The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease.

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e.

The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels.

Context: Two recent and simultaneously published genome-wide association studies independently implicated clusterin (CLU), complement receptor 1 (CR1), and phosphatidylinositol binding clathrin assembly protein (PICALM) as putative novel Alzheimer disease (AD) risk loci. Despite their strong statistical support, all 3 signals emerged from heterogeneous case-control populations and lack replication in different settings.

Objective: To determine whether genetic variants in CLU, CR1, and PICALM confer risk for AD in independent data sets (n = 4254) and to test the impact of these markers on cerebrospinal fluid (CSF)-Aβ42 and total-tau protein levels (n = 425).

Impact of CYP2C8 and 2C9 polymorphisms on coronary artery disease and myocardial infarction in the LURIC cohort.

Aims: As data on the cardiovascular risk associated with CYP2C8 and CYP2C9 polymorphisms is controversial, we performed a cross-sectional analysis of subjects enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Materials & Methods: CYP2C8 and CYP2C9 genetic polymorphisms were determined with real-time PCR in 2827 patients. Based on angiography, 1052 of these patients had coronary artery disease (CAD) and 615 did not; 1160 patients had signs or a history of myocardial infarction (MI) in addition to CAD.

Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients?

Background: In inflammation and infection, cytochrome P450 (CYP) enzyme activities are down-regulated. Information on possible discrepancies in activities of CYP enzymes and drug transporters between HIV-infected patients and healthy people is limited.

Methods: We used midazolam, dextromethorphan and digoxin as in vivo phenotyping probes for CYP3A (CYP3A4/5), CYP2D6 and P-glycoprotein activities, respectively, and compared these activities between 12 healthy Caucasian volunteers and 30 treatment-naive HIV-infected patients.

Genetic variants of the insulin receptor substrate-1 are influencing the therapeutic efficacy of oral antidiabetics.

Aim: The therapeutic efficacy of oral hypoglycaemic drugs varies between individuals, and pharmacogenetic factors contribute to this variability. The Gly972Arg polymorphism in the insulin receptor substrate-1 (IRS-1) has been shown to play a role in insulin signal transduction and therapeutic failure to sulphonylurea drugs.

Methods: We studied the association between the IRS-1 polymorphism and the haemoglobin A1c (HbA1c) level in diabetic patients treated with insulinotropic versus non-insulinotropic hypoglycaemic drugs as a marker for the efficacy of an antidiabetic treatment.

Assessment of activity levels for CYP2D6*1, CYP2D6*2, and CYP2D6*41 genes by population pharmacokinetics of dextromethorphan.

The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and *41 variants on DM metabolism in vivo and to identify other sources of pharmacokinetic variability. Concentrations of DM and dextrorphan (DO) in plasma and urine were evaluated in 36 healthy Caucasian men.

Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

Objective: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug-metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens.

A systematic review of cost-effectiveness analyses of pharmacogenetic-guided dosing in treatment with coumarin derivatives.

Anticoagulant therapy with coumarin derivatives is often sub- or supra-therapeutic, resulting in an increased risk of thromboembolic events or hemorrhage, respectively. Pharmacogenetic-guided dosing has been proposed as an effective way of reducing bleeding rates. Clinical trials to confirm the safety, efficacy and effectiveness of this strategy are ongoing, but in addition, it is also necessary to consider the cost-effectiveness of this strategy.

CYP2D6 in the brain: genotype effects on resting brain perfusion.

The cytochrome P450 2D6 (CYP2D6) is a genetically polymorphic enzyme involved in the metabolism of several psychoactive drugs. Beside its expression in the liver, CYP2D6 is highly expressed in several regions of the brain, such as the hippocampus, thalamus, hypothalamus and the cortex, but its function in the brain is not well understood. The CYP2D6 enzyme may also have a physiological role due to its involvement in neurotransmitter biotransformation.

Human lymphoblastoid cell line panels: novel tools for assessing shared drug pathways.

Aims: While powerful in silico tools are emerging for predicting drug targets and pathways, general in vitro tools for assessing such predictions are lacking. We present a novel in vitro method for distinguishing shared versus distinct drug pathways based on comparative cell growth inhibition profiles across a small panel of human lymphoblastoid cell lines (LCLs) from individual donors.

