Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics.

J Am Heart Assoc. 2017 Dec 29;7(1):

Authors: Shahin MH, Gong Y, Frye RF, Rotroff DM, Beitelshees AL, Baillie RA, Chapman AB, Gums JG, Turner ST, Boerwinkle E, Motsinger-Reif A, Fiehn O, Cooper-DeHoff RM, Han X, Kaddurah-Daouk R, Johnson JA

Abstract
BACKGROUND: Although hydrochlorothiazide (HCTZ) is a well-established first-line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure (BP) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response.
METHODS AND RESULTS: First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway (P=5.8E-05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C-allele carriers had a better BP response to HCTZ versus noncarriers (∆SBP/∆DBP: -11.4/-6.9 versus -6.8/-3.5 mm Hg; ∆SBP P=6.7E-04; ∆DBP P=4.8E-04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC3 genomic region significantly associated with the BP response to HCTZ (P<0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate <0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP-response (r=-0.42; P=7E-03) and SBP-response (r=-0.36; P=2E-02).
CONCLUSIONS: This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC3 is a potential determinant of the BP response to HCTZ.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519.

PMID: 29288159 [PubMed - in process]

Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients.

Pediatr Blood Cancer. 2017 Dec 29;:

Authors: Conyers R, Devaraja S, Elliott D

Abstract
Many paediatric patients with cancer experience significant chemotherapy side effects. Predisposition to drug reactions is governed by single nucleotide polymorphisms (SNPs). We performed a systematic review of the literature from 2006 through 2016. Outcomes of interest included patient characteristics, cancer type drug of interest, genes investigated, toxicity identified and genetic polymorphisms implicated. The primary toxicities studied were neurotoxicity cardiotoxicity, osteonecrosis, and thromboembolism and hypersensitivity reactions. The retrieved studies were grouped according to toxicity reported and SNP associations. This review highlights the discoveries to date in pharmacogenomics and paediatric oncology along with highlighting some of the important limitations in the area.

PMID: 29286579 [PubMed - as supplied by publisher]

Facilitators and Barriers to the Adoption of Pharmacogenetic Testing in an Inner City Population.

Pharmacotherapy. 2017 Dec 29;:

Authors: Lee YM, Manzoor BS, Cavallari LH, Nutescu EA

Abstract
OBJECTIVES: To examine the knowledge, attitudes, and interest of an inner city population toward pharmacogenetic testing, with the primary objective of identifying facilitators and barriers toward pharmacogenetic testing; and secondary objectives of determining predictors of patient interest in pharmacogenetic testing and how much patients would pay for the test.
METHODS: Patients were recruited from an Antithrombosis Clinic from March to April 2014. A cross-sectional 19-question survey was administered in-person to determine patients' knowledge and awareness of pharmacogenetic testing and collect demographic information. After explaining pharmacogenetics, patients ranked their interest toward the test and answered open-ended questions that elicited facilitators and barriers toward pharmacogenetic testing and elucidated how much patients would pay for testing.
RESULTS: A total of 120 patients (mean age 55.0 ± 14.0 years, 39.2% male, 69.2% African American) were surveyed. Facilitators included providing further information about pharmacogenetic testing; elaborating on benefits of testing to predict treatment efficacy; patients' trust in their providers to make correct genotype-guided prescribing decisions; and insurance coverage and test affordability. Barriers to testing included concerns about the negative consequences associated with test results; burden of the testing process; perceived lack of utility among elderly and those whose medications were working; privacy issues; and concerns regarding insurance coverage and test affordability. Females had 4.2 times higher adjusted odds of being interested in pharmacogenetic testing. Almost half (44.4%) of the patients with high interest in the test were willing to pay $20 or more, whereas 76.2% of patients with low interest wanted testing at no cost.
CONCLUSION: This study identified facilitators, such as providing additional pharmacogenetic test information, and barriers, such as perceived negative impact of the results and test utility, as issues to address when engaging an urban, largely minority population in pharmacogenetic testing. Female gender was a predictor of interest toward pharmacogenetic testing. These facilitators and barriers should be taken into consideration as pharmacogenetic testing gains widespread utility among inner city populations. This article is protected by copyright. All rights reserved.

