Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers.

Drug Des Devel Ther. 2017;11:3543-3550

Authors: Oh M, Park SE, Ghim JL, Choi YK, Shim EJ, Shin JG, Kim EY

Abstract
Objective: This study compared the pharmacokinetic (PK) and safety profiles of a fixed-dose combination (FDC) formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs.
Materials and methods: This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S-amlodipine and were also coadministered the same dose of both drugs given separately. The crossover study design included a 14-day washout period between the two treatments. Blood samples were collected up to 168 h following drug administration. The plasma concentrations of telmisartan and S-amlodipine were determined by liquid chromatography tandem mass spectrometry. PK parameters and plasma concentration-time curves were compared. Safety was assessed by measuring vital signs, clinical laboratory tests, physical examinations, and patient interviews.
Results: The geometric mean ratios and 90% CIs for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 0.8782 (0.8167-0.9444) and 0.9662 (0.9210-1.0136) for telmisartan and 1.0069 (0.9723-1.0427) and 1.0324 (0.9969-1.0690) for S-amlodipine, respectively. A total of 36 adverse events (AEs) were reported by 23 subjects, but no statistical differences were observed between the two treatments. The most frequently reported AE was a mild-to-moderate headache that was generally self-limiting.
Conclusion: For both telmisartan and S-amlodipine, the Cmax and AUCt 90% CIs were between ln (0.8) and ln (1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile to the coadministration of these drugs.

PMID: 29270003 [PubMed - in process]

[Expression and activity identification of APOBEC3A-HBc fusion protein].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017 Nov;33(11):1521-1528

Authors: DU J, Cheng S, Bai H, Ji Q, Guo Y

Abstract
Objective To construct the expression vector of the fusion protein of apolipoprotain B mRNA editing enzyme catalytic polypeptide-like 3A (APOBEC3A) and hepatitis B virus core proteins (HBc) with different sequences, and identify its expression, intracellular localization and cytosine deamination activity. Methods The APOBEC3A gene and the coding sequence of HBc and four kinds of truncated HBc containing C-termimal domain were amplified by PCR. The APOBEC3A with full-length HBc antigen or four kinds of truncated HBc were cloned into a eukaryotic expression vector pcDNA3.0 by In-Fusion method, and confirmed by DNA sequencing. The recombinants were then transfected into HEK293T cells. The expression and localization of the fusion proteins were detected by Western blotting and immunofluorescence cytochemistry. The cytosine deamination activity was analyzed by electrophoresis on a urea denaturing polyacrylamide gel. Results Five kinds of fusion protein were expressed in HEK293T cells successfully, and the expression of the vectors containing the truncated HBc were higher than that of the APOBEC3A-HBc vector containing the full-length HBc. The fusion protein of APOBEC3A-HBc was mainly expressed in the cytoplasm of HEK293T cells, and the fusion proteins of APOBEC3A-HBc144S, APOBEC3A-HBc144E, APOBEC3A-HBc144AAA, APOBEC3A-HBc144A were expressed mainly in the nuclei of HEK293T cells. The cytosine deamination activity of the fusion proteins containing the truncated HBc was higher than that of the fusion protein APOBEC3A-HBc. Conclusion The fusion protein expression vectors of APOBEC3A and HBc with different lengths and sequences have been constructed successfully. The expressing ability, intracellular localization and cytosine deamination activity are obviously different between the fusion protein APOBEC3A-HBc and the fusion proteins containing the truncated HBc.

PMID: 29268857 [PubMed - in process]

Association of BDNF Polymorphisms with the Risk of Epilepsy: a Multicenter Study.

Mol Neurobiol. 2016 Jul;53(5):2869-2877

Authors: Sha'ari HM, Haerian BS, Baum L, Tan HJ, Rafia MH, Kwan P, Cherny SS, Sham PC, Gui H, Raymond AA, Lim KS, Mohamed Z

