Progress in pharmacogenetics: consortiums and new strategies.

Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach.

Systems medicine, personalized health and therapy.

The 7th Santorini Conference was held in Santorini, Greece, and brought together 200 participants from 40 countries in several continents, including Europe, USA but also Japan, Korea, Brazil and South Africa. The attendees had the opportunity to: listen to 60 oral presentations; participate in two lunch symposia; look at 103 posters, which were divided in two groups ('systems medicine and environment' and 'pharmacogenomics and cancer') and attend a dedicated exhibition with six companies. The meeting was organized by the Institut National de la Santé et de la Recherche Médicale (INSERM) U1122; IGE-PCV and by 'Biologie Prospective' with the collaboration of the European Society of Pharmacogenomics and Theranostics (ESPT), under the auspices of international organizations (e.g., International Federation of Clinical Chemistry and Laboratory medicine [IFCC], European Federation of Clinical Chemistry and Laboratory Medicine [EFLM], European Diagnostic Manufacturers Association [EDMA], Federation of European Pharmacological Societies [EPHAR], European Science Foundation [ESF]). The 3 days of the conference stimulated intensive discussions on systems biology and the influence of omics technologies on personalized health. Sixty speakers were invited or selected from early abstracts and gave presentations on the following topics: From systems biology to systems medicine/pharmacology; Omics/translating pharmacogenomics/proteomic biomarkers/metabolomics; Human nutrition and health/personalized medicine. We are summarizing here the main topics and presentations, according to the successive sessions.

Is laboratory medicine ready for the era of personalized medicine? A survey addressed to laboratory directors of hospitals/academic schools of medicine in Europe.

Developments in "-omics" are creating a paradigm shift in laboratory medicine leading to personalized medicine. This allows the increase in diagnostics and therapeutics focused on individuals rather than populations. In order to investigate whether laboratory medicine is ready to play a key role in the integration of personalized medicine in routine health care and set the state-of-the-art knowledge about personalized medicine and laboratory medicine in Europe, a questionnaire was constructed under the auspices of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and the European Society of Pharmacogenomics and Personalised Therapy (ESPT). The answers of the participating laboratory medicine professionals indicate that they are aware that personalized medicine can represent a new and promising health model, and that laboratory medicine should play a key role in supporting the implementation of personalized medicine in the clinical setting. Participants think that the current organization of laboratory medicine needs additional/relevant implementations such as (i) new technological facilities in -omics; (ii) additional training for the current personnel focused on the new methodologies; (iii) incorporation in the laboratory of new competencies in data interpretation and counseling; and (iv) cooperation and collaboration among professionals of different disciplines to integrate information according to a personalized medicine approach.

Is laboratory medicine ready for the era of personalized medicine? A survey addressed to laboratory directors of hospitals/academic schools of medicine in Europe.

Developments in "-omics" are creating a paradigm shift in laboratory medicine leading to personalized medicine. This allows the increase in diagnostics and therapeutics focused on individuals rather than populations. In order to investigate whether laboratory medicine is ready to play a key role in the integration of personalized medicine in routine health care and set the state-of-the-art knowledge about personalized medicine and laboratory medicine in Europe, a questionnaire was constructed under the auspices of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and the European Society of Pharmacogenomics and Personalised Therapy (ESPT). The answers of the participating laboratory medicine professionals indicate that they are aware that personalized medicine can represent a new and promising health model, and that laboratory medicine should play a key role in supporting the implementation of personalized medicine in the clinical setting. Participants think that the current organization of laboratory medicine needs additional/relevant implementations such as (i) new technological facilities in -omics; (ii) additional training for the current personnel focused on the new methodologies; (iii) incorporation in the laboratory of new competencies in data interpretation and counseling; and (iv) cooperation and collaboration among professionals of different disciplines to integrate information according to a personalized medicine approach.

Genetic determined low response to thienopyridines is associated with higher systemic inflammation in smokers.