PMID: 29286540 [PubMed - as supplied by publisher]

Endogenous metabolites-mediated communication between OAT1/OAT3 and OATP1B1 may explain the association between SLCO1B1 SNPs and methotrexate toxicity.

Clin Pharmacol Ther. 2017 Dec 29;:

Authors: Martinez D, Muhrez K, Woillard JB, Berthelot A, Gyan E, Choquet S, Andrès CR, Marquet P, Barin-Le Guellec C

Abstract
Although OATP1B1 is not expressed in the kidney, polymorphisms in SLCO1B1 have been associated with methotrexate clearance or toxicity. This unexpected pharmacogenetic association may reflect remote communication between liver and kidney transporters. This study confirms the pharmacogenetic association with methotrexate toxicity in adult patients with hematological malignancies. Using a targeted urinary metabolomics approach, we identified 38 and 34 metabolites which were differentially excreted between wild-type and carriers of the c.388A>G or c.521T>C variant alleles, respectively, half of them being associated with methotrexate toxicity. These metabolites mainly consisted of fatty acid derivatives and microbiota catabolites, including glycine conjugates and other uremic toxins, all known OATs substrates. These results suggest that dysfunction of a transporter affects the excretion profile of endogenous or exogenous substrates, possibly through metabolite-mediated interactions involving other transport systems, even in distant organs. This opens the way for better comprehension of complex pharmacokinetics and transporter-mediated drug-drug or nutrient-drug interactions. This article is protected by copyright. All rights reserved.

PMID: 29285751 [PubMed - as supplied by publisher]

Expression and splicing of ABC and SLC transporters in the human blood-brain barrier measured with RNAseq.

Eur J Pharm Sci. 2017 May 30;103:47-51

Authors: Suhy AM, Webb A, Papp AC, Geier EG, Sadee W

Abstract
The blood-brain barrier (BBB) expresses numerous membrane transporters that supply needed nutrients to the central nervous system (CNS), consisting mostly of solute carriers (SLC transporters), or remove unwanted substrates via extrusion pumps through the action of ATP binding cassette (ABC) transporters. Previous work has identified many BBB transporters using hybridization arrays or qRT-PCR, using targeted probes. Here we have performed next-generation sequencing of the transcriptome (RNAseq) extracted from cerebral cortex tissues and brain microvessel endothelial cells (BMEC) obtained from two donors. The same RNA samples had previously been measured for transporter expression using qRT-PCR (Geier et al., 2013), yielding similar expression levels for overlapping mRNAs (R=0.66, p<0.001). RNAseq confirms a number of transporters highly enriched in BMECs (e.g., ABCB1, ABCG2, SLCO2B1, and SLC47A1), but also detects novel BMEC transporters. Multiple splice isoforms detected by RNAseq are either robustly enriched or depleted in BMECs, indicating differential RNA processing in the BBB. The Complete RNAseq data are publically available (GSE94064).

PMID: 28188910 [PubMed - indexed for MEDLINE]

Transcriptional, Functional, and Mechanistic Comparisons of Stem Cell-Derived Hepatocytes, HepaRG Cells, and Three-Dimensional Human Hepatocyte Spheroids as Predictive In Vitro Systems for Drug-Induced Liver Injury.