Abstract
Epilepsy is a common neurological disease characterized by recurrent unprovoked seizures. Evidence suggested that abnormal activity of brain-derived neurotrophic factor (BDNF) contributes to the pathogenesis of epilepsy. Some previous studies identified association between genetic variants of BDNF and risk of epilepsy. In this study, this association has been examined in the Hong Kong and Malaysian epilepsy cohorts. Genomic DNA of 6047 subjects (1640 patients with epilepsy and 4407 healthy individuals) was genotyped for rs6265, rs11030104, rs7103411, and rs7127507 polymorphisms by using Sequenom MassArray and Illumina HumanHap 610-Quad or 550-Duo BeadChip arrays techniques. Results showed significant association between rs6265 T, rs7103411 C, and rs7127507 T and cryptgenic epilepsy risk (p = 0.00003, p = 0.0002, and p = 0.002, respectively) or between rs6265 and rs7103411 and symptomatic epilepsy risk in Malaysian Indians (TT vs. CC, p = 0.004 and T vs. C, p = 0.0002, respectively) as well as between rs6265 T and risk of cryptogenic epilepsy in Malaysian Chinese (p = 0.005). The Trs6265-Crs7103411-Trs7127507 was significantly associated with cryptogenic epilepsy in Malaysian Indians (p = 0.00005). In conclusion, our results suggest that BDNF polymorphisms might contribute to the risk of epilepsy in Malaysian Indians and Chinese.

PMID: 25876511 [PubMed - indexed for MEDLINE]

Creation of the Swiss group of Pharmacogenomics and personalised Therapy (SPT).

Drug Metab Pers Ther. 2017 Dec 21;:

Authors: Amstutz U, Mlakar V, Curtis PH, Samer C, Baumann P, Bühlmann RP, Meier-Abt P, Meyer UA, van Schaik RHN, Ansari M, Swiss group of Pharmacogenomics and Personalised Therapy

PMID: 29267167 [PubMed - as supplied by publisher]

Pharmacogenetic effects of naltrexone in individuals of East Asian descent: Human laboratory findings from a randomized trial.

Alcohol Clin Exp Res. 2017 Dec 19;:

Authors: Ray LA, Green R, Roche DJO, Bujarski S, Hartwell EE, Lim AC, Rohrbaugh T, Ghahremani D, Hutchison K, Miotto K

Abstract
BACKGROUND: Genetic variation in the endogenous opioid system has been identified as one potential source of individual variability in naltrexone treatment outcomes. The majority of naltrexone pharmacogenetic studies have focused on a particular single nucleotide polymorphism (SNP) of the mu-opioid receptor gene (OPRM1; rs1799971; commonly known as the Asn40Asp SNP) in Caucasian samples with decidedly mixed results. The goal of this study is to test the pharmacogenetic effects of naltrexone on subjective response to alcohol and self-administration of alcohol in individuals of East Asian descent. We hypothesized that naltrexone, compared with placebo, would potentiate the aversive and sedative effects of alcohol and reduce alcohol self-administration to a greater extent in Asp40 carriers.
METHOD: Participants (N = 87; Asn40Asn, n = 29; Asn40Asp, n= 34, and Asp40Asp, n = 14) completed two double-blinded and counterbalanced experimental sessions: one after taking naltrexone (50 mg/day) for five days and one after taking matched placebo for five days. In each experimental session, participants received a priming dose of IV alcohol up to the breath alcohol concentration (BrAC) target of 0.06 g/dl which was immediately followed by an alcohol self-administration period (1 hour).
RESULTS: There were no pharmacogenetic effects observed for alcohol-induced stimulation, sedation, craving for alcohol, or alcohol self-administration in the laboratory. During the self-administration period, Asp40 carriers consumed fewer drinks and had a longer latency to first drink as compared to Asn40 homozygotes.
CONCLUSIONS: These findings in East Asians add to the mixed literature on naltrexone pharmacogenetics from predominantly Caucasian samples and highlight the complexity of these effects and their overall limited replicability. It is plausible that a consistent pharmacogenetic effect in tightly controlled preclinical and experimental medicine models "fades" in more complex and heterogeneous settings and samples. This article is protected by copyright. All rights reserved.

PMID: 29265379 [PubMed - as supplied by publisher]

Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy.

Epilepsia. 2017 Dec 19;:

