Pharmacogenetic Evidence Research Articles

Implementation of clopidogrel pharmacogenetic clinical decision support for a preemptive return of results program.

To describe our experiences implementing and iterating CYP2C19 genotype-guided clopidogrel pharmacogenetic clinical decision support (CDS) tools over time in the setting of a large health system-wide, preemptive pharmacogenomics program. Clopidogrel-treated patients who are genetically predicted cytochrome P450 isozyme 2C19 (CYP2C19) intermediate or poor metabolizers have an increased risk of atherothrombotic events, some of which can be life-threatening. The Clinical Pharmacogenetics Implementation Consortium provides guidance for the use of clopidogrel based on CYP2C19 genotype in patients with cardiovascular and cerebrovascular diseases. Our multidisciplinary team implemented an automated, interruptive alert that fires when clopidogrel is ordered or refilled for biobank participants with structured CYP2C19 intermediate or poor metabolizer genomic indicators in the electronic health record. The implementation began with a narrow cardiovascular indication and setting and was then scaled in 4 primary dimensions: (1) clinical indication; (2) availability across health-system locations; (3) care venue (e.g., inpatient vs outpatient); and (4) provider groups (eg, cardiology and neurology). We iterated our approach over time based on evolving clinical evidence and proactive strategies to optimize CDS maintenance and sustainability. A key facilitator of expansion was socialization of the broader pharmacogenomics initiative among our academic medical center community, accompanied by clinician acceptance of pharmacogenetic alerts in practice. A multidisciplinary collaboration is recommended to facilitate the use of CYP2C19 genotype-guided antiplatelet therapy in patients with cardiovascular and cerebrovascular diseases. Evolving clopidogrel pharmacogenetic evidence necessitates thoughtful iteration of implementation efforts and strategies to optimize long-term maintenance and sustainability.

Identification of adverse drug reactions that may be related to pharmacogenetics in a public hospital in the South of Brazil

ABSTRACT Background Adverse drug reactions (ADRs) are of great concern in clinical practice. Pharmacogenetics can identify individuals and groups at increased risk of developing ADRs, enabling treatment adjustments to improve outcomes. The study aimed to determine the prevalence of ADRs related to drugs with pharmacogenetic evidence level 1A in a public hospital in Southern Brazil. Research design and methods ADR information was collected from the pharmaceutical registries from 2017 to 2019. Drugs that have pharmacogenetic evidence level 1A were selected. Public genomic databases were used to estimate the genotypes/phenotypes frequency. Results During the period, 585 ADRs were spontaneously notified. Most were moderate (76.3%), whereas severe reactions accounted for 33.8%. Additionally, 109 ADRs caused by 41 drugs presented pharmacogenetic evidence level 1A, representing 18.6% of all notified reactions. Depending on the drug-gene pair, up to 35% of individuals from Southern Brazil could be at risk of developing ADRs. Conclusions Relevant amount of ADRs were related to drugs with pharmacogenetic recommendations on drug labels and/or guidelines. Genetic information could guide and improve clinical outcomes, decreasing ADR incidence and reducing treatment costs.

Immunogenetics and pharmacogenetics of allergic asthma in Africa.

Asthma is a common chronic condition in children and in an African setting is often highly prevalent in urban areas as compared to rural areas. Asthma is a heritable disease and the genetic risk is often exacerbated by unique localised environmental factors. The Global Initiative for Asthma (GINA) recommendation for the control of asthma includes inhaled corticosteroids (ICS) alone or together with short-acting β2-agonists (SABA) or long-acting β2-agonists (LABA). While these drugs can relieve asthma symptoms, there is evidence of reduced efficacy in people of African ancestry. Whether this is due to immunogenetics, genomic variability in drug metabolising genes (pharmacogenetics) or genetics of asthma-related traits is not well defined. Pharmacogenetic evidence of first-line asthma drugs in people of African ancestry is lacking and is further compounded by the lack of representative genetic association studies in the continent. In this review, we will discuss the paucity of data related to the pharmacogenetics of asthma drugs in people of African ancestry, mainly drawing from African American data. We will further discuss how this gap can be bridged to improve asthma health outcomes in Africa.