Drug Metab Dispos. 2017 Apr;45(4):419-429

Authors: Bell CC, Lauschke VM, Vorrink SU, Palmgren H, Duffin R, Andersson TB, Ingelman-Sundberg M

Abstract
Reliable and versatile hepatic in vitro systems for the prediction of drug pharmacokinetics and toxicity are essential constituents of preclinical safety assessment pipelines for new medicines. Here, we compared three emerging cell systems-hepatocytes derived from induced pluripotent stem cells, HepaRG cells, and three-dimensional primary human hepatocyte (PHH) spheroids-at transcriptional and functional levels in a multicenter study to evaluate their potential as predictive models for drug-induced hepatotoxicity. Transcriptomic analyses revealed widespread gene expression differences between the three cell models, with 8148 of 17,462 analyzed genes (47%) being differentially expressed. Expression levels of genes involved in the metabolism of endogenous as well as xenobiotic compounds were significantly elevated in PHH spheroids, whereas genes involved in cell division and endocytosis were significantly upregulated in HepaRG cells and hepatocytes derived from induced pluripotent stem cells, respectively. Consequently, PHH spheroids were more sensitive to a panel of drugs with distinctly different toxicity mechanisms, an effect that was amplified by long-term exposure using repeated treatments. Importantly, toxicogenomic analyses revealed that transcriptomic changes in PHH spheroids were in compliance with cholestatic, carcinogenic, or steatogenic in vivo toxicity mechanisms at clinically relevant drug concentrations. Combined, the data reveal important phenotypic differences between the three cell systems and suggest that PHH spheroids can be used for functional investigations of drug-induced liver injury in vivo in humans.

PMID: 28137721 [PubMed - indexed for MEDLINE]

Pharmacogenomics of CYP2C9: Functional and Clinical Considerations.

J Pers Med. 2017 Dec 28;8(1):

Authors: Daly AK, Rettie AE, Fowler DM, Miners JO

Abstract
CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare 'variants of uncertain significance', which are increasingly detected as more exome and genome sequencing of diverse populations is conducted.

PMID: 29283396 [PubMed]

Pharmacogenomics of methotrexate: Current status and future outlook.

Curr Drug Metab. 2017 Dec 27;:

Authors: Cao M, Guo M, Wu DQ, Meng L

Abstract
BACKGROUND: Methotrexate (MTX) is a folate analogue with high therapeutic efficiency in the treatment of cancers and autoimmune diseases. The efficacy and toxicity of MTX may be altered by genetic polymorphisms in genes involved in MTX metabolic pathway. Personalized pharmacotherapy based on gene polymorphisms enables a more efficient, compatible and cost-effective treatment of patients.
OBJECTIVE: Present article aims to review genetic polymorphisms associated with MTX pharmacokinetics, toxicity, and outcome, and try to point out future development directions of individualized MTX therapy.
METHOD: Details regarding the pharmacogenetics and pharmacogenomics of MTX are obtained from PubMed literatures.
CONCLUSION: The influences of single nucleotide polymorphisms (SNPs) in genes involved in MTX pathway are controversial. Many pharmacogenetic associations are disease specific and race specific. The present studies have almost limited to some certain ethnic groups and diseases. The data from these studies are not convincing enough to draw far-reaching conclusions about the applicability of MTX pharmacogenetics in clinical practice. Studies with large scale and multiple centers are needed in the future. MTX-PG inhibits folic metabolism through three mechanisms. TS, MTHFR and ATIC are the rate-limiting enzymes separately. The function of SNPs in these genes is often one-sided. Works focusing on the analysis of polymorphism in MTX transporters should be more efficient and meaningful.

PMID: 29283070 [PubMed - as supplied by publisher]

Influence of genetic polymorphisms on mycophenolic acid pharmacokinetics and patient outcomes in renal transplantation.

