CRISPLD1 rs12115090 polymorphisms alters antiplatelet potency of clopidogrel in coronary artery disease patients in Chinese Han.

Gene. 2018 Aug 07;:

Authors: Wang JY, Zhang YJ, Li H, Hu XL, Li MP, Song PY, Ma QL, Peng LM, Chen XP

Abstract
BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is a recommended treatment for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI) to reduce the rate of ischemic events and stent thrombosis. However, high on-treatment platelet reactivity (HTPR) during clopidogrel therapy for some patients may lead to outcome failure and occurrence of cardiovascular events. Amounts of studies have proved that genetic factors may contribute to HTPR. In our study, we explored the predictive value of 10 single nucleotide polymorphisms (SNPs) in 8 genes indicated by exome sequencing with clopidogrel efficacy.
METHODS: Two hundred and forty-one Han Chinese CAD patients (mean age: 61 ± 10 years) receiving dual antiplatelet therapy were recruited, among which 118 patients administered with 300 mg loading dose (LD) clopidogrel for 12-24 h and 123 subjects administered with 75 mg/day maintain dose (MD) clopidogrel for at least 5 days before discharge. The platelet reaction index (PRI) was determined to reflect clopidogrel response in the patients. Venous blood samples were drawn from all participants to extract genomic DNA. MassARRAY, Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to determine the genotypes of 10 SNPs.
RESULTS: Allelic tests showed significant differences in genotype distribution between HTPR and normal on-treatment platelet reactivity (NTPR) patients for 3 SNPs including CYP2C19 rs4244285 (CYP2C19*2) (co-dominant model: p = 0.003, dominant model: p = 0.004, recessive model: p = 0.012), CRISPLD1 rs12115090 (co-dominant model: p = 0.011, dominant model: p = 0.004), and LTA4H rs11108379 (dominant model: p = 0.041). After adjusting for covariates including clinical characteristics of patients, concomitant medications and complications, we confirmed that carriers of the CYP2C19*2 showed significantly increased risk of HTPR (*2/*2 vs *1/*1: OR = 12.266, 95% CI: 1.336-112.592, p = 0.027; *1/*2 + *2/*2 vs *1/*1: OR = 2.202, 95% CI: 1.083-4.480, p = 0.029). Contrarily, carriers of the CRISPLD1 rs12115090 C allele showed significantly reduced risk of HTPR (CC vs AA: OR = 0.242, 95% CI: 0.078-0.752, p = 0.014; CA + CC vs AA: OR = 0.457, 95% CI: 0.232-0.904, p = 0.024) in Chinese CAD patients. In addition, carriers of the CYP2C19*2 allele showed was significantly increased PRI (*1/*2 vs *1/*1: p = 0.008, 2/*2 vs 1/*1: p < 0.001, *2/*2 vs 1/*2: p = 0.011), while patients carrying the rs12115090 C allele showed significantly decreased PRI than the wild-type AA homozygotes (CA vs AA: p = 0.046, CA + CC vs AA: p = 0.023).
CONCLUSION: CYP2C19*2 reduced the antiplatelet potency of clopidogrel and increased the risk of HTPR, while CRISPLD1 rs12115090 A>C polymorphism increased the antiplatelet potency of clopidogrel. Genetic tests, especially for CYP2C19*2 are recommended in Han Chinese CAD patients before using of clopidogrel.

PMID: 30096456 [PubMed - as supplied by publisher]

Correction to: Clopidogrel Pharmacogenetics in Iranian Patients Undergoing Percutaneous Coronary Intervention.

Cardiovasc Toxicol. 2018 Aug 09;:

Authors: Mahdieh N, Rabbani A, Firouzi A, Zahedmehr A, Hoseinimoghaddam M, Saedi S, Sanati H, Basiri H, Noohi F, Rabbani B, Maleki M

Abstract
The original version of this article unfortunately contained a typo in the co-author name.

PMID: 30094619 [PubMed - as supplied by publisher]

Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer.