ABCB1 Gene Variants and Antidepressant Treatment Outcomes: A Systematic Review and Meta-Analysis Including Results from the CAN-BIND-1 Study.

The P-glycoprotein efflux pump, encoded by the ABCB1 gene, has been shown to alter concentrations of various antidepressants in the brain. In this study, we conducted a systematic review and meta-analysis to investigate the association between six ABCB1 single-nucleotide polymorphisms (SNPs; rs1045642, rs2032582, rs1128503, rs2032583, rs2235015, and rs2235040) and antidepressant treatment outcomes in individuals with major depressive disorder (MDD), including new data from the Canadian Biomarker and Integration Network for Depression (CAN-BIND-1) cohort. For the CAN-BIND-1 sample, we applied regression models to investigate the association between ABCB1 SNPs and antidepressant treatment response, remission, tolerability, and antidepressant serum levels. For the meta-analysis, we systematically summarized pharmacogenetic evidence of the association between ABCB1 SNPs and antidepressant treatment outcomes. Studies were included in the meta-analysis if they investigated at least one ABCB1 SNP in individuals with MDD treated with at least one antidepressant. We did not find a significant association between ABCB1 SNPs and antidepressant treatment outcomes in the CAN-BIND-1 sample. A total of 39 studies were included in the systematic review. In the meta-analysis, we observed a significant association between rs1128503 and treatment response (T vs. C-allele, odds ratio=1.30, 95% confidence interval=1.15-1.48, P value (adjusted)=0.024, n=2,526). We did not find associations among the six SNPs and treatment remission nor tolerability. Our findings provide limited evidence for an association between common ABCB1 SNPs and antidepressant outcomes, which do not support the implementation of ABCB1 genotyping to inform antidepressant treatment at this time. Future research, especially on rs1128503, is recommended.

How to Implement a Pharmacogenetics Service at your Institution.

The vast majority of patients possess one or more pharmacogenetic variants that can influence optimal medication use. When pharmacogenetic data are used to guide drug choice and dosing, evidence points to improved disease outcomes, fewer adverse effects, and lower healthcare spending. Although its science is well established, clinical use of pharmacogenetic data to guide drug therapy is still in its infancy. Pharmacogenetics essentially involves the intersection of an individual's genetic data with their medications, which makes pharmacists uniquely qualified to provide clinical support and education in this field. In fact, most pharmacogenetics implementations, to date, have been led by pharmacists as leaders or members of a multidisciplinary team or as individual practitioners. A successful large-scale pharmacogenetics implementation requires coordination and synergy among administrators, clinicians, informatics teams, laboratories, and patients. Because clinical implementation of pharmacogenetics is in its early stages, there is an urgent need for guidance and dissemination of shared experiences to provide a framework for clinicians. Many early adopters of pharmacogenetics have explored various strategies among diverse practice settings. This article relies on the experiences of early adopters to provide guidance for critical steps along the pathway to implementation, including strategies to engage stakeholders; evaluate pharmacogenetic evidence; coordinate laboratory testing, results interpretation and their integration into the electronic health record; identify reimbursement avenues; educate providers and patients; and maintain a successful program. Learning from early adopters' published experiences and strategies can allow clinicians leading a new pharmacogenetics implementation to avoid pitfalls and adapt and apply lessons learned by others to their own practice.

Pharmacogenetics and Precision Medicine Approaches for the Improvement of COVID-19 Therapies.