Materials & Methods: LCLs from unrelated healthy donors were examined in parallel for growth inhibition profiles of various drugs, including antidepressants (paroxetine, fluoxetine, fluvoxamine, citalopram, amitriptyline and imipramine); anticancer drugs (5-fluorouracil, 6-mercaptopurine, azathioprine, methotrexate and resveratrol); steroid drugs (dexamethasone, beclomethasone and prednisolone); and antipsychotic drugs (haloperidol and clozapine).

Pharmacogenetics in psychiatry--a useful clinical tool or wishful thinking for the future?

More than fifty years of pharmacogenetic research have produced many examples of the impact of inherited variability in the response to psychotropic drugs. These successes, however, have as yet failed to translate into broadly applicable strategies for the improvement of individual drug treatment in psychiatry. One important argument against the widespread adoption of pharmacogenetics as a clinical tool is the lack of evidence showing its impact on medical decision making and on risk benefit ratio for the patients.

[Interactions with antiretroviral drugs].

Drug-drug interactions are frequently encountered in the therapy of HIV-infected patients, since the highly active antiretroviral therapy always contains several drugs. Drugs against opportunistic infections and concomitant diseases are added frequently. All protease inhibitors are inhibitors of CYP3A, which is important in the metabolism of approximately 50% of all drugs, e.

A novel presenilin1 mutation (Q223R) associated with early onset Alzheimer's disease, dysarthria and spastic paraparesis and decreased Abeta levels in CSF.

Background And Purpose: A novel presenilin1 (PSEN1) mutation associated with dementia and spastic paraplegia in a family with five affected individuals is described. The index patient was a 35-year-old man presenting with cognitive decline, behavioural symptoms, dysarthria, and gait disorder due to spasticity.

Methods And Results: Genetic analysis revealed a missense mutation Gln223Arg in exon 7.

Baseline brain perfusion and the serotonin transporter promoter polymorphism.

Background: The serotonin transporter length repeat polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been associated in healthy subjects with changes in basal perfusion levels in the limbic system and ventral prefrontal areas, regions involved in the pathophysiology of depression and anxiety, suggesting the existence of a neurobiological trait predisposing to these disorders. We reassess the findings of an increased baseline perfusion in the amygdala and ventral prefrontal areas in healthy carriers of the risk genotype in a much larger sample than in previous studies.

Methods: A cohort of 183 healthy European individuals underwent perfusion imaging with continuous arterial spin-labeling (CASL) while resting quietly in the scanner for 8 minutes.

Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design.

The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements.

Sex-specific differences in side effects of psychotropic drugs: genes or gender?

Sex differences observed in the adverse effects associated with psychotropic drugs have not been reported consistently in the literature. In this review, we discuss the current published data on sex differences observed in the occurrence, symptomatology and reporting of the adverse effects associated with psychotropic drug effects, and discuss their clinical relevance. We reviewed the published data up to April 2009 on sex differences in the side effects of antipsychotics, antidepressant and mood stabilizers, by systematically searching PubMed using combinations of search terms and retrieving relevant references specifically reporting on these issues.

The role of human CYP2C8 and CYP2C9 variants in pioglitazone metabolism in vitro.

The cytochrome P450 enzyme CYP2C8 appears to have a major role in pioglitazone metabolism. The present study was conducted to further clarify the role of individual CYPs and of the CYP2C8/9 polymorphisms in the primary metabolism of pioglitazone in vitro. Pioglitazone (2-400 microM) was incubated with isolated cytochrome P450 enzymes or human liver microsomes, some of them carrying either the CYP2C8*3/*3 genotype (and also the CYP2C9*2/*2 genotype) or the CYP2C8*1/*1 genotype (five samples each).

Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism.

Background: Both atorvastatin and rifampicin are substrates of OATP1B1 (organic anion transporting polypeptide 1B1) encoded by SLCO1B1 gene. Rifampicin is a potent inhibitor of SLCO1B1 (IC50 1.5 umol/l) and SLCO1B1 521T>C functional genetic polymorphism alters the kinetics of atorvastatin in vivo.