Breast Cancer Res Treat. 2018 Aug 09;:

Authors: Borrie AE, Rose RV, Choi YH, Perera FE, Read N, Sexton T, Lock M, Vandenberg TA, Hahn K, Dinniwell R, Younus J, Logan D, Potvin K, Yaremko B, Yu E, Lenehan J, Welch S, Tyndale RF, Teft WA, Kim RB

Abstract
PURPOSE: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia.
METHODS: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms.
RESULTS: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline.
CONCLUSIONS: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

PMID: 30094551 [PubMed - as supplied by publisher]

Clinical and molecular characteristics of colombian patients with mucopolysaccharidosis IVA, and description of a new galns gene mutation.

Mol Genet Metab Rep. 2018 Sep;16:53-56

Authors: Moreno Giraldo LJ, Escudero Rodríguez ÁM, Sánchez Gómez A, Satizabal Soto JM

Abstract
A study published in 2012 estimated incidence of MPS IVA, in 0.68 cases per 100, 000 live births in Colombia, and according to the Colombian Fund for High-Cost Diseases, in 2014 there were 15 people diagnosed with MPS IV. To enhance the knowledge of the disease in the country, we aimed to characterize clinical and molecular findings in 12 MPS IVA patients. Twelve patients were included in the study, with most patients of female gender (n = 7, 58,3%), age range 2 to 28 years, average weight 26 kg (17.6-43 kg), average height 97 cm (92-104 cm), average BMI 27.6 kg/m2 (19.92-47.65 kg/m2). Clinical findings were similar to those described in the literature. GALNS gene molecular analysis showed five homozygous missense mutations in exon 11 c.1156C > T or p.R386C, a single nonsense mutation in the heterozygous state c.974G > A p.W325, and heterozygous in exon 9 mutation of exon 3 c.280C > T p.R94C, missense variant reported by Ogawa in 1995 [17]. There was only one patient that presented a homozygous missense mutation in exon 9 c.901G > T p.G301C and four patients showed the heterozygous form. A heterozygous missense mutation in exon 5 c.425A > T p.H142L, which has not been previously reported, was found in a female patient, 2 years 11 months of age. The diagnosis algorithms that include molecular analysis, bioinformatic predictive tools, pharmacogenomics, and proteomics helps to improve the diagnosis, treatment, and prognosis of patients affected by MPS IVA.

PMID: 30094185 [PubMed]

Cross-ethnicity tagging SNPs for HLA alleles associated with adverse drug reaction.

Pharmacogenomics J. 2018 Aug 10;:

Authors: Erlichster M, Goudey B, Skafidas E, Kwan P

Abstract
Reduction of adverse drug reaction (ADR) incidence through screening of predisposing human leucocyte antigen (HLA) alleles is a promising approach for many widely used drugs. However, application of these associations has been limited by the cost burden of HLA genotyping. Use of single nucleotide polymorphisms (SNPs) that can approximate ('tag') HLA alleles of interest has been proposed as a cost-effective and simple alternative to conventional genotyping. However, most reported SNP tags have not been validated and there is concern regarding clinical utility of this approach due to tagging inconsistency across different populations. We assess the ability of 67 previously reported and 378 novel tagging SNPs, identified here in 5 HLA reference panels, to tag 15 ADR-associated HLA alleles in a panel of 955 ethnically diverse samples. Tags for 8 HLA alleles of interest were identified with 100% sensitivity and >95% specificity. These SNPs may act as a reliable genotyping approach for the routine screening of patients, without the need to account for patient ethnicity.

PMID: 30093715 [PubMed - as supplied by publisher]

Polymorphisms in CEP68 gene associated with risk of immediate selective reactions to non-steroidal anti-inflammatory drugs.