AIM: To investigate whether the interactions of CYP2C19*2 and CYP2C19*17 with smoking are associated with the levels of P2Y12 receptor inhibition and CRP, in on-thienopyridine post-stenting patients. METHODS & RESULTS: At 1-month follow-up, the interactions of smoking and CYP2C19 polymorphisms on the vasodilator-stimulated phosphoprotein - platelet reactivity index (VASP PRI), and CRP were explored in three metabolizing groups (1128 patients) as follow: poor metabolizers (*2 carriers/*17 noncarriers); intermediate metabolizers (*2 carriers/*17 carriers or *2 noncarriers/*17 noncarriers); and ultrarapidmetabolizers (*2 allele noncarriers/*17 carriers). The interactions of metabolizing status and smoking was significant for CRP (p = 0.001) but not for VASP PRI (p = 0.734). CONCLUSION: Interaction between CYP2C19 polymorphisms and smoking modifies on-treatment CRP level of post-stenting, on-thienopyridine patients. This effect seems to be independent to the level of P2Y12 receptor inhibition.

Human cytochrome P450 epoxygenases: variability in expression and role in inflammation-related disorders.

Beyond their contribution to the metabolism of xenobiotics, cytochrome P450 (CYP) epoxygenases are actively involved in the metabolism of endogenous substances, like arachidonic acid (AA). The main human CYP epoxygenases, i.e. CYP2C8, CYP2C9, CYP2C19 and CYP2J2, convert AA to four regioisomer epoxyeicosatrienoic acids (EETs). EETs possess a wide range of established protective effects on the human cardiovascular system of which anti-inflammatory actions have gained great recent interest. The expression of CYP epoxygenases is regulated through an extremely complex network of nuclear receptors, microRNAs and genetic/epigenetic factors. Accordingly, a large number of biological variables as well as xenobiotics and environmental factors can influence the expression of CYP epoxygenases, resulting in a significant intra- and inter-individual variability in the expression and activity of these enzymes and subsequently in EET biosynthesis. Moreover, human CYP epoxygenases are mainly expressed in the liver; however, these enzymes are also expressed, at various extents, in most extrahepatic tissues, resulting in a marked inter-tissue variability in the expression of CYP epoxygenases. The inter-tissue, inter- and intra-individual variability in the expression of epoxygenases may lead to differences in the relative abundance of EETs among tissues, among individuals of a population and/or different ethnicities and in a given individual under various conditions. The variation in the abundance of EETs may explain, at least in part, the inter-tissue and inter-individual differences observed in the prevalence of inflammation-related disorders including cardiovascular disease, and why in a given individual, various conditions can contribute to the development of diseases with an important inflammatory component.

Conference scene: pharmacogenomics: from cell to clinic (part 2).

Second International ESPT Meeting Lisbon, Portugal, 26-28 September 2013 The second European Society of Pharmacogenomics and Theranostics (ESPT) conference was organized in Lisbon, Portugal, and attracted 250 participants from 37 different countries. The participants could listen to 50 oral presentations, participate in five lunch symposia and were able to view 83 posters and an exhibition. Part 1 of this Conference Scene was presented in the previous issue of Pharmacogenomics. This second part will focus on: clinical implementation of pharmacogenomics tests; transporters and pharmacogenomics; stem cells and other new tools for pharmacogenomics and drug discovery; from system pharmacogenomics to personalized medicine; and, finally, we will discuss the Posters and Awards that were presented at the conference.

Pharmacogenomics: from cell to clinic (Part 1).