CYP2D6 genotyping for psychiatric patients treated with risperidone: considerations for cost-effectiveness studies.

In order to ascertain data availability and feasibility for conducting cost-effectiveness studies in pharmacogenetics, and as part of a European Commission Joint Research Center, Institute for Prospective Technological Studies (JRC-IPTS) study, data concerning risperidone use and cytochrome P450 (CYP2D6) genotyping in medical care was collected in Germany, Spain and the USA, and are summarized in this perspective. The gene coding for CYP2D6 is highly polymorphic, resulting in a significant part of the population being poor metabolizers and ultrarapid metabolizers. Individuals who are CYP2D6 poor metabolizers, have an increased risk of adverse drug reactions (ADRs) when treated with CYP2D6-metabolized drugs, suggesting that CYP2D6 genotyping might be beneficial for patient care.

Relative impact of genotype and enzyme induction on the metabolic capacity of CYP2C9 in healthy volunteers.

Pharmacokinetics in individual subjects is determined by genes and environment. The relative contributions of enzyme induction and inherited genomic variation to cytochrome P450 enzyme 2C9 (CYP2C9) activity are unknown. In 130 volunteers, CYP2C9 activity was measured in vivo using tolbutamide as a probe drug.

Drug monitoring in child and adolescent psychiatry for improved efficacy and safety of psychopharmacotherapy.

Most psychotropic drugs used in the treatment of children and adolescents are applied "off label" with a direct risk of under- or overdosing and a delayed risk of long-term side effects. The selection of doses in paediatric psychiatric patients requires a consideration of pharmacokinetic parameters and the development of central nervous system, and warrants specific studies in children and adolescents. Because these are lacking for most of the psychotropic drugs applied in the Child and Adolescent and Psychiatry, therapeutic drug monitoring (TDM) is a valid tool to optimise pharmacotherapy and to enable to adjust the dosage of drugs according to the characteristics of the individual patient.

Cytochrome P450 2D6 genotyping: potential role in improving treatment outcomes in psychiatric disorders.

The specific reaction toward a given drug varies a lot between individuals and, for many drugs, pharmacogenetic polymorphisms are known to affect biotransformation and clinical outcome. Estimation of the individual's drug-metabolizing capacity can be undertaken by genotyping drug-metabolizing enzymes involved in the respective drug metabolism. Consequences that arise from genotyping may be the adjustment of dose according to genotype, choice of therapeutic strategy, or even choice of drug.

Determination of CYP2D6 gene copy number by multiplex polymerase chain reaction analysis.

Cytochrome P450 2D6 (CYP2D6) copy number variation (CNV) influences the metabolism of 15-25% of clinical drugs. Here we describe a novel multiplex polymerase chain reaction (PCR) analysis method that accurately detects CYP2D6 CNV and CYP2D6*9 allele. It includes the amplification of 2 CYP2D6 and 7 control (AQP1, CYP3A4, MDR1, and SDHB) fluorescent PCR products that are separated on a capillary sequencer and normalized using reference samples.

In vivo role of cytochrome P450 2E1 and glutathione-S-transferase activity for acrylamide toxicokinetics in humans.

Acrylamide, a potential food carcinogen in humans, is biotransformed to the epoxide glycidamide in vivo. Both acrylamide and glycidamide are conjugated with glutathione, possibly via glutathione-S-transferases (GST), and bind covalently to proteins and nucleic acids. We investigated acrylamide toxicokinetics in 16 healthy volunteers in a four-period change-over trial and evaluated the respective role of cytochrome P450 2E1 (CYP2E1) and GSTs.

Pharmacogenetics-guided dose modifications of antidepressants.

The efficacy of a drug therapy is influenced by many different factors, such as age, weight, comorbidity, and comedication, which vary among patients, as do the fixed parameters of sex and genotype. Enzymes involved in drug metabolism are genetically polymorphic, meaning that their activities differ depending on certain genotypes. Drugs are metabolized slowly in individuals carrying a genetic polymorphism that causes absent or decreased enzyme activity, and these individuals are at an increased risk for adverse drug reactions or therapeutic failure.