Copy number variation meta-analysis reveals a novel duplication at 9p24 associated with multiple neurodevelopmental disorders.

BACKGROUND: Neurodevelopmental and neuropsychiatric disorders represent a wide spectrum of heterogeneous yet inter-related disease conditions. The overlapping clinical presentations of these diseases suggest a shared genetic etiology. We aim to identify shared structural variants spanning the spectrum of five neuropsychiatric disorders. METHODS: We investigated copy number variations (CNVs) in five cohorts, including schizophrenia (SCZ), bipolar disease (BD), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and depression, from 7849 cases and 10,799 controls. CNVs were called based on intensity data from genome-wide SNP arrays and CNV frequency was compared between cases and controls in each disease cohort separately. Meta-analysis was performed via a gene-based approach. Quantitative PCR (qPCR) was employed to validate novel significant loci. RESULTS: In our meta-analysis, two genes containing CNVs with exonic overlap reached genome-wide significance threshold of meta P value < 9.4 × 10-6 for deletions and 7.5 × 10-6 for duplications. We observed significant overlap between risk CNV loci across cohorts. In addition, we identified novel significant associations of DOCK8/KANK1 duplications (meta P value = 7.5 × 10-7) across all cohorts, and further validated the CNV region with qPCR. CONCLUSIONS: In the first large scale meta-analysis of CNVs across multiple neurodevelopmental/psychiatric diseases, we uncovered novel significant associations of structural variants in the locus of DOCK8/KANK1 shared by five diseases, suggesting common etiology of these clinically distinct neurodevelopmental conditions.

Large-scale candidate gene study to identify genetic risk factors predictive of paliperidone treatment response in patients with schizophrenia.

OBJECTIVE: Clinical response to antipsychotic medications can vary markedly in patients with schizophrenia. Identifying genetic variants associated with treatment response could help optimize patient care and outcome. To this end, we carried out a large-scale candidate gene study to identify genetic risk factors predictive of paliperidone efficacy. PATIENTS AND METHODS: A central nervous system custom chip containing single nucleotide polymorphisms from 1204 candidate genes was utilized to genotype a discovery cohort of 684 schizophrenia patients from four clinical studies of paliperidone extended-release and paliperidone palmitate. Variants predictive of paliperidone efficacy were identified and further tested in four independent replication cohorts of schizophrenic patients (N=2856). RESULTS: We identified an SNP in ERBB4 that may contribute toward differential treatment response to paliperidone. The association trended in the same direction as the discovery cohort in two of the four replication cohorts, but ultimately did not survive multiple testing corrections. The association was not replicated in the other two independent cohorts. We also report several SNPs in well-known schizophrenia candidate genes that show suggestive associations with paliperidone efficacy. CONCLUSION: These preliminary findings suggest that genetic variation in the ERBB4 gene may differentially affect treatment response to paliperidone in individuals with schizophrenia. They implicate the neuregulin 1 (NRG1)-ErbB4 pathway for modulating antipsychotic response. However, these findings were not robustly reproduced in replication cohorts.

Prospective-retrospective biomarker analysis for regulatory consideration: white paper from the industry pharmacogenomics working group.

One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine). Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development. In this article, the Industry Pharmacogenomics Working Group provides, for regulatory consideration, its perspective on the rationale for the conduct of what is commonly referred to as the prospective-retrospective analysis (PRA) of biomarkers. Reflecting on published proposals and materials presented by the US FDA, a decision tree for generating robust scientific data from samples collected from an already conducted trial to allow PRA is presented. The primary utility of the PRA is to define a process that provides robust scientific evidence for decision-making in situations where it is not necessary, nor practical or ethical to conduct a new prospective clinical study.

Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin.

Single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and P-glycoprotein 1 (MDR1) genes modulate their ability to mediate drug resistance. We therefore sought to retrospectively evaluate their influence on outcomes in relapsed and/or refractory myeloma patients treated with bortezomib or bortezomib with pegylated liposomal doxorubicin (PLD). The MRP1/R723Q polymorphism was found in five subjects among the 279 patient study population, all of whom received PLD + bortezomib. Its presence was associated with a longer time to progression (TTP; median 330 vs. 129 days; p = 0.0008), progression-free survival (PFS; median 338 vs. 129 days; p = 0.0006), and overall survival (p = 0.0045). MDR1/3435(C > T), which was in Hardy-Weinberg equilibrium, showed a trend of association with PFS (p = 0.0578), response rate (p = 0.0782) and TTP (p = 0.0923) in PLD + bortezomib patients, though no correlation was found in the bortezomib arm. In a recessive genetic model, MDR1/3435 T was significantly associated with a better TTP (p = 0.0405) and PFS (p = 0.0186) in PLD + bortezomib patients. These findings suggest a potential role for MRP1 and MDR1 SNPs in modulating the long-term outcome of relapsed and/or refractory myeloma patients treated with PLD + bortezomib. Moreover, they support prospective studies to determine if such data could be used to tailor therapy to the genetic makeup of individual patients.