Curr Drug Metab. 2017 Dec 27;:

Authors: Guo M, Wang ZJ, Yang HW, Meng L, Tan RY, Gu M, Wei JF

Abstract
Mycophenolic acid (MPA) is an immunosuppressive drug widely used in the treatment of organ transplantation and autoimmune diseases. Pharmacokinetics and pharmacodynamics of MPA varies between individuals, the potential reasons being the genetic polymorphisms in key enzymes, drug transporters and target proteins of MPA, involving uridine diphosphate glucuronosyltransferase enzymes, organic anion transport polypeptides, multidrug resistance-associated protein 2, inosine monophosphate dehydrogenase and others. These genetic polymorphisms are associated with the metabolism, efficacy and toxicity of MPA, thus resulting in different MPA exposure and patient outcomes. Genetic variations in immune-response mediators are also responsible for renal transplant outcomes. In this review, we summarize MPA-related single nucleotide polymorphisms (SNPs) in the clinical randomized controlled trials and cohort studies of renal transplant patients in recent 15 years, and try to provide pharmacogenomics information for drug selection and dose adjustment, aiming to improve drug efficacy and reduce side effects in clinical application of MPA.

PMID: 29283068 [PubMed - as supplied by publisher]

Genetic and clinic predictors of new onset diabetes mellitus after transplantation.

Pharmacogenomics J. 2017 Dec 27;:

Authors: Saigi-Morgui N, Quteineh L, Bochud PY, Crettol S, Kutalik Z, Mueller NJ, Binet I, Van Delden C, Steiger J, Mohacsi P, Dufour JF, Soccal PM, Pascual M, Eap CB, Swiss Transplant Cohort Study

Abstract
New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36-1.90], p = 3.72*10-8 and ORreplication: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04-1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01-1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.

PMID: 29282365 [PubMed - as supplied by publisher]

Mir-pharmacogenetics of Vincristine and peripheral neurotoxicity in childhood B-cell acute lymphoblastic leukemia.

Pharmacogenomics J. 2017 Dec 27;:

Authors: Gutierrez-Camino Á, Umerez M, Martin-Guerrero I, García de Andoin N, Santos B, Sastre A, Echebarria-Barona A, Astigarraga I, Navajas A, Garcia-Orad A

Abstract
Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.

PMID: 29282364 [PubMed - as supplied by publisher]

The impact of genetic polymorphisms on CYP1A2 activity in humans: a systematic review and meta-analysis.

Pharmacogenomics J. 2017 Dec 27;:

Authors: Koonrungsesomboon N, Khatsri R, Wongchompoo P, Teekachunhatean S

Abstract
A large interindividual variation in the activity of cytochrome P450 1A2 (CYP1A2) raises concern about therapeutic failure or toxicity when medical professionals prescribe drugs extensively metabolized by CYP1A2. To date, a number of studies have assessed the association between genetic polymorphisms and CYP1A2 activity; however, there are controversies as to the functional importance of CYP1A2 polymorphisms on the metabolism of CYP1A2 substrates. This systematic review and meta-analysis assessed the effects of genetic polymorphisms on CYP1A2 activity, as measured by caffeine metabolism, in a total of 3570 individual subjects. Higher enzyme activity was observed among those who were homozygous or heterozygous for the -163C>A polymorphism (rs762551), when compared to the wild-type individuals (SMD = 0.40, 95%CI = 0.12-0.68, p = 0.005; SMD = 0.32, 95%CI = 0.11-0.54, p = 0.003, respectively) and this was more pronounced among smokers (SMD = 0.92, 95%CI = 0.27-1.57, p = 0.005; SMD = 0.56, 95%CI = 0.22-0.90, p = 0.001, respectively). For other CYP1A2 polymorphisms, altered caffeine metabolic ratios were not seen. Our results indicate the functional importance of -163C>A polymorphism on CYP1A2 inducibility in humans.

PMID: 29282363 [PubMed - as supplied by publisher]

Genetic variants in the VEGF pathway as prognostic factors in stages II and III colon cancer.