The second international European Society of Pharmacogenomics and Theranostics (ESPT) conference was organized in Lisbon, Portugal, and attracted 250 participants from 37 different countries. The participants could listen to 50 oral presentations, participate in five lunch symposia and were able to view 83 posters and an exhibition. The first part of this Conference Scene will focus on the pharmacogenomics and biomarkers used in medical oncology, and in particular solid tumors. In addition, this article covers the two keynote conference introductory lectures by Ann K Daly and Magnus Ingelman-Sundberg. The second part of this article will discuss the clinical implementation of pharmacogenomic tests; the role of transports and pharmacogenomics; how stem cells and other new tools are helping the development of pharmacogenomics and drug discovery; and an update on the clinical translation of pharmacogenomics to personalized medicine. Part two of this Conference Scene will be featured in the next issue of Pharmacogenomics.

Influence of inflammation on cardiovascular protective effects of cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids.

In addition to their role as xenobiotic metabolizing enzymes, cytochrome P450 (CYP) epoxygenases actively contribute to the metabolism of endogenous substances such as arachidonic acid. Epoxyeicosatrienoic acids (EETs) are epoxide derivative of arachidonic acid. CYP2C8/9 and CYP2J2 are the main epoxygenases expressed in human tissues including endothelial cells which are the chief sources of EET formation in human body. Once formed, EETs are primarily metabolized to their less biologically active metabolites, dihydroxyeicosatrienoic acids, by soluble epoxy hydrolase (sEH) enzyme. EETs possess a wide range of established protective effects on human cardiovascular system of which vasodilatory, angiogenic and anti-inflammatory actions have been more extensively described. On the other hand, inflammation has shown to decrease the expression and activity of CYP enzyme, including epoxygenases. Given the fact that CYP epoxygenase-derive EETs exhibit potent cardiovascular protective effects, including anti-inflammation, and that inflammation suppress CYP activation and EET formation, it would make sense to speculate that under inflammatory conditions there exists an inflammation-epoxygenase-EET-inflammation vicious cycle in which the inflammation-induced downregulation of CYP epoxygenases causes a decrease in the EET production. Insufficient EET synthesis would, in turn, lead to an ineffective EET-mediated anti-inflammatory effect, leading to an augmentation of systemic and regional inflammatory responses and further downregulation of CYP epoxygenase activity/EET production. This cycle, if any, might help to better understanding of pathophysiology of chronic cardiovascular diseases and also could be an emerging target for further pharmacological therapy of disorders in which increased inflammatory responses are known to occur.

Conference Scene: Systems biology and personalized health science and translation.

After a 1-day advanced course on systems biology, the main themes of this 3-day colloquium were developed: from systems biology to systems medicine with special applications to cancer; pharmacogenomics in drug discovery and clinical application; and epigenomics and genome-wide association studies in cardiovascular diseases. In two roundtable discussions on pharmacogenomics and genome-wide association studies, the progress and the difficulties in the implementation of omics technologies in clinical practice were discussed. Three workshops were also organized on technical tools linked to the meeting themes.

Influence of genetic variations on levels of inflammatory markers of healthy subjects at baseline and one week after clopidogrel therapy; results of a preliminary study.

We aimed to assess the association between the most common polymorphisms of cytochrome P450 (CYP) epoxygenases on the plasma levels of inflammatory markers in a population of healthy subjects. We also sought to determine whether CYP2C19 2 polymorphism is associated with the anti-inflammatory response to clopidogrel. In a population of 49 healthy young males, the baseline plasma levels of inflammatory markers including C-reactive protein, haptoglobin, orosomucoid acid, CD-40 were compared in carriers vs. non-carriers of the most frequent CYP epoxygenase polymorphisms: CYP2C9 2, CYP2C9 3, CYP2C19 2, CYP2C8 2 and CYP2J2 7. Also, the variation of inflammatory markers from baseline to 7 days after administration of 75 mg per day of clopidogrel were compared in carriers vs. non-carriers of CYP2C19 allele and also in responders vs. hypo-responders to clopidogrel, determined by platelet reactivity tests. There was no significant association between epoxygenase polymorphisms and the baseline levels of inflammatory markers. Likewise, CYP2C19 allele was not associated with anti-inflammatory response to clopidogrel. Our findings did not support the notion that the genetic variations of CYP epoxygenases are associated with the level of inflammatory markers. Moreover, our results did not support the hypothesis that CYP2C19 2 polymorphism is associated with the variability in response to the anti-inflammatory properties of clopidogrel.