Many drugs are being administered to tackle coronavirus disease 2019 (COVID-19) pandemic situations without establishing clinical effectiveness or tailoring safety. A repurposing strategy might be more effective and successful if pharmacogenetic interventions are being considered in future clinical studies/trials. Although it is very unlikely that there are almost no pharmacogenetic data for COVID-19 drugs, however, from inferring the pharmacokinetic (PK)/pharmacodynamic(PD) properties and some pharmacogenetic evidence in other diseases/clinical conditions, it is highly likely that pharmacogenetic associations are also feasible in at least some COVID-19 drugs. We strongly mandate to undertake a pharmacogenetic assessment for at least these drug–gene pairs (atazanavir–UGT1A1, ABCB1, SLCO1B1, APOA5; efavirenz–CYP2B6; nevirapine–HLA, CYP2B6, ABCB1; lopinavir–SLCO1B3, ABCC2; ribavirin–SLC28A2; tocilizumab–FCGR3A; ivermectin–ABCB1; oseltamivir–CES1, ABCB1; clopidogrel–CYP2C19, ABCB1, warfarin–CYP2C9, VKORC1; non-steroidal anti-inflammatory drugs (NSAIDs)–CYP2C9) in COVID-19 patients for advancing precision medicine. Molecular docking and computational studies are promising to achieve new therapeutics against SARS-CoV-2 infection. The current situation in the discovery of anti-SARS-CoV-2 agents at four important targets from in silico studies has been described and summarized in this review. Although natural occurring compounds from different herbs against SARS-CoV-2 infection are favorable, however, accurate experimental investigation of these compounds is warranted to provide insightful information. Moreover, clinical considerations of drug–drug interactions (DDIs) and drug–herb interactions (DHIs) of the existing repurposed drugs along with pharmacogenetic (e.g., efavirenz and CYP2B6) and herbogenetic (e.g., andrographolide and CYP2C9) interventions, collectively called multifactorial drug–gene interactions (DGIs), may further accelerate the development of precision COVID-19 therapies in the real-world clinical settings.

Moving Pharmacogenetics Into Practice: It's All About the Evidence!

The evidence for pharmacogenetics has grown rapidly in recent decades. However, the strength of evidence required for the clinical implementation of pharmacogenetics is highly debated. Therefore, the purpose of this review is to summarize different perspectives on the evidence required for the clinical implementation of pharmacogenetics. First, we present two patient cases that demonstrate how knowledge of pharmacogenetic evidence affected their care. Then we summarize resources that curate pharmacogenetic evidence, types of evidence (with an emphasis on randomized controlled trials [RCT]) and their limitations, and different perspectives from implementers, clinicians, and patients. We compare pharmacogenetics to a historical example (i.e., the evidence required for the clinical implementation of pharmacokinetics/therapeutic drug monitoring), and we provide future perspectives on the evidence for pharmacogenetic panels and the need for more education in addition to evidence. Although there are differences in the interpretation of pharmacogenetic evidence across resources, efforts for standardization are underway. Survey data illustrate the value of pharmacogenetic testing from the patient perspective, with their providers seen as key to ensuring maximum benefit from test results. However, clinicians and practice guidelines from medical societies often rely on RCT data to guide treatment decisions, which are not always feasible or ethical in pharmacogenetics. Thus, recognition of other types of evidence to support pharmacogenetic implementation is needed. Among pharmacogenetic implementers, consistent evidence of pharmacogenetic associations is deemed most critical. Ultimately, moving pharmacogenetics into practice will require consideration of multiple stakeholder perspectives, keeping particularly attuned to the voice of the ultimate stakeholder-the patient.

Pharmacogenetics to guide cardiovascular drug therapy.

Over the past decade, pharmacogenetic testing has emerged in clinical practice to guide selected cardiovascular therapies. The most common implementation in practice is CYP2C19 genotyping to predict clopidogrel response and assist in selecting antiplatelet therapy after percutaneous coronary intervention. Additional examples include genotyping to guide warfarin dosing and statin prescribing. Increasing evidence exists on outcomes with genotype-guided cardiovascular therapies from multiple randomized controlled trials and observational studies. Pharmacogenetic evidence is accumulating for additional cardiovascular medications. However, data for many of these medications are not yet sufficient to support the use of genotyping for drug prescribing. Ultimately, pharmacogenetics might provide a means to individualize drug regimens for complex diseases such as heart failure, in which the treatment armamentarium includes a growing list of medications shown to reduce morbidity and mortality. However, sophisticated analytical approaches are likely to be necessary to dissect the genetic underpinnings of responses to drug combinations. In this Review, we examine the evidence supporting pharmacogenetic testing in cardiovascular medicine, including that available from several clinical trials. In addition, we describe guidelines that support the use of cardiovascular pharmacogenetics, provide examples of clinical implementation of genotype-guided cardiovascular therapies and discuss opportunities for future growth of the field.