Authors: Vanhoof-Villalba SL, Gautier NM, Mishra V, Glasscock E

Abstract
OBJECTIVES: Antiseizure drugs are the leading therapeutic choice for treatment of epilepsy, but their efficacy is limited by pharmacoresistance and the occurrence of unwanted side effects. Here, we examined the therapeutic efficacy of KCNQ channel activation by retigabine in preventing seizures and neurocardiac dysfunction in 2 potassium channelopathy mouse models of epilepsy with differing severity that have been associated with increased risk of sudden unexpected death in epilepsy (SUDEP): the Kcna1-/- model of severe epilepsy and the Kcnq1A340E/A340E model of mild epilepsy.
METHODS: A combination of behavioral, seizure threshold, electrophysiologic, and gene expression analyses was used to determine the effects of KCNQ activation in mice.
RESULTS: Behaviorally, Kcna1-/- mice exhibited unexpected hyperexcitability instead of the expected sedative-like response. In flurothyl-induced seizure tests, KCNQ activation decreased seizure latency by ≥50% in Kcnq1 strain mice but had no effect in the Kcna1 strain, suggesting the influence of genetic background. However, in simultaneous electroencephalography and electrocardiography recordings, KCNQ activation significantly reduced spontaneous seizure frequency in Kcna1-/- mice by ~60%. In Kcnq1A340E/A340E mice, KCNQ activation produced adverse cardiac effects including profound bradycardia and abnormal increases in heart rate variability and atrioventricular conduction blocks. Analyses of Kcnq2 and Kcnq3 mRNA levels revealed significantly elevated Kcnq2 expression in Kcna1-/- brains, suggesting that drug target alterations may contribute to the altered drug responses.
SIGNIFICANCE: This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of KCNQ channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting KCNQ modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby SUDEP risk. Our data also uncover a potential role for KCNQ2-5 channels in autonomic control of chronotropy.

PMID: 29265344 [PubMed - as supplied by publisher]

Clinical Implications of Genetic Variation in Carboxylesterase Drug Metabolism.

Expert Opin Drug Metab Toxicol. 2017 Dec 21;:

Authors: Chen F, Zhang B, Parker RB, Laizure SC

Abstract
INTRODUCTION: Mammalian carboxylesterase enzymes are a highly conserved metabolic pathway involved in the metabolism of endogenous and exogenous compounds including many widely prescribed therapeutic agents. Recent advances in our understanding of genetic polymorphisms affecting enzyme activity have exposed potential therapeutic implications. Areas covered: The aims of this review are to provide an overview of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) gene structure, to summarize the known polymorphism affecting substrate-drug metabolism, and to assess the potential therapeutic implications of genetic variations affecting enzyme function. Expert opinion: Genetic variability in carboxylesterase drug metabolism is a nascent area of research with only a handful of the thousands of SNPs investigated for their potential effects of enzyme activity or carboxylesterase-substrate disposition and therapeutics. It remains to be determined if the wide variability in enzyme activity can be explained by genetic variation, and used in personalized medicine to improve clinical outcomes.

PMID: 29264996 [PubMed - as supplied by publisher]

Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age.

J Endocr Soc. 2017 Jun 01;1(6):560-576

Authors: Grigorova M, Punab M, Poolamets O, Adler M, Vihljajev V, Laan M

Abstract
Context: Testosterone (T) is a central androgenic hormone, and sex hormone-binding globulin (SHBG) is the major determinant of its bioactivity. There are no acknowledged genetic variants with clear-cut clinical implications, modulating T levels in men.
Objective: To confirm genetic associations of top loci (SHBG, GCKR, SLCO1B1, and JMJD1C) from genome-wide association (GWA) studies for serum SHBG and T.
Design Patients: Groups differing in general and reproductive parameters: young men (n = 540; 19.3 ± 1.8 years), severe idiopathic male infertility patients (n = 641; 31.6 ± 6.0 years), and male partners of pregnant women (n = 324; 31.9 ± 6.6 years). All patients were recruited at the Andrology Centre, Tartu University Hospital, Estonia.
Main Outcome Measures: Genetic associations with reproductive hormones, testicular and sperm parameters (linear regression, additive model); intergroup allele/genotype distribution comparisons.
Results: Associations with serum SHBG levels were robust for SHBG -68 G>A [rs1799941; meta-analysis: P = 3.7 × 10-14; allelic effect (standard error) = 4.67 (0.62) nmol/L], SHBG +1091 C>T [rs727428; P = 7.3 × 10-11; -3.74 (0.57)], SHBG Pro185Leu [rs6258; P = 1.2 × 10-4, -12.2 (3.17)], and GCKR Pro446Leu [rs1260326; P = 1.5 × 10-4; -2.2 (0.59)]. Measured T concentrations correlated with genetically modulated levels of SHBG (r = 0.48 to 0.74, P < 0.0001), guaranteeing stable availability of free T. Among infertile men, SHBG Pro185Leu substitution showed additional downstream effect on luteinizing hormone [P = 5.1 × 10-5; -1.66 (0.57) IU/L] and follicle-stimulating hormone [P = 3.4 × 10-3; -2.48 (1.23) IU/L]. No associations with male reproductive parameters were detected for SHBG Asp327Asn (rs6259), SLCO1B1 Val174Ala (rs4149056), and JMJD1C intronic variant rs7910927.
Conclusions: Claims were replicated and additional associations were detected for four of seven tested GWAS top loci. Perspective clinical investigations of these variants are hypotestosteronemia among aging men and pharmacogenetics of hormone replacement therapy.