Pharmacogenomics J. 2018 Aug 10;:

Authors: Perkins JR, Acosta-Herrera M, Plaza-Serón MC, Jurado-Escobar R, Doña I, García-Martín E, Isidoro-García M, Bartra J, Ribas-Perez D, Mayorga C, Torres MJ, Flores C, Cornejo-García JA

Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions. Such reactions can be pharmacologically or immunologically mediated, but in both cases individual susceptibility can be influenced by genetic factors. Polymorphisms in centrosomal protein of 68 kDa (CEP68) have been associated with pharmacologically mediated NSAIDs reactions. Here, we evaluated this gene in immunologically mediated single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) by analyzing 52 single nucleotide polymorphisms in CEP68 in 176 patients and 363 NSAIDs-tolerant controls. Two intronic variants (rs2241160 and rs2241161) were significantly associated with an increased risk of SNIUAA, suggesting CEP68 to be a key player in both types of NSAIDs hypersensitivity. However, we found no overlap with genetic variants previously associated with pharmacologically mediated hypersensitivity, pointing to a complex role for this gene and its potential use in the development of biomarkers of clinical utility to diagnose patients at risk of these reactions and to differentiate entities.

PMID: 30093714 [PubMed - as supplied by publisher]

Frequency of vitamin K oxidoreductase complex subunit-1 (VKORC1) polymorphisms and warfarin dose management in patients with venous thromboembolism.

Pharmacogenomics J. 2018 Aug 10;:

Authors: Kabalak PA, Savaş İ, Akar N, Demir N, Eğin Y

Abstract
Warfarin works by inhibiting VKORC1, so polymorphisms of this gene modify the required drug dose. The aim of this study is to examine the relation between therapeutic weekly dose of warfarin and C1173T/G1639A polymorphism of VKORC1 in patients with VTE. Seventy-five patients with VTE were enrolled. Weekly warfarin doses and time (day) to reach therapeutic INR were evaluated retrospectively along with VKORC1-C1173T and G1639A alleles. The mean weekly warfarin dose was lower and time to reach therapeutic INR was shorter in homozygote alleles (AA and TT) (p < 0.05). The multivariate regression model was produced, R2 = 0.05% for age (p = 0.04), R2 = 6% for VKORC1 (p = 0.03), the model for estimating warfarin dose R2 = 17% (p > 0.05). In particular, patients who need overdose of warfarin or whose bleeding score is high, study of these polymorphisms can be considered.

PMID: 30093713 [PubMed - as supplied by publisher]

Systematic identification of non-coding pharmacogenomic landscape in cancer.

Nat Commun. 2018 Aug 09;9(1):3192

Authors: Wang Y, Wang Z, Xu J, Li J, Li S, Zhang M, Yang D

Abstract
Emerging evidence has shown long non-coding RNAs (lncRNAs) play important roles in cancer drug response. Here we report a lncRNA pharmacogenomic landscape by integrating multi-dimensional genomic data of 1005 cancer cell lines and drug response data of 265 anti-cancer compounds. Using Elastic Net (EN) regression, our analysis identifies 27,341 lncRNA-drug predictive pairs. We validate the robustness of the lncRNA EN-models using two independent cancer pharmacogenomic datasets. By applying lncRNA EN-models of 49 FDA approved drugs to the 5605 tumor samples from 21 cancer types, we show that cancer cell line based lncRNA EN-models can predict therapeutic outcome in cancer patients. Further lncRNA-pathway co-expression analysis suggests lncRNAs may regulate drug response through drug-metabolism or drug-target pathways. Finally, we experimentally validate that EPIC1, the top predictive lncRNA for the Bromodomain and Extra-Terminal motif (BET) inhibitors, strongly promotes iBET762 and JQ-1 resistance through activating MYC transcriptional activity.

PMID: 30093685 [PubMed - in process]

Correction to: Population-Based Analysis of Cluster Headache-Associated Genetic Polymorphisms.

J Mol Neurosci. 2018 Aug 09;:

Authors: Katsarou MS, Papasavva M, Latsi R, Toliza I, Gkaros AP, Papakonstantinou S, Gatzonis S, Mitsikostas DD, Kovatsi L, Izotov BN, Tsatsakis AM, Drakoulis N

Abstract
The original version of this article unfortunately contained mistakes in author group section.