239-OR: Genome-Wide Association Study (GWAS) of Hypoglycemia in the Million Veteran Program (MVP)

Hypoglycemia is a preventable adverse effect of treatment in diabetes patients, but actionable pharmacogenetic evidence to minimize hypoglycemia risk is lacking. We used the MVP biospecimen and clinical biobank to perform a case/control GWAS of hypoglycemia in 96,406 diabetes patients receiving care in the U.S. Veterans Health Administration. Cases had an outpatient random plasma glucose (RPG) <70 mg/dL or an emergency room visit for hypoglycemia; controls had an RPG or clinic visit annually during follow-up but did not meet the case criteria. Genotypes were based on a custom MVP Affymetrix array, imputed with ancestry-specific HRC reference panels and limited to variants with minor allele frequency (MAF) >1%. GWAS were conducted in 72,244 participants (22,045 cases) of European ancestry [EUR] and 24,162 (10,441 cases) of African ancestry [AFR]), adjusted for age at MVP enrollment, sex, and 10 genetic principal components. We identified a single locus associated with hypoglycemia in EUR individuals (rs1064173, HLA-DQB1 locus, odds ratio [OR] 1.15, p=5.6E-19, MAF 0.20) and in AFR individuals (rs12712928, SIX3 locus, OR 0.87, p=2.7E-8, MAF 0.17). In a phenomewide association study (PheWAS) in MVP EUR diabetes patients, rs1064173 was associated with type 1 diabetes (T1D, OR 1.41, p=7.8E-25) and diabetes complications (retinopathy, OR 1.24, p=9E-24; neuropathy, OR 1.16, p=1.3E-5). To address the known association of the HLA locus with T1D, we performed a sensitivity analysis excluding patients with any use of T1D diagnosis codes. In this sample enriched for type 2 diabetes, rs1064173 remained nominally associated with hypoglycemia (OR 1.23, p=0.02) and retinopathy (OR 1.10, p=0.003). Rs12712928 - previously associated with glucose and hemoglobin A1c in an East Asian sample - was not associated with any diagnoses in a PheWAS of MVP AFR diabetes patients. In conclusion, a GWAS of hypoglycemia in a clinical biobank found ancestry-specific genetic associations that may have treatment implications. Disclosure S. Raghavan: None. Z. Wang: None. A.M. Hung: None. B.R. Charest: None. L. Costa: None. E.M. Litkowski: None. A. Leong: None. J.B. Meigs: Consultant; Self; Quest Diagnostics. P.W. Wilson: None. P. Reaven: Consultant; Self; Boston Heart Diagnostics, Intercept Pharmaceuticals, Inc. Research Support; Self; Bristol-Myers Squibb, Lysulin. M.K. Rhee: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Y.V. Sun: None. L.S. Phillips: Research Support; Self; AbbVie Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis. Other Relationship; Self; Diasyst, Janssen Pharmaceuticals, Inc. Funding U.S. Department of Veterans Affairs (I01-CX001737, IK2-CX001907-01)

Personalized pediatric anesthesia and pain management: problem-based review.

Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.' Although oncology spearheaded the clinical implementation of personalized medicine, other specialties are rapidly catching up. In anesthesia, classical examples of genetically mediated idiosyncratic reactions have been long known (e.g., malignant hyperthermia and prolonged apnea after succinylcholine). The last two decades have witnessed an expanding body of pharmacogenetic evidence in anesthesia. This review highlights some of the prominent pharmacogenetic associations studied in anesthesia and pain management, with special focus on pediatric anesthesia.

Enhanced and Persistent Inhibition of Organic Cation Transporter 1 Activity by Preincubation of Cyclosporine A.