PMID: 29264510 [PubMed]

Precision Military Medicine: Conducting a multi-site clinical utility study of genomic and lifestyle risk factors in the United States Air Force.

NPJ Genom Med. 2017;2:2

Authors: Delaney SK, Brenner R, Schmidlen TJ, Dempsey MP, London KE, Gordon ES, Bellafante M, Nasuti A, Scheinfeldt LB, Rajula KD, Jose L, Jarvis JP, Gerry NP, Christman MF

Abstract
Following several years enrolling disease-specific and otherwise healthy cohorts into the Coriell Personalized Medicine Collaborative, a prospective study aimed at evaluating the clinical utility of personal genomic information for common complex disease and pharmacogenomics, the Coriell Personalized Medicine Collaborative expanded to create a military cohort, specifically, the United States Air Force. Initial recruitment focused on Air Force Medical Service personnel and later expanded to include all Active Duty Air Force members and beneficiaries. Now in its 6th year, the study has produced a wide variety of insights, including optimal study design for military-sponsored genomic research, and discussion on genetic information sharing between and amongst Air Force study participants, civilian and military researchers, and the United States Department of Defense. Over the longer term, analyses will further contribute to the development of policies and processes relevant to clinical decision support and data sharing within the US military, and on-going work with the Air Force Medical Service sub-cohort will generate critical insights into how best to deploy useful genomic information in clinical care. Here we discuss challenges faced and critical success factors for military-civilian collaborations around genomic research.

PMID: 29263822 [PubMed]

Regulation profile of the intestinal peptide transporter 1 (PepT1).

Drug Des Devel Ther. 2017;11:3511-3517

Authors: Wang CY, Liu S, Xie XN, Tan ZR

Abstract
The intestinal peptide transporter 1 (PepT1) was first identified in 1994. It plays a crucial role in the absorption of small peptides including not only >400 different dipeptides and 8,000 tripeptides digested from dietary proteins but also a repertoire of structurally related compounds and drugs. Owing to its critical role in the bioavailability of peptide-like drugs, such as the anti-cancer agents and anti-virus drug, PepT1 is increasingly becoming a striking prodrug-designing target. Therefore, the understanding of PepT1 gene regulation is of great importance both for dietary adaptation and for clinical drug treatment. After decades of research, it has been recognized that PepT1 could be regulated at the transcriptional and post-transcriptional levels by numerous factors. Therefore, the present review intends to summarize the progress made in the regulation of PepT1 and provide insights into the PepT1's potential in clinical aspects of nutritional and drug therapies.

PMID: 29263649 [PubMed - in process]

The role of the ITIH3 rs2535629 variant in antipsychotic response.

Schizophr Res. 2016 Oct;176(2-3):131-135

Authors: Brandl EJ, Lett TA, Chowdhury NI, Tiwari AK, Bakanidze G, Meltzer HY, Potkin SG, Lieberman JA, Kennedy JL, Müller DJ

Abstract
INTRODUCTION: There is mounting evidence that schizophrenia risk variants influence response to antipsychotic medication. Common single nucleotide polymorphisms (SNPs) in or near the inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) gene have been repeatedly associated with schizophrenia and related psychiatric disorders in genome-wide association studies. Here, we provide the first study to assess the relevance of the ITIH3 rs2535629 SNP in response to antipsychotic medication.
METHODS: The rs2535629 SNP was genotyped in N=256 patients receiving various antipsychotics for up to 26weeks. Treatment response was assessed using the Brief Psychiatric Rating Scale (BPRS) including its positive and negative subscales. Follow-up analyses were performed after stratifying for ethnicity and medication.
RESULTS: We found significant association of rs2535629 with improvement of negative symptoms in patients of European ancestry after six months of clozapine treatment (F1,87=8.8, pcorr=0.032). Patients homozygous for the minor A-allele showed the best improvement of negative BPRS scores. However, we observed no association between rs2535629 and changes in total BPRS score in the entire sample or the clozapine-treated subgroup.
DISCUSSION: Although there was no association of genotype with overall changes in BPRS scores, the greater improvement of negative symptoms in minor allele carriers indicates that rs2535629 may help to identify a subset of schizophrenia patients with better treatment response to clozapine. Therefore, our findings provide the first suggestive evidence that rs2535629 is relevant in antipsychotic response.

