, the interaction of DRD2 TaqIA1 and 5-HT2CR -759T alleles was associated with smoking initiation in a model adjusted for age, sex, BMI and type 2 diabetes mellitus (OR=0.70, p=0.022) but did not improve the model that includes 5-HT2CR -759C>T polymorphism alone (OR=0.52, p=0.028). DRDR2 TaqIA and DβH -1021C>T polymorphisms were not associated with smoking initiation. The lower risk for smoking initiation conferred by the combination of DRD2 TaqIA1 and 5-HT2CR -759T variant alleles, indicates the presence of dopaminergic/serotonergic system interaction in smoking behavior; however, this interaction does not substantially improve the predictive value of 5-HT2CR -759T allele alone on smoking initiation risk. To the best of our knowledge, this is the first study of gene polymorphisms in multiple dopaminergic components in relation to smoking initiation, and of the interaction of gene polymorphisms of dopaminergic and serotonergic components in relation to this smoking phenotype in a large sample free of alcohol or drug dependencies.

Gliomas are the most common form of brain tumor, originate from glial cells and characterized by rapidly proliferating cells frequently associated with an invasive phenotype. Several focused studies have successfully demonstrated the genetic origin of these tumors; however, a systems level study to provide comprehensive overview of complex molecular alterations associated with glioma pathogenesis is essential. In this study the main aim was to identify molecular targets associated with high-grade gliomas using systems based investigation, and to identify pathways, molecular networks and functional modules associated with curated genes/ proteins that have altered expression in highgrade glioma cell lines. DAVID and PANTHER analysis tools were used to identify molecular functions, and functional annotation clusters associated with curated dataset. IPA, MetaCore and GeneSpring were used to study the complex interaction of curated molecules and identification of associated signaling pathways. The signaling pathways mediated by TLRs, IL-8, STATs and Wnt, which regulate malignant behavior of high-grade gliomas, were identified as candidates for therapeutic targets. STXBP1, PDK1, MAP3K8 and HIF1A/ARNT appeared as most significant modules in GeneSpring functional analysis. GLIPR1 and MDH1 were identified as potential candidates for further study in gliomas. This study represents a systems level approach to extract biologically relevant information from existing resources and provide new contexts for future research in gliomas.

Medulloblastomas are the most aggressive pediatric brain tumors originating from self-renewing common progenitor cells and associated with high rate of invasion along with rapid spread. The hereditary origin of these tumors can be studied to define it at genome level; however, to understand the molecular mechanism and pathogenesis, systems level investigation is required. In this study we used systems level analysis to identify molecular targets, pathways, molecular networks and functional modules associated with genes/proteins with altered expression in medulloblastoma. Molecular functions, annotated functions, associated pathways, networks and functional modules were identified with PANTHER, DAVID, Ingenuity Pathway Analysis, MetaCore and GeneSpring software analysis, respectively. P53 signaling, PI3K/AKT signaling, Notch signaling, Hedgehog signaling and HGF signaling were identified as significant pathways, indicating the signature of molecules involved in medulloblastoma. Network analysis using IPA revealed new set of molecules, HNRNPK, PDE4A, HES5, GSTP1, SLC16A2, and GADD45A, which also appeared as significant functional modules in GeneSpring analysis. The systems biology approach used in this study provides a comprehensive understanding of complex molecular alterations involved in medulloblastoma and reveals potential novel targets, which could be used for future targeted or personalized therapeutic interventions.