PMID: 30091080 [PubMed - as supplied by publisher]

Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients.

Pharmacogenomics. 2018 Aug 08;:

Authors: Elsayed AH, Cao X, Crews KR, Gandhi V, Plunkett W, Rubnitz JE, Ribeiro RC, Pounds SB, Lamba JK

Abstract
AIM: Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP.
METHOD:  We investigated SNPs in 14 ara-C metabolic-pathway genes, for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68).
RESULTS:  Nine SNPs were significantly associated with leukemic cell intracellular concentration of ara-CTP. A comprehensive ara-CTP-SNP-score (ACSS) was further developed from top four SNPs identified in regression model. Patients were classified into three groups based on ACSS: high-ACSS (score >0), intermediate-ACSS (score = 0) and low-ACSS (score <0). ACSS designation was significant predictor of intracellular ara-CTP levels (p = 0.00012), suggesting a cumulative or synergistic effect of the significant SNPs.
CONCLUSION: ACSS score designation holds promise in definfing ara-C dose. Validation of the clinical utility of ACSS score in other independent cohorts will help identification of patients with potentially lower or higher levels of the ara-CTP in leukemic cells, thereby opening up opportunities for dose management to reduce toxicity and enhance efficacy.

PMID: 30088438 [PubMed - as supplied by publisher]

A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening.

Front Oncol. 2018;8:279

Authors: Tong CC, Lam CW, Lam KO, Lee VHF, Luk MY

Abstract
Background: The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity. Patients and methods: A 49-year-old lady with resected stage III carcinoma of sigmoid colon was scheduled to have a course of 5-FU based adjuvant chemotherapy. She developed unexpected acute severe (grade 4) toxicity after the first cycle of chemotherapy. Genomic DNA was isolated from 3 ml peripheral blood cells for full sequencing of DPYD (the gene encoding DPD). Results: Exome sequencing confirmed that she is heterozygous for NM_000110.3: c.321+2T>C of the DPYD gene. To the best of our knowledge, this variant is a novel pathogenic splicing variant of the DPYD gene resulting in a non-functional allele. As she has a heterozygous genotype and considered having decreased DPD activity, we followed the international recommendation and restart chemotherapy with at least 50% reduction for 5-FU dose. We then titrated the 5-FU dose, and she tolerated the subsequent cycles of chemotherapy and completed the whole course of adjuvant chemotherapy. Conclusions: With a pre-emptive test on DPD deficiency before the administration of the fluoropyrimidine drugs, the aforementioned patient's life-threatening event could be avoided. This clinical utility has been confirmed by two recent large-scale studies and called for a drug label update.

PMID: 30087856 [PubMed]

Modeling Corticosteroid Pharmacogenomics and Proteomics in Rat Liver.

J Pharmacol Exp Ther. 2018 Aug 07;:

Authors: Ayyar VS, Sukumaran S, DuBois DC, Almon RR, Jusko WJ

Abstract
Corticosteroids (CS) regulate the expression of numerous genes at the mRNA and protein levels. The time-course of CS pharmacogenomics and proteomics were examined in livers obtained from adrenalectomized rats given a 50 mg/kg bolus dose of methylprednisolone. Microarrays and mass-spectrometry based proteomics were employed to quantify hepatic transcript and protein dynamics. A total of 163 differentially expressed mRNA and their corresponding proteins (163 genes) were clustered into two dominant groups. The temporal profiles of most proteins were delayed compared to its mRNA, attributable to synthesis delays and slower degradation kinetics. Based upon our fifth-generation model of CS, mathematical models were developed to simultaneously describe the emergent time-patterns for an array of steroid-responsive mRNA and proteins. The majority of genes showed time-dependent increases in mRNA and protein expression before returning to baseline. A model assuming direct, steroid-mediated stimulation of mRNA synthesis was applied. Some mRNAs and their proteins displayed down-regulation following CS. A model assuming receptor-mediated inhibition of mRNA synthesis was utilized. More complex patterns were observed for other genes (e.g. biphasic behaviors and opposite directionality in mRNA and protein). Models assuming either stimulation or inhibition of mRNA synthesis coupled with dual secondarily-induced regulatory mechanisms affecting mRNA or protein turnover were derived. These findings indicate that CS-regulated gene expression manifested at the mRNA and protein levels are controlled via mechanisms affecting key turnover processes. Our quantitative models of CS pharmacogenomics were expanded from mRNA to proteins and provide extended hypotheses for understanding the direct, secondary, and downstream mechanisms of CS actions.