Effect of the cytochrome P450 2C19 inhibitor omeprazole on the pharmacokinetics and safety profile of bortezomib in patients with advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma.

BACKGROUND AND OBJECTIVE: Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated. PATIENTS AND METHODS: This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin's lymphoma or multiple myeloma, were aged >/=18 years, weighed >/=50 kg and had a life expectancy of >/=3 months were eligible. Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6-10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood samples for pharmacokinetic/pharmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood samples for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin version 4.0.1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay. RESULTS: Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively. Bortezomib pharmacokinetic parameters were similar when bortezomib was administered alone or with omeprazole (maximum plasma concentration 120 vs 123 ng/mL; area under the plasma concentration-time curve from 0 to 72 hours 129 vs 135 ng . h/mL). The pharmacodynamic parameters were also similar (maximum effect 85.8% vs 93.7%; area under the percent inhibition-time curve over 72 hours 4052 vs 3910 % x h); the differences were not statistically significant. Pharmacogenomic analysis revealed no meaningful relationships between CYP enzyme polymorphisms and pharmacokinetic/pharmacodynamic parameters. Toxicities were generally similar between patients in sequence 1 and sequence 2, and between cycle 1 and cycle 2 in both treatment sequences. Among 26 evaluable patients, 13 (50%) were assessed as benefiting from bortezomib at the end of cycle 2 and continued to receive treatment. CONCLUSION: No impact on the pharmacokinetics, pharmacodynamics and safety profile of bortezomib was seen with coadministration of omeprazole. Concomitant administration of bortezomib and omeprazole is unlikely to cause clinically significant drug-drug interactions and is unlikely to have an impact on the efficacy or safety of bortezomib.

Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients.

Administration of specific drugs may occasionally induce acquired long QT syndrome (aLQTS), a disorder that predisposes to ventricular arrhythmias, typically of the torsade de pointes (TdP) type, and sudden cardiac death. "Forme fruste" mutations in congenital LQTS (cLQTS) genes have been reported repeatedly as the underlying cause of aLQTS, and are therefore considered as an important risk factor. We evaluated the impact of genetic susceptibility for aLQTS through mutations in cLQTS genes. Five cLQTS genes ( KCNH2, KCNQ1, SCN5A, KCNE1, KCNE2) were thoroughly screened for genetic variations in 32 drug-induced aLQTS patients with confirmed TdP and 32 healthy individuals. Missense forme frust mutations were identified in four aLQTS patients: D85N in KCNE1 (two cases), T8A in KCNE2, and P347S in KCNH2. Three other missense variations were found both in patients and controls, and are thus unlikely to significantly influence aLQTS susceptibility. In addition, 13 silent and six intronic variations were detected, four of which were found in a single aLQTS patient but not in the controls. We conclude that missense mutations in the examined cLQTS genes explain only a minority of aLQTS cases.

A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency.

The congenital long QT syndrome is a cardiac disease characterized by an increased susceptibility to ventricular arrhythmias. The clinical hallmark is a prolongation of the QT interval, which reflects a delay in repolarization caused by mutations in cardiac ion channel genes. Mutations in the HERG (human ether-à-go-go-related gene KCNH2 can cause a reduction in I(Kr), one of the currents responsible for cardiac repolarization. We describe the identification and characterization of a novel missense mutation T65P in the PAS (Per-Arnt-Sim) domain of HERG, resulting in defective trafficking of the protein to the cell membrane. Defective folding of the mutant protein could be restored by decreased cell incubation temperature and pharmacologically by cisapride and E-4031. When trafficking was restored by growing cells at 27 degrees C, the kinetics of the mutated channel resembled that of wild-type channels although the rate of activation, deactivation, and recovery from inactivation were accelerated. No positive evidence for the formation of heterotetramers was obtained by co-expression of wild-type with mutant subunits at 37 degrees C. As a consequence the clinical symptoms may be explained rather by haploinsufficiency than by dominant negative effects. This study is the first to relate a PAS domain mutation in HERG to a trafficking deficiency at body temperature, apart from effects on channel deactivation.