Recent pharmacogenetic evidence indicates that hepatic organic cation transporter (OCT) 1 can serve as the locus of drug-drug interactions (DDIs) with significant pharmacokinetic and pharmacodynamic consequences. We examined the impact of preincubation on the extent of OCT1 inhibition in transfected human embryonic kidney 293 (HEK293) cells. Following 30-minute preincubation with an inhibitor, approximately 50-fold higher inhibition potency was observed for cyclosporine A (CsA) against OCT1-mediated uptake of metformin compared with coincubation, with IC50 values of 0.43 ± 0.12 and 21.6 ± 4.5 µM, respectively. By comparison, only small shifts (≤2-fold) in preincubation IC50 versus coincubation were observed for quinidine, pyrimethamine, ritonavir, and trimethoprim. The shift in CsA OCT1 IC50 was substrate dependent since it ranged from >1.2- to 50.2-fold using different experimental substrates. The inhibition potential of CsA toward OCT1 was confirmed by fenoterol hepatocyte uptake experiment. Furthermore, no shift in CsA IC50 was observed with HEK293 cells transfected with OCT2 and organic anion transporter (OAT) 1 and OAT3. Short exposure (30 minutes) to 10 µM CsA produced long-lasting inhibition (at least 120 minutes) of the OCT1-mediated uptake of metformin in OCT1-HEK293 cells, which was likely attributable to the retention of CsA in the cells, as shown by the fact that inhibitory cellular concentrations of CsA were maintained long after the removal of the compound from the incubation buffer. The potent and persistent inhibitory effect after exposure to CsA warrants careful consideration in the design and interpretation of clinical OCT1 DDI studies. SIGNIFICANCE STATEMENT: Preincubation of OATP1B1 and OATP1B3 with their inhibitor may result in the enhancement of the inhibitory potency in a cell-based assay. However, limited data are available on potentiation of OCT1 inhibition by preincubation, which is a clinically relevant drug transporter. For the first time, we observed a 50-fold increase in CsA inhibitory potency against OCT1-mediated transport of metformin following a preincubation step. The CsA preincubation effect on OCT1 inhibition is substrate dependent. Moreover, the inhibition potential of CsA toward OCT1 is confirmed by hepatocyte uptake experiment. This study delivers clear evidences about the potent and persistent inhibitory effect on OCT1 after exposure to CsA. Further studies are needed to assess the effect of CsA on OCT1 drug substrates in vivo.

Pharmacogenetic guidelines and decision support tools for depression treatment: application to late-life.

Late-life depression (LLD) is a major depressive disorder that affects someone after the age of 60years. LLD is frequently associated with inadequate response and remission from antidepressants, in addition to polypharmacy. Pharmacogenetics offers a promising approach to improve clinical outcomes in LLD via new discoveries determining the genetic basis of response rates and side effects, as well as the development of tailored pharmacogenetic-based decision support tools. This invited review evaluates the LLD pharmacogenetic evidence base and the extent to which this was incorporated into existing commercial decision support tools and clinical pharmacogenetic guidelines.

Depletion of rostral ventrolateral medullary catecholaminergic neurons impairs the hypoxic ventilatory response in conscious rats

The stimuli that commonly activate the catecholaminergic C1 neurons (nociception, hypotension, and hypoxia) also increase breathing. Pharmacogenetic evidence suggests that catecholaminergic neurons regulate breathing. Therefore, we evaluated whether the loss of C1 cells affects cardiorespiratory control during resting, hypoxic (8% O2) and hypercapnic (7% CO2) conditions. A bilateral injection of the immunotoxin anti-dopamine β-hydroxylase-saporin (anti-DβH-SAP; 2.4ng/100nl) or saline was performed in adult male Wistar rats (270–300g, N=5–8/group). Histology revealed a 60–75% loss of C1 neurons in anti-DβH-SAP-treated rats, but no significant changes or C1 cell loss was observed in sham-treated rats or those with off-target injection sites. Bilateral depletion of C1 neurons did not alter cardiorespiratory variables during rest and hypercapnia (7% CO2), but it did affect the response to hypoxia. Specifically, the increase in ventilation, the number of sighs, and the tachycardia were reduced, but unexpectedly, the mean arterial pressure increased during hypoxia (8% O2). The present study indicates that C1 neurons contribute to cardiorespiratory control during hypoxia rather than at rest or during hypercapnia.

Pharmacogenomics in diabetes mellitus: insights into drug action and drug discovery.