Epistatic study reveals two genetic interactions in blood pressure regulation.

BACKGROUND: Although numerous candidate gene and genome-wide association studies have been performed on blood pressure, a small number of regulating genetic variants having a limited effect have been identified. This phenomenon can partially be explained by possible gene-gene/epistasis interactions that were little investigated so far. METHODS: We performed a pre-planned two-phase investigation: in phase 1, one hundred single nucleotide polymorphisms (SNPs) in 65 candidate genes were genotyped in 1,912 French unrelated adults in order to study their two-locus combined effects on blood pressure (BP) levels. In phase 2, the significant epistatic interactions observed in phase 1 were tested in an independent population gathering 1,755 unrelated European adults. RESULTS: Among the 9 genetic variants significantly associated with systolic and diastolic BP in phase 1, some may act through altering the corresponding protein levels: SNPs rs5742910 (Padjusted≤0.03) and rs6046 (Padjusted =0.044) in F7 and rs1800469 (Padjusted ≤0.036) in TGFB1; whereas some may be functional through altering the corresponding protein structure: rs1800590 (Padjusted =0.028, SE=0.088) in LPL and rs2228570 (Padjusted ≤9.48×10-4) in VDR. The two epistatic interactions found for systolic and diastolic BP in the discovery phase: VCAM1 (rs1041163) * APOB (rs1367117), and SCGB1A1 (rs3741240) * LPL (rs1800590), were tested in the replication population and we observed significant interactions on DBP. In silico analyses yielded putative functional properties of the SNPs involved in these epistatic interactions trough the alteration of corresponding protein structures. CONCLUSIONS: These findings support the hypothesis that different pathways and then different genes may act synergistically in order to modify BP. This could highlight novel pathophysiologic mechanisms underlying hypertension.

Dairy product consumption, calcium intakes, and metabolic syndrome-related factors over 5 years in the STANISLAS study.

OBJECTIVE: We assessed the associations of total dairy products; milk, yogurt, and cottage cheese; cheese; and calcium with 5-y changes in components of the metabolic syndrome. METHODS: Two hundred eighty-eight men and 300 women 28 to 60 y of age from the suivi temporaire annuel non invasif de la santé des lorrains assurés sociaux (STANISLAS) cohort completed at baseline a 3-d dietary record. Statistics were performed using multivariate regression analysis. RESULTS: In men, no relation was found between the four dietary indices and components of the metabolic syndrome measured at baseline. Conversely, the consumption of milk, yogurt, and cottage cheese at entry was inversely associated with 5-y changes in glucose levels (P ≤ 0.05, P ≤ 0.01 for sex interaction) and positively with 5-y changes in high-density lipoprotein cholesterol (P ≤ 0.05). Higher calcium intakes were significantly related to a lower 5-y increase of the body mass index (BMI) and waist circumference in men (P ≤ 0.01, P ≤ 0.05 for sex interaction). In addition, changes in diastolic blood pressure were inversely associated with the consumption of milk, yogurt, and cottage cheese only in men with a normal BMI (P ≤ 0.05 for BMI interaction). In women, unlike men, associations were shown for some components measured at baseline: total dairy positively related to BMI and waist circumference; total dairy, milk, yogurt, and cottage cheese, and calcium were positively related to triacylglycerols and negatively to high-density lipoprotein cholesterol. However, no significant association was found for any 5-y-changes. CONCLUSION: In men only, a higher consumption of dairy products was associated with positive changes in the metabolic profile in a 5-y period; a higher calcium consumption was associated with a lower 5-y increase of the BMI and waist circumference.