PMID: 27396837 [PubMed - indexed for MEDLINE]

Novel copy-number variations in pharmacogenes contribute to interindividual differences in drug pharmacokinetics.

Genet Med. 2017 Oct 26;:

Authors: Santos M, Niemi M, Hiratsuka M, Kumondai M, Ingelman-Sundberg M, Lauschke VM, Rodríguez-Antona C

Abstract
PurposeVariability in pharmacokinetics and drug response is shaped by single-nucleotide variants (SNVs) as well as copy-number variants (CNVs) in genes with importance for drug absorption, distribution, metabolism, and excretion (ADME). While SNVs have been extensively studied, a systematic assessment of the CNV landscape in ADME genes is lacking.MethodsWe integrated data from 2,504 whole genomes from the 1000 Genomes Project and 59,898 exomes from the Exome Aggregation Consortium to identify CNVs in 208 relevant pharmacogenes.ResultsWe describe novel exonic deletions and duplications in 201 (97%) of the pharmacogenes analyzed. The deletions are population-specific and frequencies range from singletons up to 1%, accounting for >5% of all loss-of-function alleles in up to 42% of the genes studied. We experimentally confirmed novel deletions in CYP2C19, CYP4F2, and SLCO1B3 by Sanger sequencing and validated their allelic frequencies in selected populations.ConclusionCNVs are an additional source of pharmacogenetic variability with important implications for drug response and personalized therapy. This, together with the important contribution of rare alleles to the variability of pharmacogenes, emphasizes the necessity of comprehensive next-generation sequencing-based genotype identification for an accurate prediction of the genetic variability of drug pharmacokinetics.GENETICS in MEDICINE advance online publication, 26 October 2017; doi:10.1038/gim.2017.156.

PMID: 29261188 [PubMed - as supplied by publisher]

Preemptive pharmacogenetic testing: exploring the knowledge and perspectives of US payers.

Genet Med. 2017 Oct 26;:

Authors: Keeling NJ, Rosenthal MM, West-Strum D, Patel AS, Haidar CE, Hoffman JM

Abstract
PurposePreemptive pharmacogenetic testing aims to optimize medication use by having genetic information at the point of prescribing. Payers' decisions influence implementation of this technology. We investigated US payers' knowledge, awareness, and perspectives on preemptive pharmacogenetic testing.MethodsA qualitative study was conducted using semistructured interviews. Participants were screened for eligibility through an online survey. A blended inductive and deductive approach was used to analyze the transcripts. Two authors conducted an iterative reading process to code and categorize the data.ResultsMedical or pharmacy directors from 14 payer organizations covering 122 million US lives were interviewed. Three concept domains and ten dimensions were developed. Key findings include clinical utility concerns and limited exposure to preemptive germ-line testing, continued preference for outcomes from randomized controlled trials, interest in guideline development, importance of demonstrating an impact on clinical decision making, concerns of downstream costs and benefit predictability, and the impact of public stakeholders such as the Food and Drug Administration and Centers for Medicare and Medicaid Services.ConclusionBoth barriers and potential facilitators exist to developing cohesive reimbursement policy for pharmacogenetics, and there are unique challenges for the preemptive testing model. Prospective outcome studies, more precisely defining target populations, and predictive economic models are important considerations for future research.GENETICS in MEDICINE advance online publication, 26 October 2017; doi:10.1038/gim.2017.181.

PMID: 29261180 [PubMed - as supplied by publisher]

Regulation of autophagic proteolysis by the N-recognin SQSTM1/p62 of the N-end rule pathway.

Autophagy. 2017 Dec 20;:1-6

Authors: Cha-Molstad H, Lee SH, Kim JG, Sung KW, Hwang J, Shim SM, Ganipisetti S, McGuire T, Mook-Jung I, Ciechanover A, Xie XQ, Kim BY, Kwon YT

