Clinical implications of glutathione S-transferase genotyping in patients with diffuse large B-cell lymphoma.

J BUON. 2016 Nov-Dec;21(6):1459-1465

Authors: Atanaskovic L, Cikota-Aleksic B, Tarabar O, Trimcev J, Zivanovic-Ivic A, Marjanovic S, Magic Z

Abstract
PURPOSE: Polymorphic deletions in glutathione S-transferase (GST) genes are recognized as a risk factor for lymphoma, other hematological and non-hematological malignancies. The purpose of the present study was to investigate whether deletions of GSTT1 and GSTM1 as well as GSTP1 Ile- 105Val single nucleotide polymorphism influence clinical presentation, response to therapy and outcome in patients with diffuse large B-cell lymphoma (DLBCL).
METHODS: The study included a total of 82 DLBCL patients treated with rituximab-CHOP (R-CHOP) therapy (6-8 cycles). GST genes were analyzed with PCR-based methodology.
RESULTS: The obtained frequencies of GSTT1 and GSTM1 null genotypes were 24 and 63%, respectively. The variant GSTP1 Val allele was present in 76% of the patients. No association between GST genotypes and clinical presentation was found. However, a higher frequency of GSTM1 null genotype was observed in patients who developed DLBCL before the age of 60 [odds ratio (OR) 3.12, 95% confidence interval (CI) 1.11-9.17; p=0.03]. Patients carrying at least one GSTP1 Val allele achieved remission in a shorter time period than patients with GSTP1 Ile/Ile genotype (p=0.05). GST genotypes didn't influence the incidence of relapse and survival. There were no toxic effects, life-threatening infections or significant delay in immunochemotherapy in the analyzed group of patients.
CONCLUSION: The present study showed the association of GSTM1 null genotype and DLBCL development before the age of 60 (prognostic cutoff). GST genotypes didn't influence survival, but patients with at least one low-producing GSTP1 Val allele achieved clinical remission in a shorter time period.

PMID: 28039708 [PubMed - indexed for MEDLINE]

FcγRIIa-H131R variant is associated with inferior response in diffuse large B cell lymphoma: A meta-analysis of genetic risk.

J BUON. 2016 Nov-Dec;21(6):1454-1458

Authors: Ziakas PD, Poulou LS, Zintzaras E

Abstract
PURPOSE: Low-affinity variants FcγRIIIa-V158F and FcγRIIa- H131R may alter response to rituximab-based chemotherapy in diffuse large B-cell lymphoma (DLBCL) but available clinical evidence is inconclusive. Our purpose was to explore their association in terms of treatment response.
METHODS: We performed a meta-analysis of published literature to associate these variants with complete remission after upfront immunochemotherapy in DLBCL, and summarized the genetic risk using the model-free approach of generalized odds ratio (ORG). PubMed and EMBASE search (up to July 2014) yielded five pertinent studies.
RESULTS: FcγRIIa-H131R was associated with an inferior response to treatment (ORG 0.67; 95%CI 0.46-0.97) and an additive mode of inheritance, with the genetic risk of heterozygotes assigned in the middle between high affinity (H/H) and lower affinity (R/R) genotypes. This effect was unrelated to risk stratification, as no association was documented for FcγRIIa-H131R variant with the international prognostic index (IPI) (ORG 1.02; 95%CI 0.79-1.31 for IPI 3-5 over 0-2). FcγRIIIa-V158F had no impact on treatment response but linkage disequilibrium and defective antibody-dependent cell-mediated cytotoxicity may have affected the outcome.
CONCLUSION: FcγRIIa-H131R but not FcγRIIIa-V158F may modify treatment response in DLBCL.

PMID: 28039707 [PubMed - indexed for MEDLINE]

Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates.