Genomic studies have greatly advanced our understanding of the multifactorial aetiology of type 2 diabetes mellitus (T2DM) as well as the multiple subtypes of monogenic diabetes mellitus. In this Review, we discuss the existing pharmacogenetic evidence in both monogenic diabetes mellitus and T2DM. We highlight mechanistic insights from the study of adverse effects and the efficacy of antidiabetic drugs. The identification of extreme sulfonylurea sensitivity in patients with diabetes mellitus owing to heterozygous mutations in HNF1A represents a clear example of how pharmacogenetics can direct patient care. However, pharmacogenomic studies of response to antidiabetic drugs in T2DM has yet to be translated into clinical practice, although some moderate genetic effects have now been described that merit follow-up in trials in which patients are selected according to genotype. We also discuss how future pharmacogenomic findings could provide insights into treatment response in diabetes mellitus that, in addition to other areas of human genetics, facilitates drug discovery and drug development for T2DM.

Pharmacogenomics of hypertension and heart disease.

Heart disease is a leading cause of death in the United States, and hypertension is a predominant risk factor. Thus, effective blood pressure control is important to prevent adverse sequelae of hypertension, including heart failure, coronary artery disease, atrial fibrillation, and ischemic stroke. Over half of Americans have uncontrolled blood pressure, which may in part be explained by interpatient variability in drug response secondary to genetic polymorphism. As such, pharmacogenetic testing may be a supplementary tool to guide treatment. This review highlights the pharmacogenetics of antihypertensive response and response to drugs that treat adverse hypertension-related sequelae, particularly coronary artery disease and atrial fibrillation. While pharmacogenetic evidence may be more robust for the latter with respect to clinical implementation, there is increasing evidence of genetic variants that may help predict antihypertensive response. However, additional research and validation are needed before clinical implementation guidelines for antihypertensive therapy can become a reality.

Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation

ObjectiveRecent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. MethodIn two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. ResultsFor abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X2=8.15, df=2, omnibus-p=0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald=3.94, df=1, p=0.047), this non-replication can alter the interpretation of pharmacogenetic findings. ConclusionsResults from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking.

Serotonin reuptake inhibitors and serotonin transporter genotype modulate performance monitoring functions but not their electrophysiological correlates.

Serotonin (5-HT) has been hypothesized to be implicated in performance monitoring by promoting behavioral inhibition in the face of aversive events. However, it is unclear whether this is restricted to external (punishment) or includes internal (response errors) events. The aim of the current study was to test whether higher 5-HT levels instigate inhibition specifically in the face of errors, measured as post-error slowing (PES), and whether this is represented in electrophysiological correlates of error processing, namely error-related negativity (ERN) and positivity. Therefore, from a large sample of human subjects (n = 878), two extreme groups were formed regarding hypothesized high and low 5-HT transporter (5-HTT) expression based on 5-HTTLPR and two additional single nucleotide polymorphisms (rs25531, rs25532). Seventeen higher (LL) and 15 lower (SS) expressing Caucasian subjects were administered the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg) intravenously in a double-blind crossover design. We found pharmacogenetic evidence for a role of 5-HT in mediating PES: SSRI administration increased PES in both genetic groups, and SS subjects displayed higher PES. These effects were absent on post-conflict slowing. However, ERN and error positivity were unaffected by pharmacogenetic factors, but ERN was decoupled from behavioral adaptation by SSRI administration in the LL group. Thus, pharmacogenetic evidence suggests that increased 5-HT levels lead to behavioral inhibition in the context of internal aversive events, but electrophysiological correlates of performance monitoring appear unrelated to the 5-HT system. Therefore, our findings are consistent with theories suggesting that 5-HT mediates the link between aversive processing and inhibition.

Genetics of drug response in type 2 diabetes.

The introduction of several new drug groups into the treatment of type 2 diabetes in the past few decades leads to an increased requirement for an individualized treatment approach. A personalized treatment is important from the point of view of both efficacy and safety. Recent guidelines are based mainly on entirely phenotypic characteristics such as diabetes duration, presence of macrovascular complications, or risk of hypoglycemia with the use of individual drugs. So far, genetic knowledge is used to guide treatment in the monogenic forms of diabetes. With the accumulating pharmacogenetic evidence in type 2 diabetes, there are reasonable expectations that genetics might help in the adjustment of drug doses to reduce severe side effects, as well as to make better therapeutic choices among the drugs available for the treatment of diabetes.