Abstract
In macroautophagy/autophagy, cargoes are collected by specific receptors, such as SQSTM1/p62 (sequestosome 1), and delivered to phagophores for lysosomal degradation. To date, little is known about how cells modulate SQSTM1 activity and autophagosome biogenesis in response to accumulating cargoes. In this study, we show that SQSTM1 is an N-recognin whose ZZ domain binds N-terminal arginine (Nt-Arg) and other N-degrons (Nt-Lys, Nt-His, Nt-Trp, Nt-Phe, and Nt-Tyr) of the N-end rule pathway. The substrates of SQSTM1 include the endoplasmic reticulum (ER)-residing chaperone HSPA5/GRP78/BiP. Upon N-end rule interaction with the Nt-Arg of arginylated HSPA5 (R-HSPA5), SQSTM1 undergoes self-polymerization via disulfide bonds of Cys residues including Cys113, facilitating cargo collection. In parallel, Nt-Arg-bound SQSTM1 acts as an inducer of autophagosome biogenesis and autophagic flux. Through this dual regulatoray mechanism, SQSTM1 plays a key role in the crosstalk between the ubiquitin (Ub)-proteasome system (UPS) and autophagy. Based on these results, we employed 3D-modeling of SQSTM1 and a virtual chemical library to develop small molecule ligands to the ZZ domain of SQSTM1. These autophagy inducers accelerated the autophagic removal of mutant HTT (huntingtin) aggregates. We suggest that SQSTM1 can be exploited as a novel drug target to modulate autophagic processes in pathophysiological conditions.

PMID: 29261001 [PubMed - as supplied by publisher]

Hot Genes in Schizophrenia: How Clinical Datasets Could Help to Refine their Role.

J Mol Neurosci. 2017 Dec 19;:

Authors: Porcelli S, Lee SJ, Han C, Patkar AA, Albani D, Jun TY, Pae CU, Serretti A

Abstract
We investigated the effect of a set of SNPs within 5 genes identified by GWASs as possible risk genes for schizophrenia (SCZ) in two independent samples, comprising 176 SCZ patients and 326 controls of Korean origin and 83 SCZ patients and 194 controls of Italian origin. The PANSS was used to assess psychopathology severity and antipsychotic response (AR). Several clinical features were assessed at recruitment. In the Korean sample, the SP4 gene haplotype rs2282888-rs2237304-rs10272006-rs12673091 (p = 0.02) was associated with SCZ. In the Italian sample, PPP3CC rs11780915 (genotypic: p = 0.006; allelic: p = 0.001) and rs2249098 (genotypic: p = 0.0004; allelic: p = 0.00006) were associated with SCZ, as well as the PPP3CC rs11780915-rs10108011-rs2249098 and the ZNF804A rs7603001-rs1344706 haplotypes (p = 0.03 and p = 0.02). Several RORA variants were associated with AR in both the samples, although only the haplotype rs1020729-rs1871858 in the Korean sample survived to the statistical correction (p = 0.01). Exploratory analyses suggested that: (1) PPP3CC, ST8SIA2, and SP4 genes may modulate psychotic symptoms, and (2) RORA and ZNF804A genes may influence AR. Our results partially support a role for these genes in SCZ and AR. Analyses in well phenotyped samples may help to refine the role of the genes identified by GWASs.

PMID: 29260453 [PubMed - as supplied by publisher]

Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel.

Eur J Clin Pharmacol. 2017 Dec 19;:

Authors: Mirjana N, Dragan M, Jelena KT, Nebojsa A, Dragica R, Ljiljana R

Abstract
PURPOSE: Bleeding is one of the possible adverse events during clopidogrel therapy. The CYP2C19 gene is the most significant genetic factor which influences response to clopidogrel treatment. We aimed to examine the contribution of the CYP2C19 gene to bleeding occurrence during clopidogrel therapy in Serbian patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).
METHODS: This case-control study included 53 patients who experienced bleeding and 55 patients without bleeding. Bleeding events were defined and classified using the Bleeding Academic Research Consortium (BARC) criteria. All patients were prescribed daily doses of clopidogrel during the 1-year follow-up after PCI. The CYP2C19*17 (c.-806C>T, rs12248560), rs11568732 (c.-889T>G, CYP2C19*20), CYP2C19*2 (c.681G>A; rs4244285) and CYP2C19*3 (c.636G>A; rs4986893) variants were analysed in all 108 patients. Additionally, sequencing of all nine exons, 5'UTR and 3'UTR in the rs11568732 carriers was performed.
RESULTS: Association between bleeding (BARC type ≥ 2) and the CYP2C19*17 variant was not observed [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.2-1.1; p = 0.107). The rs11568732 variant showed significant association with bleeding (OR, 3.7; 95% CI, 1.12-12.44; p = 0.025). Also, we found that the rs11568732 variant appears independently of haplotype CYP2C19*3B, which is contrary to the previous findings.
CONCLUSIONS: Our results indicate the absence of CYP2C19*17 influence and turn the attention to the potential significance of the rs11568732 variant in terms of adverse effects of clopidogrel. However, it is necessary to conduct an independent conformation study in order to verify this finding. Also, an analysis of the functional implication of the rs11568732 variant is necessary in order to confirm the significance of this variant, both in relation to its influence on gene expression and in relation to its medical significance.