Chem Res Toxicol. 2016 Dec 19;29(12):1936-1955

Authors: Lauschke VM, Hendriks DF, Bell CC, Andersson TB, Ingelman-Sundberg M

Abstract
The liver is an organ with critical importance for drug treatment as the disposition and response to a given drug is often determined by its hepatic metabolism. Patient-specific factors can entail increased susceptibility to drug-induced liver injury, which constitutes a major risk for drug development programs causing attrition of promising drug candidates or costly withdrawals in postmarketing stages. Hitherto, mainly animal studies and 2D hepatocyte systems have been used for the examination of human drug metabolism and toxicity. Yet, these models are far from satisfactory due to extensive species differences and because hepatocytes in 2D cultures rapidly dedifferentiate resulting in the loss of their hepatic phenotype and functionality. With the increasing comprehension that 3D cell culture systems more accurately reflect in vivo physiology, in the recent decade more and more research has focused on the development and optimization of various 3D culture strategies in an attempt to preserve liver properties in vitro. In this contribution, we critically review these developments, which have resulted in an arsenal of different static and perfused 3D models. These systems include sandwich-cultured hepatocytes, spheroid culture platforms, and various microfluidic liver or multiorgan biochips. Importantly, in many of these models hepatocytes maintain their phenotype for prolonged times, which allows probing the potential of newly developed chemical entities to cause chronic hepatotoxicity. Moreover, some platforms permit the investigation of drug action in specific genetic backgrounds or diseased hepatocytes, thereby significantly expanding the repertoire of tools to detect drug-induced liver injuries. It is concluded that the development of 3D liver models has hitherto been fruitful and that systems are now at hand whose sensitivity and specificity in detecting hepatotoxicity are superior to those of classical 2D culture systems. For the future, we highlight the need to develop more integrated coculture model systems to emulate immunotoxicities that arise due to complex interactions between hepatocytes and immune cells.

PMID: 27661221 [PubMed - indexed for MEDLINE]

A Multi-scale Computational Platform to Mechanistically Assess the Effect of Genetic Variation on Drug Responses in Human Erythrocyte Metabolism.

PLoS Comput Biol. 2016 Jul;12(7):e1005039

Authors: Mih N, Brunk E, Bordbar A, Palsson BO

Abstract
Progress in systems medicine brings promise to addressing patient heterogeneity and individualized therapies. Recently, genome-scale models of metabolism have been shown to provide insight into the mechanistic link between drug therapies and systems-level off-target effects while being expanded to explicitly include the three-dimensional structure of proteins. The integration of these molecular-level details, such as the physical, structural, and dynamical properties of proteins, notably expands the computational description of biochemical network-level properties and the possibility of understanding and predicting whole cell phenotypes. In this study, we present a multi-scale modeling framework that describes biological processes which range in scale from atomistic details to an entire metabolic network. Using this approach, we can understand how genetic variation, which impacts the structure and reactivity of a protein, influences both native and drug-induced metabolic states. As a proof-of-concept, we study three enzymes (catechol-O-methyltransferase, glucose-6-phosphate dehydrogenase, and glyceraldehyde-3-phosphate dehydrogenase) and their respective genetic variants which have clinically relevant associations. Using all-atom molecular dynamic simulations enables the sampling of long timescale conformational dynamics of the proteins (and their mutant variants) in complex with their respective native metabolites or drug molecules. We find that changes in a protein's structure due to a mutation influences protein binding affinity to metabolites and/or drug molecules, and inflicts large-scale changes in metabolism.

PMID: 27467583 [PubMed - indexed for MEDLINE]

Chronic Treatment with Isoniazid Causes Protoporphyrin IX Accumulation in Mouse Liver.

Chem Res Toxicol. 2016 Aug 15;29(8):1293-7

Authors: Sachar M, Li F, Liu K, Wang P, Lu J, Ma X

Abstract
Isoniazid (INH) can cause hepatotoxicity. In addition, INH is contraindicated in patients suffering from porphyrias. Our metabolomic analysis revealed that chronic treatment with INH in mice causes a hepatic accumulation of protoporphyrin IX (PPIX). PPIX is an intermediate in the heme biosynthesis pathway, and it is also known as a hepatotoxin. We further found that INH induces delta-aminolevulinate synthase 1 (ALAS1), the rate-limiting enzyme in heme biosynthesis. We also found that INH downregulates ferrochelatase (FECH), the enzyme that converts PPIX to heme. In summary, this study illustrated that chronic treatment with INH causes PPIX accumulation in mouse liver in part through ALAS1 induction and FECH downregulation. This study also highlights that drugs can disrupt the metabolic pathways of endobiotics and increase the risk of liver damage.