Pharmacogenomics J. 2017 Dec 27;:

Authors: Riera P, Virgili AC, Salazar J, Sebio A, Tobeña M, Sullivan I, Páez D

Abstract
The role of vascular endothelial growth factor (VEGF) gene polymorphisms in the prognosis of colon cancer prognosis remains unclear. We evaluated the influence of 28 single-nucleotide polymorphisms in 12 genes in the VEGF pathway on the prognosis of 347 patients with stage II-III colon cancer. We found that rs9513070 (VEGFR1) and rs1137282 (KRAS) were associated with overall survival in stage II colon cancer patients (p = 0.025 and p = 0.001, respectively). When primary tumor location was considered, rs9513070 was also associated with relapse-free and overall survival (p = 0.033 and p = 0.031, respectively) in left colon cancer patients. Additionally, rs35251833 in the ITGAV gene correlated with relapse-free survival (p = 0.032). This study provides evidence that germline polymorphisms in VEGFR1, KRAS and ITGAV genes are associated with prognosis in stages II-III colon cancer patients. As stage and tumor location are correlated with prognosis, future genetic studies should stratify colon cancer patients according to these parameters.

PMID: 29282362 [PubMed - as supplied by publisher]

Influence of BCL2L11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia.

Pharmacogenomics J. 2017 Dec 27;:

Authors: Plesa M, Gagné V, Glisovic S, Younan M, Sharif-Askari B, Laverdière C, Alos N, Leclerc JM, Sallan SE, Neuberg D, Kutok JL, Silverman LB, Sinnett D, Krajinovic M

Abstract
Osteonecrosis (ON) is corticosteroid-related complication, reported in children with acute lymphoblastic leukemia (ALL). We have previously found that polymorphisms in BCL2L11 gene coding for pro-apoptotic Bim protein influence reduction of overall survival (OS) in a corticosteroid (CS) dose-dependent manner in childhood ALL patients. The same set of SNPs was here investigated for an association with CS-related ON assessed retrospectively in 304 children with ALL from Quebec (QcALL cohort) who received Dana-Farber Cancer Institute (DFCI) ALL treatment protocols. Two-year cumulative incidence of symptomatic ON was 10.6%. Two BCL2L11 polymorphisms, the 891T>G (rs2241843) in all QcALL patients and 29201C>T (rs724710) in high-risk group were significantly associated with ON, P = 0.009 and P = 0.003, respectively. The association remained significant in multivariate model (HR891TT = 2.4, 95% CI 1.2-4.8, P = 0.01 and HR29201CC = 5.7, 95% CI 1.6-20.9, P = 0.008). Both polymorphisms influenced viability of dexamethasone treated lymphoblastoid cell lines (P ≤ 0.03). The 891T>G influenced Bim gamma isoform levels (0.03) and its association with ON was also confirmed in replication DFCI cohort (N = 168, P = 0.03). QcALL children had a high incidence of ON during therapy, which was highly associated with BCL2L11 polymorphisms.

PMID: 29282361 [PubMed - as supplied by publisher]

Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study.

BMC Cancer. 2017 Dec 28;17(1):901

Authors: Falkowski S, Woillard JB, Postil D, Tubiana-Mathieu N, Terrebonne E, Pariente A, Smith D, Guimbaud R, Thalamas C, Rouguieg-Malki K, Marquet P, Picard N

Abstract
BACKGROUND: Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC.
METHODS: Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6-9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and "environmental" risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with "environmental" risk factors.
RESULTS: No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29-8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10-3.39], p = 0.0257) in the "never alcohol consumption subgroup" (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70-10.9], p < 0.0001), living or working in rural or mix area (OR = 2.50[1.48-4.23], p = 0.0006 and OR = 2.99[1.63-5.48], p = 0.004, respectively) and tobacco exposure >30 years (3.37[1.63-6.96], p = 0.0010).
CONCLUSIONS: Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup.
TRIAL REGISTRATION: Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008-0144.

PMID: 29282011 [PubMed - in process]

Polymorphisms in the GNAS Gene as Predictors of Ventricular Tachyarrhythmias and Sudden Cardiac Death: Results From the DISCOVERY Trial and Oregon Sudden Unexpected Death Study.