PMID: 29260275 [PubMed - as supplied by publisher]

Pharmacogenomic analyzis of the responsiveness of gastrointestinal tumor cell lines to drug therapy: A transportome approach.

Pharmacol Res. 2016 Nov;113(Pt A):364-375

Authors: Grañé-Boladeras N, Pérez-Torras S, Lozano JJ, Romero MR, Mazo A, Marín JJ, Pastor-Anglada M

Abstract
In this study, we have addressed the pharmacogenomic basis of the response of gastrointestinal tumors to six anticancer drugs using a panel of fifteen cell lines derived from pancreatic, stomach and biliary tract cancers. We determined the constitutive expression levels of 96 genes, whose encoded proteins contribute to drug action, and identified a major gene network that contains broad selectivity nucleoside transporter genes, as well as several genes known to be involved in cell proliferation and survival. All cell lines were exposed to 5'-DFUR, 5-FU, gemcitabine, cisplatin, doxorubicin and paclitaxel for 48h and cell response was measured using MTT assays. We correlated the cell response of the fifteen cell lines with the mRNA expression of the selected 96 genes and identified sets of 4-5 genes whose expression profiles correlated to responsiveness to each anticancer drug. These genes may be good candidates as response predictors to such therapies.

PMID: 27620070 [PubMed - indexed for MEDLINE]

Gene polymorphisms as predictors of response to biological therapies in psoriasis patients.

Pharmacol Res. 2016 Nov;113(Pt A):71-80

Authors: Linares-Pineda TM, Cañadas-Garre M, Sánchez-Pozo A, Calleja-Hernández MÁ

Abstract
Psoriasis is a chronic inflammatory autoimmune skin disease, characterized by the formation of erythematous scaly plaques on the skin and joints. The therapies for psoriasis are mainly symptomatic and sometimes with poor response. Response among patients is very variable, especially with biological drugs (adalimumab, etarnecept, infliximab and ustekimumab). This variability may be partly explained by the effect of different genetic backgrounds. This has prompted the investigation of many genes, such as FCGR3A, HLA, IL17F, IL23R, PDE3A-SLCO1C1, TNFα and other associated genes, as potential candidates to predict response to the different biological drugs used for the treatment of psoriasis. In this article, we will review the influence of gene polymorphisms investigated to date on response to biological drugs in psoriasis patients.

PMID: 27524442 [PubMed - indexed for MEDLINE]