This study was designed to determine the effect of CYP2C19 polymorphisms on platelet response in patients with atherothrombotic-risks receiving clopidogrel treatment. Ninety-five antiplatelet naive atherothrombotic-risk patients were enrolled consecutively. Clopidogrel at 75 mg/day was administered for 2 weeks, followed by a platelet function test (PFT). Non-responders were identified and randomized for receiving either 75 mg or 150 mg of clopidogrel for a further 2 weeks. Twenty-four subjects were non-responders with 75 mg/day, which correlated with poor metabolizer (PM) status (OR 5.69; 1.41-23.03, p = 0.015). However, the mean maximal platelet aggregation (MPA) in the 2nd test was significantly lower in the extensive metabolizers (EM) when compared to the intermediate metabolizers (IM) and PM (23.6 vs 28.1 vs 39.7; p = 0.0001). After randomizing to either 75mg or 150 mg of clopidogrel, no patient had an improved platelet response of more than 30%. However, after administering 150 mg of clopidogrel, MPA reduction (ΔMPA) was significantly greater in IM and PM when compared to that in EM (absolute ΔMPA 20.22% vs 2.6%, p 0.014; relative ΔMPA 45.07% vs 5.27%, p = 0.037). We report here the first pharmacogenetics study of clopidogrel response and show that the common CYP2C19 variants are an important determinant of ADP-stimulated platelet aggregation in Thailand. CYP2C19 genotype may be beneficial in assisting clinicians select the appropriate effective antiplatelet therapy and optimal dose for a given individual. These results collectively inform the emerging field of public health pharmacogenomics with attention to progress in the Asia-Pacific.

Food has societal, economic, medical and ethical implications, being fundamental for life. It plays an important role also in sports medicine, since a healthy diet is an important part of an athlete's training. Nutrigenomics and nutriproteomics are emerging as a result of a convergence of nutritional, genomics and proteomics knowledge strands in the postgenomics era. These fields of inquiry present an opportunity for the design of customized diets potentially able to counterbalance the extant obesity epidemic and remedy metabolic diseases, among others. They are noteworthy for sport medicine as well since they could provide athletes with crucial information for personalized training and nutrition, in order to achieve the best results possible and express one's own potential. But they could also be used as a form of personalized doping, thus constituting an advancement of “classical nutrition-based doping” (i.e., the use of nutraceuticals, stimulants and supplements). However, nutrigenomics (or nutriproteomics)-based nutritional doping is different from the first-generation doping because it is specifically tailored to the genomics and proteomics makeup of the athlete, although their effectiveness remain to be discerned in future systematic studies. Against this scientific background, ethical issues of nutrigenomics and nutriproteomics are discussed in the present paper with emphasis on the current limitations and the dizzying potentials of the omics data-intensive research for science and society. Additionally, I discuss the need to communicate uncertainty as a fundamental construct and intrinsic part of postgenomics personalized medicine, not to forget the gaps regarding the lack of adequate governance, and issues over providing a proper nutritional education to athletes as onus of the international sports organizations.

Nutrigenomics and nutrigenetics are receiving growing attention from a diverse range of stakeholders including health care professionals, citizens, governments, insurers and industry. Currently there is special focus on research on how our food influences us and might cause discomfort or even symptoms of disease, but also the fact that several food intolerances are caused by genetic alterations. The strong interest expressed by certain segments of the general population for predictive and preventive diagnostic testing in relation to diet and ways in which this can improve overall health led to a fast growing market of nutrigenetic based tests. This puts pressures and challenges on governments and insurers for how best to reimburse new genetic tests. These discussions are best informed by a sound understanding of nutrigenetics science and technology, its promises and challenges, which are addressed in this paper. For example, some of the most common food intolerances caused by genetic variations are lactose intolerance, inherited fructose intolerance, congenital sucrase isomaltase deficiency (sucrose intolerance), celiac disease, glucose-6-phosphate deficiency (favism), alcohol intolerance and hemochromatosis. The increasing understanding of molecular mechanisms associated with these conditions is stimulating the development of a broad range of diagnostics allowing any person with adequate resources to have their genetic predispositions determined. However, many of the currently available tests cover only one of the above mentioned diseases or a small set of responsible mutations, which is in strong contrast to the evolution of medicine towards a more holistic approach as, for example, P4 medicine. Additionally, available tests are often not based on evidence or other guidelines for genetic test development as recommended by the ACCE evidentiary framework. In this paper we discuss the most common nutrigenetic diseases and their potential and demonstrated impacts on public health, as well as ways to devise personalized diet informed by human genomics variation in the future.