J Am Heart Assoc. 2016 Nov 28;5(12):

Authors: Wieneke H, Svendsen JH, Lande J, Spencker S, Martinez JG, Strohmer B, Toivonen L, Le Marec H, Garcia-Fernandez FJ, Corrado D, Huertas-Vazquez A, Uy-Evanado A, Rusinaru C, Reinier K, Foldesi C, Hulak W, Chugh SS, Siffert W

Abstract
BACKGROUND: Population-based studies suggest that genetic factors contribute to sudden cardiac death (SCD).
METHODS AND RESULTS: In the first part of the present study (Diagnostic Data Influence on Disease Management and Relation of Genetic Polymorphisms to Ventricular Tachy-arrhythmia in ICD Patients [DISCOVERY] trial) Cox regression was done to determine if 7 single-nucleotide polymorphisms (SNPs) in 3 genes coding G-protein subunits (GNB3, GNAQ, GNAS) were associated with ventricular tachyarrhythmia (VT) in 1145 patients receiving an implantable cardioverter-defibrillator (ICD). In the second part of the study, SNPs significantly associated with VT were further investigated in 1335 subjects from the Oregon SUDS, a community-based study analyzing causes of SCD. In the DISCOVERY trial, genotypes of 2 SNPs in the GNAS gene were nominally significant in the prospective screening and significantly associated with VT when viewed as recessive traits in post hoc analyses (TT vs CC/CT in c.393C>T: HR 1.42 [CI 1.11-1.80], P=0.005; TT vs CC/CT in c.2273C>T: HR 1.57 [CI 1.18-2.09], P=0.002). TT genotype in either SNP was associated with a HR of 1.58 (CI 1.26-1.99) (P=0.0001). In the Oregon SUDS cohort significant evidence for association with SCD was observed for GNAS c.393C>T under the additive (P=0.039, OR=1.21 [CI 1.05-1.45]) and recessive (P=0.01, OR=1.52 [CI 1.10-2.13]) genetic models.
CONCLUSIONS: GNAS harbors 2 SNPs that were associated with an increased risk for VT in ICD patients, of which 1 was successfully replicated in a community-based population of SCD cases. To the best of our knowledge, this is the first example of a gene variant identified by ICD VT monitoring as a surrogate parameter for SCD and also confirmed in the general population.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00478933.

PMID: 27895044 [PubMed - indexed for MEDLINE]

Ticagrelor in modern cardiology - an up-to-date review of most important aspects of ticagrelor pharmacotherapy.

Expert Opin Pharmacother. 2017 Dec 27;:1-10

Authors: Danielak D, Karaźniewicz-Łada M, Główka F

Abstract
INTRODUCTION: Ticagrelor is a first drug of a new chemical class cyclopentyltriazolopyrimidines. It is an antiplatelet agent with a unique mechanism of action, allowing a direct and reversible competitive inhibition of P2Y12 receptor. According to newest guidelines, it is recommended for prevention of thrombotic events in patients with acute coronary syndromes. Moreover, it is preferred over clopidogrel, an older generation antiplatelet drug, and therefore gains more interest in modern cardiology and vascular medicine. Areas covered: This review is a comprehensive and thorough summary of the most important findings on ticagrelor. Pharmacokinetics, pharmacogenetics, drug-drug interactions, adverse effects, efficacy in specific patient populations and off-label properties of ticagrelor are discussed in this paper. Moreover, the results from pivotal clinical trials are presented. Expert opinion: Introduction of ticagrelor, a first directly-acting and reversible P2Y12 inhibitor, gave some new possibilities as the efficacy of older drugs was often insufficient. Despite some drawbacks, such as a risk of bleeding events or dyspnea, a rapid onset of action, consistency in the antiplatelet effect and reports on pleiotropic properties make this drug a promising candidate for a first-choice antiplatelet agent in patients with acute coronary events.