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

Sci Data. 2017 Dec 19;4:170179

Authors: Jason F, Fuchsberger C, Mahajan A, Teslovich TM, Agarwala V, Gaulton KJ, Caulkins L, Koesterer R, Ma C, Moutsianas L, McCarthy DJ, Rivas MA, Perry JRB, Sim X, Blackwell TW, Robertson NR, Rayner NW, Cingolani P, Locke AE, Tajes JF, Highland HM, Dupuis J, Chines PS, Lindgren CM, Hartl C, Jackson AU, Chen H, Huyghe JR, van de Bunt M, Pearson RD, Kumar A, Müller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen Y, Scott RA, Below JE, Chen P, Huang J, Go MJ, Stitzel ML, Pasko D, Parker SCJ, Varga TV, Green T, Beer NL, Day-Williams AG, Ferreira T, Fingerlin T, Horikoshi M, Hu C, Huh I, Ikram MK, Kim BJ, Kim Y, Kim YJ, Kwon MS, Lee J, Lee S, Lin KH, Maxwell TJ, Nagai Y, Wang X, Welch RP, Yoon J, Zhang W, Barzilai N, Voight BF, Han BG, Jenkinson CP, Kuulasmaa T, Kuusisto J, Manning A, Ng MCY, Palmer ND, Balkau B, Stančáková A, Abboud HE, Boeing H, Giedraitis V, Prabhakaran D, Gottesman O, Scott J, Carey J, Kwan P, Grant G, Smith JD, Neale BM, Purcell S, Butterworth AS, Howson JMM, Lee HM, Lu Y, Kwak SH, Zhao W, Danesh J, Lam VKL, Park KS, Saleheen D, So WY, Tam CHT, Afzal U, Aguilar D, Arya R, Aung T, Chan E, Navarro C, Cheng CY, Palli D, Correa A, Curran JE, Rybin D, Farook VS, Fowler SP, Freedman BI, Griswold M, Hale DE, Hicks PJ, Khor CC, Kumar S, Lehne B, Thuillier D, Lim WY, Liu J, Loh M, Musani SK, Puppala S, Scott WR, Yengo L, Tan ST, Taylor HA, Thameem F, Wilson G, Wong TY, Njølstad PR, Levy JC, Mangino M, Bonnycastle LL, Schwarzmayr T, Fadista J, Surdulescu GL, Herder C, Groves CJ, Wieland T, Bork-Jensen J, Brandslund I, Christensen C, Koistinen HA, Doney ASF, Kinnunen L, Esko T, Farmer AJ, Hakaste L, Hodgkiss D, Kravic J, Lyssenko V, Hollensted M, Jørgensen ME, Jørgensen T, Ladenvall C, Justesen JM, Käräjämäki A, Kriebel J, Rathmann W, Lannfelt L, Lauritzen T, Narisu N, Linneberg A, Melander O, Milani L, Neville M, Orho-Melander M, Qi L, Qi Q, Roden M, Rolandsson O, Swift A, Rosengren AH, Stirrups K, Wood AR, Mihailov E, Blancher C, Carneiro MO, Maguire J, Poplin R, Shakir K, Fennell T, DePristo M, de Angelis MH, Deloukas P, Gjesing AP, Jun G, Nilsson P, Murphy J, Onofrio R, Thorand B, Hansen T, Meisinger C, Hu FB, Isomaa B, Karpe F, Liang L, Peters A, Huth C, O'Rahilly SP, Palmer CNA, Pedersen O, Rauramaa R, Tuomilehto J, Salomaa V, Watanabe RM, Syvänen AC, Bergman RN, Bharadwaj D, Bottinger EP, Cho YS, Chandak GR, Chan JC, Chia KS, Daly MJ, Ebrahim SB, Langenberg C, Elliott P, Jablonski KA, Lehman DM, Jia W, Ma RCW, Pollin TI, Sandhu M, Tandon N, Froguel P, Barroso I, Teo YY, Zeggini E, Loos RJF, Small KS, Ried JS, DeFronzo RA, Grallert H, Glaser B, Metspalu A, Wareham NJ, Walker M, Banks E, Gieger C, Ingelsson E, Im HK, Illig T, Franks PW, Buck G, Trakalo J, Buck D, Prokopenko I, Mägi R, Lind L, Farjoun Y, Owen KR, Gloyn AL, Strauch K, Tuomi T, Kooner JS, Lee JY, Park T, Donnelly P, Morris AD, Hattersley AT, Bowden DW, Collins FS, Atzmon G, Chambers JC, Spector TD, Laakso M, Strom TM, Bell GI, Blangero J, Duggirala R, Tai ES, McVean G, Hanis CL, Wilson JG, Seielstad M, Frayling TM, Meigs JB, Cox NJ, Sladek R, Lander ES, Gabriel S, Mohlke KL, Meitinger T, Groop L, Abecasis G, Scott LJ, Morris AP, Kang HM, Altshuler D, Burtt NP, Florez JC, Boehnke M, McCarthy MI

Abstract
To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

PMID: 29257133 [PubMed - in process]

Dataset on the activation of Müller cells through macrophages upon hypoxia in the retina.

Data Brief. 2018 Feb;16:489-500

Authors: Nürnberg C, Kociok N, Brockmann C, Lischke T, Crespo-Garcia S, Reichhart N, Wolf S, Baumgrass R, Eming SA, Beer-Hammer S, Joussen AM

Abstract
The dataset presented in this article complements the article entitled "Myeloid cells contribute indirectly to VEGF expression upon hypoxia via activation of Müller cells" (C. Nürnberg, N. Kociok, C. Brockmann, T. Lischke, S. Crespo-Garcia, N. Reichhart, S. Wolf, R. Baumgrass, S.A. Eming, S. Beer-Hammer, and A.M. Joussen). This complementary dataset provides further insight into the experimental validation of the VEGFfl/fl LysMCre (here named VEGFmcko) knockout model used in the main article through genomic and quantitative Real-Time PCR in various murine tissues as well as additional flow cytometry data and immunohistochemical stainings. By providing these data, we aim to enable researcher to reproduce and critically analyze our data.

PMID: 29255783 [PubMed]