PMID: 27438535 [PubMed - indexed for MEDLINE]

Characterization and inhibition studies of tissue nonspecific alkaline phosphatase by aminoalkanol derivatives of 1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5,10-trione, new competitive and non-competitive inhibitors, by capillary electrophoresis.

J Pharm Biomed Anal. 2017 Jun 01;143:285-290

Authors: Grodner B, Napiórkowska M

Abstract
The article describes the inhibitory effect of two new aminoalkanol derivatives on the enzymatic kinetic of tissue non-specific alkaline phosphatase with use of capillary zone electrophoresis to evaluate the inhibitory effect. This technique allows to investigate of the enzymatic kinetic by the measure of the amounts of the substrate and product in the presence of compound (I) or (II) in the reaction mixture. The separation process was conducted using an eCAP fused-silica capillary. The detector was set at 200nm. The best parameters for the analysis were: 25mM sodium dihydrogen phosphate adjusted to pH=2.5, temperature 25°C, and voltage -15kV. Lineweaver-Burk plots were constructed and determined by comparison of the Km, of alkaline phosphatase in the presence of inhibitor (I) or (II) with the Km in a solution without inhibitor. The influence of replacement the propylamine group by the dimethylamine group on tissue non-specific alkaline phosphatase inhibition activity of new derivatives (I) and (II) was investigated. The tested compounds (I) and (II) were found to be tissue non-specific alkaline phosphatase inhibitors. Detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase for compound (I) and non-competitive mode of inhibition for compound (II).

PMID: 28628862 [PubMed - as supplied by publisher]

The COMT Val(108/158)Met Genetic Polymorphism can not be Recommended as a Biomarker of Prediction of Venlafaxine Efficacy in Patients treated in Psychiatric settings.

Basic Clin Pharmacol Toxicol. 2017 Jun 19;:

Authors: Taranu A, Asmar KE, Colle R, Ferreri F, Polosan M, David D, Becquemont L, Corruble E, Verstuyft C

Abstract
The antidepressant venlafaxine is known to increase the turn-over of cerebral monoamines, which are catabolized by the cathecol-O-methyltransferase (COMT). The COMT (Val108/158Met, rs4680) genetic polymorphism affects the cerebral COMT activity. But whether this genetic polymorphism is associated with response to venlafaxine remains unclear. We assessed the impact of the COMT Val(108/158)Met, rs4680 genetic polymorphism on the efficacy of venlafaxine in depressed patients. This study was nested in the METADAP cohort, a real-world naturalistic treatment study in psychiatric settings. 206 Caucasian patients with a unipolar Major Depressive Episode (DSM-IVTR) treated with venlafaxine and evaluated with the Hamilton Depression Rating Scale (HDRS) were studied. 180 patients were genotyped for the COMT Val(108/158)Met, rs4680 genetic polymorphism and classified into 3 genotype subgroups: Val/Val, Val/Met, Met/Met. The COMT genotype was the explanatory variable and the variables to be explained were the HDRS score, the HDRS score improvement over time, response and remission rates. Venlafaxine had a trend to higher efficacy in the Val/Val patients as compared to Met/Met carriers, as shown by the HDRS score improvement after 3 months of treatment but this result was not significant in mixed models (Val/Val: 59.78% (±22.4); Val/Met: 51.64% (±26.3); Met/Met: 39.52% (±27.6). The percentage of responders and remitters after 3 months of treatment were not significantly different in the 3 genotype groups, although coherent trends were shown. The COMT Val(108/158)Met, rs4680 genetic polymorphism can not be recommended as a biomarker of prediction of venlafaxine efficacy in patients treated in psychiatric settings. This article is protected by copyright. All rights reserved.