CYP2C19 LOF alleles confer no risk for HTPR but higher risk for recurrent ischemic events in clopidogrel treated elderly ACS patients

Dual antiplatelet therapy (DAPT), combining aspirin with P2Y12 inhibitor of clopidogrel, has been recommended with compelling evidence for the treatment of acute coronary syndrome (ACS) or the prevention of stent thrombosis in patients who underwent percutaneous coronary intervention (PCI) [ [1] Amsterdam E.A. Wenger N.K. Brindis R.G. et al. 2014 AHA/ACC Guideline for the management of patients with non-ST-Elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2014; 64: e139-e228 Abstract Full Text Full Text PDF PubMed Scopus (1907) Google Scholar ]. As an inactive pro-drug, clopidogrel requires the activation by the hepatic cytochrome P450 (CYP) system to generate its active metabolite, which exerts its antiplatelet effects by irreversibly inhibiting the P2Y12 receptor on platelets. Due to the variability of active metabolite generation, there is marked inter-individual variability (~30%) in the antiplatelet effects of clopidogrel, and a reduced response to this drug may be a risk factor for cardiovascular events [ [2] Mallouk N. Labruyere C. Reny J.L. et al. Prevalence of poor biological response to clopidogrel: a systematic review. Thromb. Haemost. 2012; 107: 494-506 Crossref PubMed Scopus (71) Google Scholar ]. Accumulated pharmacogenetic evidence verified that carriers of CYP2C19 loss-of-function (LOF) alleles have decreased clopidogrel active transformation and diminished platelet inhibition. Genotyping of CYP2C19 may offer a promising clue for a personalized approach of antiplatelet treatments [ [3] Scott S.A. Sangkuhl K. Stein C.M. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin. Pharmacol. Ther. 2013; 94: 317-323 Crossref PubMed Scopus (663) Google Scholar ]. Elderly individuals represent a growing population of patients diagnosed with ACS and treated by PCI. Complex with more comorbidity and concomitant medications, as well as the difficulties for the balance between ischemic and bleeding events, elderly patients should be of priority for personalized antiplatelet therapy [ [4] Silvain J. Cayla G. Hulot J.S. et al. High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study. Eur. Heart J. 2012; 33: 1241-1249 Crossref PubMed Scopus (126) Google Scholar ]. By far, the contribution of CYP2C19 LOF alleles to clopidogrel responsiveness in the elderly, and its implication for personalized antiplatelet treatment in this population remain unknown. In the present study, we aimed to evaluate the effects of CYP2C19 LOF alleles on platelet reactivity and clinical outcomes in elderly ACS patients treated by clopidogrel.

Topiramate for alcoholism treatment: novel pharmacogenetic evidence for the journey to personalized medicine?

The small number of medications approved for the treatment of alcoholism is, by itself, an important justification for the significant efforts directed towards medication development. Perhaps an even more important issue is why a medication (approved or used off-label) does not always reproduce the same results across randomized clinical trials (RCTs). Indeed, even clinical trials that find effects report that there are both treatment responders and non-responders, and the ability to identify responders and non-responders could help explain variation across clinical trials. This variation forms the foundation of ‘personalized medicine’ approaches, and highlights the need to identify patient sub-types that respond better to a certain medication. Although typologies (Leggio et al., 2009) provide phenotypic traits that may be applied in RCTs, pharmacogenetics (Heilig et al., 2011) represents an even more compelling approach, as it is more reproducible, biologically-based and mechanistic. Although in its infancy, the alcoholism pharmacotherapy literature has already shown the potential value of pharmacogenetics as a way to develop personalized medicine. The functional OPRM1 polymorphism A118G plays an important role in the effects of naltrexone on alcohol consumption, with G-allele carriers responding more positively to treatment than A-allele homozygotes (Oslin et al., 2003; Anton et al., 2008; Barr et al., 2010; Kranzler et al., 2013). A functional polymorphism in the promoter region of the serotonin transporter gene, SLC6A4 , known as 5-HTTLPR, results in a long (L) and a short (S) allele. Alcoholic patients who were L homozygotes had significant reductions in alcohol use when treated with ondansetron, as compared to S carriers (Kenna et al., 2009b, 2014; Johnson et al., 2011, 2013). It has also been shown that the tri-allelic 5-HTTLPR polymorphism moderated the effects of sertraline and age at onset of alcohol dependence on the frequency of drinking and heavy drinking …