PMID: 29280403 [PubMed - as supplied by publisher]

Multi-site investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy.

Clin Pharmacol Ther. 2017 Dec 26;:

Authors: Empey PE, Stevenson JM, Tuteja S, Weitzel KW, Angiolillo DJ, Beitelshees AL, Coons JC, Duarte JD, Franchi F, Jeng LJB, Johnson JA, Kreutz RP, Limdi NA, Maloney KA, Owusu Obeng A, Peterson JF, Petry N, Pratt VM, Rollini F, Scott SA, Skaar TC, Vesely MR, Stouffer GA, Wilke RA, Cavallari LH, Lee CR, IGNITE Network

Abstract
CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes which are both related to CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. This article is protected by copyright. All rights reserved.

PMID: 29280137 [PubMed - as supplied by publisher]

[Update of the Rome IIII( criteria for functional constipation].

Zhonghua Wei Chang Wai Ke Za Zhi. 2017 Dec 25;20(12):1334-1338

Authors: Yu T, Jiang L, Lin L

Abstract
The Rome IIII( criteria were released in May 2016. Based on the development of brain-intestinal axis theory, intestinal microecology, pharmacogenomics and social psychology, the Rome IIII( criteria revise the definition, diagnostic criteria, clinical evaluation process, and treatments of functional constipation (FC). The revisions are as follows: (1) Definition: FC and constipation-predominant irritable bowel syndrome are considered to be on a continuum rather than as independent entities. (2) Diagnostic criteria: the Bristol stool scale type 1, type 2 and spontaneous bowel movements are added in the diagnostic criteria, respectively, refining the criteria for stool consistency and frequency. (3) Clinical evaluation process: the Rome IIII( criteria specifies the clinical assessment procedure for FC. The aim is to exclude organic disease, to detect the structural changes of the combination, to determine the type of guidance therapy, and to reduce unnecessary checks to improve diagnostic efficiency. (4) Pathophysiologic mechanism: much more newly investigated mechanisms are added, including the risk factors, genetics, inadequate colonic propulsion and defecation disorder. (5) Treatment: the treatment regimen summarizes the evidence-based medical evidence of new drugs, such as secretagogues and bile acid transport inhibitors, and evaluates the safety of all the new and old drugs. Compared to the Rome III( standard, the diagnosis of FC will be more stringent and efficient, and the treatment options will be more standardized and reasonable with the Rome IIII(.

PMID: 29280110 [PubMed - in process]

Statin drug interactions and related adverse reactions: an update.

Expert Opin Drug Saf. 2018 Jan;17(1):25-37

Authors: Bellosta S, Corsini A

Abstract
INTRODUCTION: Statins reduce the risk of cardiovascular morbidity and mortality in patients with or at risk for cardiovascular disease and their use is expanding, especially in elderly. Statins are prescribed on a long-term basis and may undergo drug-drug interactions (DDIs) with other drugs. Statins have different safety and tolerability, and this might affect the possibility of DDIs with other cardiovascular drugs, increasing the risk of statin-associated myopathy and hepatotoxicity. Polypharmacy and pharmacogenetic variability are potential causes of statin DDIs. Thus, the safety and adverse effects of statins, particularly in patients receiving multiple medications at risk of DDIs, are a matter of special concern. Areas covered: The purpose of this manuscript is to give an update on the potential statin DDIs and related adverse drug reactions (myopathy and hepatotoxicity), with special considerations on polypharmacy in elderly population, HIV patients, cardiovascular drugs and liver toxicities. The potential DDIs among statins and monoclonal antibodies including the recently approved PCSK9 inhibitors are also extensively discussed in the present review. Expert opinion: A better understanding of the incidence and clinical significance of statin DDIs will help physicians in fine-tuning the lipid-lowering therapeutic interventions thus providing their patients with an evidence-based, safe and cost-effective clinical support.

PMID: 29058944 [PubMed - indexed for MEDLINE]