PMID: 30087156 [PubMed - as supplied by publisher]

Clinical pharmacogenomics of carvedilol: the stereo-selective metabolism angle.

Pharmacogenomics. 2018 Aug 08;:

Authors: Parker BM, Rogers SL, Lymperopoulos A

PMID: 30086658 [PubMed - as supplied by publisher]

POLD1 and POLE Gene Mutations in Jewish Cohorts of Early-Onset Colorectal Cancer and of Multiple Colorectal Adenomas.

Dis Colon Rectum. 2018 Sep;61(9):1073-1079

Authors: Rosner G, Gluck N, Carmi S, Bercovich D, Fliss-Issakov N, Ben-Yehoyada M, Aharon-Caspi S, Kellerman E, Strul H, Shibolet O, Kariv R

Abstract
BACKGROUND: Germline mutations in the DNA polymerase genes POLD1 and POLE confer high risk for multiple colorectal adenomas and colorectal cancer. However, prevalence and the clinical phenotype of mutation carriers are still not fully characterized.
OBJECTIVE: The purpose of this study was to assess the prevalence of germline mutations and to describe the genotype-phenotype correlation in POLD1 and POLE genes in Jewish subjects with multiple colorectal adenomas and/or early-onset mismatch repair proficient colorectal cancers.
DESIGN: This study is a comparison of genetic and clinical data from affected and control groups.
SETTINGS: The study was conducted at a high-volume tertiary referral center.
PATIENTS: The study cohort included 132 subjects: 68 with multiple colorectal adenomas and 64 with early-onset mismatch repair proficient colorectal cancers. The control group included 5685 individuals having no colorectal cancer or colorectal adenomas.
MAIN OUTCOME MEASURES: Study and control subjects were tested for POLD1 and POLE mutations and a clinical correlation was assessed.
RESULTS: Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer. Three mutations were detected, showing statistical significance in frequency between study and control groups (p < 0.001). Eight of the 11 mutation carriers were Ashkenazi Jews carrying the same POLD1 mutation (V759I), implicating it as a possible low-to-moderate risk founder mutation. Phenotype of mutation carriers was notable for age under 50 at diagnosis, a propensity toward left-sided colorectal cancer, and extracolonic tumors (64%, 100%, and 27% of cases).
LIMITATIONS: The study cohort was limited by its relatively small size.
CONCLUSIONS: Germline mutations in POLD1 and POLE were found to be relatively frequent in our Jewish cohorts. Further studies are needed to clarify the importance of POLD1 and POLE mutations and to define the most suitable surveillance program for Jewish and other POLD1 and POLE mutation carriers. See Video Abstract at http://links.lww.com/DCR/A658.

PMID: 30086056 [PubMed - in process]

Decoding the transcriptional programs activated by psychotropic drugs in the brain.

