CYP2D6 predicted metabolizer status and safety in adult patients with attention-deficit hyperactivity disorder participating in a large placebo-controlled atomoxetine maintenance of response clinical trial.

Atomoxetine, which is indicated for treatment of attention-deficit hyperactivity disorder (ADHD), is predominantly metabolized by genetically polymorphic cytochrome P450 2D6 (CYP2D6). Based on identified CYP2D6 genotypes, individuals can be categorized into 4 phenotypic metabolizer groups as ultrarapid, extensive, intermediate, and poor. Previous studies have focused on observed differences between poor and extensive metabolizers, but it is not well understood whether the safety profile of intermediate metabolizers differs from that of ultrarapid and extensive metabolizers.

Gain and loss of function of P2X7 receptors: mechanisms, pharmacology and relevance to diabetic neuropathic pain.

Background: Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis.

A phase 2, placebo-controlled study of the opioid receptor antagonist LY2196044 for the treatment of alcohol dependence.

Background: Endogenous opioid-mediated reward pathways may play a role in the development and maintenance of alcohol dependence. This study tested whether LY2196044, an opioid receptor antagonist, in combination with medical management would reduce drinking in alcohol-dependent patients.

Methods: This was a multicenter, outpatient, randomized, double-blind, parallel, and placebo-controlled trial with a 16-week treatment period.

Association of candidate gene polymorphisms with diastolic blood pressure change in patients treated with duloxetine.

Single nucleotide polymorphisms in six genes were investigated for an association between diastolic blood pressure change and duloxetine treatment. Nominally significant within-gene association was found with SLC6A2 rs4436775 and rs4564560 and HTR2A rs6313, but after adjusting for multiple comparisons, these associations were no longer significant.

Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia.

Objective: Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population.

Evaluation of genetic models for response in a randomized clinical trial of duloxetine in major depressive disorder.

In self-identified white patients with major depressive disorder (N=126) treated with open-label duloxetine (60-120 mg/d), a significant association of (P=0.020) of a composite risk score (based on SLC6A2 rs5569 [G1287A] AA, HTR1A rs6295 [C(-1019)G] GG, and COMT rs174697 AA/AG) with 17-item Hamilton Depression Rating Scale total score change from baseline to 12 weeks was observed.

Association of common variations in the norepinephrine transporter gene with response to olanzapine-fluoxetine combination versus continued-fluoxetine treatment in patients with treatment-resistant depression: a candidate gene analysis.

Objective: To determine whether single-nucleotide polymorphisms (SNPs) in candidate genes are associated with response to olanzapine-fluoxetine combination.

Method: A post hoc analysis of a priori-selected SNPs used data from a clinical trial (dates: April 2002-July 2005) of olanzapine-fluoxetine combination, fluoxetine, and olanzapine in patients with major depressive disorder (DSM-IV criteria) and with nonresponse to prestudy antidepressant treatment and nonresponse to fluoxetine treatment during the study. Patients received open-label treatment with fluoxetine for 8 weeks (2 weeks, 25 mg/d; then 6 weeks, 50 mg/d), at the end of which nonresponders (< 25% decline in the 17-item Hamilton Depression Rating Scale score) were randomized to receive double-blind, monotherapy treatment with olanzapine-fluoxetine combination (6/50-18/50 mg/d, n = 71), fluoxetine (50 mg/d, n = 78), or olanzapine (6-18 mg/d, n = 56) for 8 weeks.

Analysis of gene variants previously associated with iloperidone response in patients with schizophrenia who are treated with risperidone.

Objective: We examined 6 single nucleotide polymorphisms (SNPs) previously reported to be associated with response to iloperidone therapy for association with response to risperidone therapy.

Method: Patients with schizophrenia (DSM-IV) were assessed during 2006 and 2007 for response/nonresponse (defined as ≥ 20%/<20% improvement in Positive and Negative Syndrome Scale [PANSS] total score) after 2 weeks of risperidone treatment (2 to 6 mg/d). Responders continued risperidone treatment; nonresponders were randomly assigned to either risperidone or olanzapine treatment (10 to 20 mg/d) for an additional 10 weeks.

Association of DRD2 and ANKK1 polymorphisms with prolactin increase in olanzapine-treated women.

Unlabelled: Dopamine D2 receptors, encoded by DRD2, play a role in regulating serum prolactin concentration. Single nucleotide polymorphisms (SNPs), rs2734842(C), rs6275(T), and rs6279(C) located within DRD2, have been shown to be associated with prolactin increase in olanzapine/fluoxetine combination (OFC)-treated women. The present analyses seek to replicate these results and test other SNPs in DRD2 and neighboring gene ANKK1 for associations with prolactin increase in women, using data from 3 pooled studies of olanzapine, and 2 previously examined studies OFC.

The association of single nucleotide polymorphisms in the catechol-O-methyltransferase gene and pain scores in female patients with major depressive disorder.