Genes Brain Behav. 2018 Aug 07;:e12511

Authors: Zygmunt M, Piechota M, Rodriguez Parkitna J, Korostynski M

Abstract
Analysis of drug-induced gene expression in the brain has long held the promise of revealing the molecular mechanisms of drug actions as well as predicting their long-term clinical efficacy. However, despite some successes, this promise has yet to be fulfilled. Here, we present an overview of the current state of understanding of drug-induced gene expression in the brain and consider the obstacles to achieving a robust prediction of the properties of psychoactive compounds based on gene expression profiles. We begin with a comprehensive overview of the mechanisms controlling drug-inducible transcription and the complexity resulting from expression of non-coding RNAs and alternative gene isoforms. Particular interest is placed on studies that examine the associations within drug classes with regard to the effects on gene transcription, alterations in cell signaling and neuropharmacological drug properties. While the ability of gene expression signatures to distinguish specific clinical classes of psychotropic and addictive drugs remains unclear, some reports show that under specific constraints, drug properties can be predicted based on gene expression. Such signatures offer a simple and effective way to classify psychotropic drugs and screen novel psychoactive compounds. Finally, we note that the amount of data regarding molecular programs activated in the brain by drug treatment has grown exponentially in recent years and that future advances may therefore come in large part from integrating the currently available high-throughput data-sets. This article is protected by copyright. All rights reserved.

PMID: 30084543 [PubMed - as supplied by publisher]

Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: an update on pharmacogenetics studies.

Pharmacogenomics. 2018 Aug 07;:

Authors: Plaza-Serón MDC, García-Martín E, Agúndez JA, Ayuso P

Abstract
Nonsteroidal anti-inflammatory drugs are the medications most frequently involved in hypersensitivity reactions to drugs. These can be induced by specific immunological and nonimmunological mechanisms, being the latter the most frequent. The nonimmunological mechanism is related to an imbalance of inflammatory mediators, which is aggravated by the cyclooxygenase inhibition. Genetic studies suggest that multiples genes and additional mechanisms might be involved. The proposals of this review is summarize the contribution of variations in genes involved in the arachidonic acid, inflammatory and immune pathways as well as the recent genome-wide association studies findings related to cross-intolerant nonsteroidal anti-inflammatory drugs hypersensitivity reactions. In addition, using integration of different genetic studies, we propose new target genes. This will help to understand the underlying mechanism of these reactions.

PMID: 30081739 [PubMed - as supplied by publisher]

Integrative clinico-biological, pharmacogenetic, neuroimagistic, neuroendocrinological and psychological correlations in depressive and anxiety disorders.

Rom J Morphol Embryol. 2017;58(3):767-775

Authors: Hogea LM, Nussbaum LA, Chiriac DV, Ageu LŞ, Andreescu NI, Grigoraş ML, Folescu R, Bredicean AC, Puiu M, Roşca ECI, Simu MA, Levai CM

Abstract
We approach the theme of modern treatment strategies, based on clinico-biological, pharmacogenetic, neuroimagistic, neuroendocrinological and psychological integrative correlations in the management of depressive and comorbid anxiety disorders. We target to evaluate the efficacy of the pharmacogenetic testing and the evolution, functioning of patients in correlation with specific neurobiological, neuroimagistic and neuroendocrinological markers. Our research was conducted between 2010-2016 on 80 children and adolescents with depressive and comorbid anxiety disorders - 40 children (G1 group), who benefited in choosing the pharmacotherapy from pharmacogenetic testing and 40 children without testing (G2 group). Also, the patients were evaluated through magnetic resonance (MR) spectroscopy at baseline and after pharmacotherapy. The efficacy of the chosen therapy in correlation with the pharmacogenetic testing was evaluated through the mean change in the CDRS (Children's Depression Rating Scale) total scores, in the CGI-S÷I (Clinical Global Impression - Severity÷Improvement), CGAS (Children's Global Assessment Scale) and through the change of the relevant neurobiological markers and MR spectroscopy metabolites. We evaluated the side effects through the PAERS (Pediatric Adverse Events Rating Scale)-Clinician. Our results show statistically significant differences of the clinical scores between the studied groups: for those subjects who benefited of pharmacogenetic testing, the CDRS, the global functioning scores prove a higher clinical improvement, a better compliance and lower PAERS side effects scores and also improvement concerning the MR spectroscopy dosed metabolites values. Our research was a proof sustaining the use of the pharmacogenetic testing in clinical practice and the value of investigating relevant neurobiological, neuroimagistic and neuroendocrinological markers for a personalized therapy in depressive disorders.

PMID: 29250653 [PubMed - indexed for MEDLINE]

Combinatorial pharmacogenomics and improved patient outcomes in depression: Treatment by primary care physicians or psychiatrists.

J Psychiatr Res. 2018 Jul 21;104:157-162

Authors: Tanner JA, Davies PE, Voudouris NC, Shahmirian A, Herbert D, Braganza N, Gugila A, Dechairo BM, Kennedy JL

Abstract
Failed medication trials are common in the treatment of major depressive disorder (MDD); however, the use of combinatorial pharmacogenomics to guide medication selection has been previously associated with improved outcomes in the psychiatric care setting. The utility of combinatorial pharmacogenomics in patients with MDD in primary care and psychiatric care settings was evaluated here. Patients enrolled in a naturalistic, open-label, prospective study [Individualized Medicine: Pharmacogenetics Assessment and Clinical Treatment (IMPACT)] with MDD were evaluated (N = 1871). Pharmacogenomic testing was performed for all patients and medications were categorized based on gene-drug interactions. Beck's Depression Inventory (BDI) was evaluated at baseline and follow-up (weeks 8-12). Symptom improvement (percent decrease in BDI), response (≥50% decrease in BDI), and remission (BDI≤10) at follow-up were evaluated according to provider type and whether medications were genetically congruent (little/no gene-drug interactions). There was a 27.9% reduction in depression symptoms at follow-up, as well as response and remission rates of 25.7% and 15.2%, respectively. Outcomes were significantly better among patients treated by primary care providers versus psychiatrists (symptom improvement 31.7% versus 24.9%, p < 0.01; response rate 30.1% versus 22.3%, p < 0.01; remission rate 19.5% versus 12.0%, p < 0.01). There was a 31% relative improvement in response rate among patients taking congruent versus incongruent medications, with slightly higher congruence among primary care providers (87.6%) versus psychiatrists (85.2%). Following combinatorial pharmacogenomic testing, outcomes were significantly improved among patients treated by primary care providers compared to psychiatrists, which supports the use of pharmacogenomics in broader treatment settings.

PMID: 30081389 [PubMed - as supplied by publisher]

Pharmacogenetics Analysis of Serotonin Receptor Gene Variants and Clinical Response to Risperidone in Han Chinese Schizophrenic Patients.

Neurosci Lett. 2018 Aug 03;:

Authors: Zhou W, Chang W, Yan Y, Shen L, Li W, Yi Z, Qin S

Abstract
Assessments of the pharmacological profiles of antipsychotic agents have shown that the serotonin receptor family is often involved in their pharmacodynamics. Response to antipsychotic therapy is highly variable, yet prognostic biomarkers are lacking. The aim of the study was to investigate the association of 14 single nucleotide polymorphisms (SNPs) selected from HTR3C, HTR3D, HTR5A and HTR6 with risperidone response in 201 Han Chinese schizophrenia patients. The results showed that the HTR6 rs6699866 was significantly associated with risperidone response and predicted greater positive symptom reduction in risperidone-treated subjects (P =  0.04 and 0.004, respectively). The current study provides insight into the relationship between genetic polymorphisms in serotonin receptor family and risperidone therapeutic response in Han Chinese population. To clarify the role of these SNPs in clinical response to antipsychotic medication, and risperidone in particular, the study warrants further investigation in larger well-characterized samples.

PMID: 30081060 [PubMed - as supplied by publisher]

Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients.

Br J Haematol. 2018 Aug 06;:

Authors: Macauda A, Castelli E, Buda G, Pelosini M, Butrym A, Watek M, Kruszewski M, Vangsted AJ, Rymko M, Jamroziak K, Abildgaard N, Haastrup EK, Mazur G, Ríos R, Jurczyszyn A, Zawirska D, Dudziński M, Raźny M, Dutka M, Tomczak W, Suska A, Druzd-Sitek A, Marques H, Petrini M, Markiewicz M, Martinez-Lopez J, Ebbesen LH, Iskierka-Jażdżewska E, Sainz J, Canzian F, Campa D

Abstract
Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.

PMID: 30079960 [PubMed - as supplied by publisher]