Unlabelled: We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene are associated with baseline pain levels in patients with major depressive disorder (MDD). Pain levels were quantified using a visual analog scale (VAS) for pain. Data from 159 female and 93 male self-reported white patients with MDD were analyzed.

Failure to replicate genetic associations with antidepressant treatment response in duloxetine-treated patients.

Background: Recent studies have identified associations of polymorphisms in several target genes with antidepressant treatment response of serotonin reuptake inhibitors and a tricyclic antidepressant. We sought to replicate these associations in a study of a serotonin-norepinephrine reuptake inhibitor.

Methods: In 250 outpatients with nonpsychotic major depressive disorder, response to treatment with once-daily duloxetine (60 mg/day) over 6 weeks was examined for associations with polymorphisms in eight candidate genes previously associated with antidepressant response using mixed-effect model repeated-measures analysis.

Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression.

Objective: To evaluate common genetic variations for association with symptomatic improvement in bipolar I depression following treatment with olanzapine/fluoxetine combination (OFC) or lamotrigine.

Method: Symptom improvement was assessed in 88 OFC-treated and 85 lamotrigine-treated white patients with bipolar I depression in the 7-week acute period of a randomized, double-blind study comparing OFC (6/25, 6/50, 12/25, or 12/50 mg/d [olanzapine/fluoxetine]) with lamotrigine (titrated to 200 mg/d). The original study was conducted from November 2003 to August 2004.

Genetic associations of prolactin increase in olanzapine/fluoxetine combination-treated patients.

In patients from two clinical trials, we investigated the associations of single nucleotide polymorphisms (SNPs) in candidate genes with prolactin level changes during treatment with olanzapine/fluoxetine combination. In both cohorts, three dopamine receptor D2 (DRD2) SNPs were associated with prolactin changes. DRD2 may influence susceptibility to hyperprolactinemia associated with antipsychotic treatment.

Variation in catechol-O-methyltransferase is associated with duloxetine response in a clinical trial for major depressive disorder.

Background: The study objective was to evaluate variations in genes implicated in antidepressant mechanism of action for association with response to duloxetine treatment in major depressive disorder (MDD).

Methods: We assessed response over 6 weeks in 250 duloxetine-treated Caucasian patients in a randomized, double-blind study of patients with MDD. Single nucleotide polymorphisms (SNPs) were genotyped in 19 candidate genes selected based on evidence for involvement in antidepressant mechanism of action.

Case-control study of the association between select HLA genes and anti-erythropoietin antibody-positive pure red-cell aplasia.

Aims: Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele.

Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration.

To examine the genetic basis of age-related macular degeneration (ARMD), a degenerative disease of the retinal pigment epithelium and neurosensory retina, we conducted a genomewide scan in 34 extended families (297 individuals, 349 sib pairs) ascertained through index cases with neovascular disease or geographic atrophy. Family and medical history was obtained from index cases and family members. Fundus photographs were taken of all participating family members, and these were graded for severity by use of a quantitative scale.

Lipoprotein lipase gene polymorphisms in Croatian patients with coronary artery disease.

Modifications in lipoprotein lipase levels lead to elevated triglycerides and reduced high density lipoprotein (HDL), both of which are risk factors for coronary artery disease (CAD). Hence, we examined the influence of the -93T/G, D9N, N291S, and S447X polymorphisms in the lipoprotein lipase (LPL) gene on CAD risk and lipid levels in Croatian patients with and without angiographically confirmed CAD. The N291S polymorphism was significantly associated with CAD (OR = 0.

A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study.

Age-related maculopathy (ARM) is a leading cause of visual impairment among the elderly in Western populations. To identify ARM-susceptibility loci, we genotyped a subset of subjects from the Beaver Dam (WI) Eye Study and performed a model-free genomewide linkage analysis for markers linked to a quantitative measure of ARM. We initially genotyped 345 autosomal markers in 325 individuals (N=263 sib pairs) from 102 pedigrees.

Analysis of mutational spectra: locating hotspots and clusters of mutations using recursive segmentation.

Mutations within different regions of disease-causing genes can vary in their impact on disease initiation and progression. Determining how individual mutations within such genes affect disease risk and progression can improve the accuracy of prognoses and help guide treatment selection. Estimates of mutation-specific risks can be poor, however, when genes have a large number of distinct mutations, and data for any given mutation is sparse.

A common promoter polymorphism in the hepatic lipase gene (LIPC-480C>T) is associated with an increase in coronary calcification in type 1 diabetes.

Type 1 diabetes is associated with coronary heart disease (CHD) and coronary artery calcification (CAC), a measure of subclinical CHD. The hepatic lipase gene promoter polymorphism (LIPC-480C>T) is a common variant affecting lipid metabolism. This study examined the relation between the LIPC-480C>T and CAC in type 1 diabetes.

Gluconic Acid as a Fresh Beef Decontaminant.

Effectiveness of 0, 1.5 and 3.0% gluconic acid (G) and/or 0 and 1.