PMID: 28627776 [PubMed - as supplied by publisher]

Impact of fixation artifacts and threshold selection on high resolution melting analysis for KRAS mutation screening.

Mol Cell Probes. 2017 Jun 13;:

Authors: Pérez-Báez W, Garcia-Latorre EA, Maldonado-Martinez HA, Coronado-Martinez I, Flores-Garcia L, Taja-Chayeb L

Abstract
INTRODUCTION: Treatment in the metastatic colorectal cancer has expanded with monoclonal antibodies targeting Epidermal Growth Factor Receptor, but is restricted to patients with a wild-type (WT) KRAS mutational status. The most sensitive assays for KRAS mutation detection in formalin-fixed paraffin embedded (FFPE) tissues are based on Real-time PCR. Among them, high resolution melting analysis (HRMA), is a simple, fast, highly sensitive, specific and cost-effective method, proposed as adjunct for KRAS mutation detection. However the method to categorize WT vs mutants sequences in HRMA is not clearly specified in available studies, besides the impact of FFPE artifacts on HRMA performance hasn't been addressed either.
METHODS: Avowedly adequate samples from 104 consecutive metastatic CRC patients were tested for KRAS mutations by Therascreen™ (FDA Validated test), HRMA, and HRMA with UDG pre-treatment to reverse FFPE fixation artifacts. Comparisons of KRAS status allocation among the three methods were done. Focusing on HRMA as screening test, ROC curve analyses were performed for HRMA and HMRA-UDG against Therascreen™, in order to evaluate their discriminative power and to determine the threshold of profile concordance between WT control and sample for KRAS status determination.
RESULTS: Comparing HRMA and HRMA-UDG against Therascreen™ as surrogate gold standard, sensitivity was 1 for both HRMA and HRMA-UDG; and specificity and positive predictive values were respectively 0.838 and 0.939; and 0.777 and 0.913. As evaluated by the McNemar test, HRMA-UDG allocate samples to a WT/mutated genotype in a significatively different way from HRMA (p > 0.001). On the other hand HRMA-UDG does not differ from Therascreen™ (p = 0.125). ROC-curve analysis showed a significant discriminative power for both HRMA and HRMA-UDG against Therascreen™ (respectively, AUC of 0.978, p > 0.0001, CI 95% 0.957-0.999; and AUC of 0.98, p > 0.0001, CI 95% 0.000-1.0). For HRMA as a screening tool, the best threshold (degree of concordance between sample curves and WT control) was attained at 92.14% for HRMA (specificity of 0.887), and at 92.55% for HRMA-UDG (specificity of 0.952).
CONCLUSIONS: HRMA is a highly sensitive method for KRAS mutation detection, with apparently adequate and statistically significant discriminative power. FFPE sample fixation artifacts have an impact on HRMA results, so for HRMA on FFPE samples pre-treatment with UDG should be strongly suggested. The choice of the threshold for melting curve concordance has also great impact on HRMA performance. A threshold of 93% or greater might be adequate if using HRMA as a screening tool. Further validation of this threshold is required.

PMID: 28627450 [PubMed - as supplied by publisher]

Evaluation of CYP2D6 Protein Expression and Activity in the Small Intestine to Determine its Metabolic Capability in the Japanese Population.

Biol Pharm Bull. 2017 Jun 14;:

Authors: Kawakami M, Takenoshita-Nakaya S, Takeba Y, Nishimura Y, Oda M, Watanabe M, Ohta Y, Kobayashi S, Ohtsubo T, Kobayashi S, Uchida N, Matsumoto N

Abstract
CYP2D6 plays an important role in the metabolism of many drugs such as opioids and antidepressants. Polymorphisms of the CYP2D6 gene are widely observed in the Japanese population, and can affect the first-pass metabolism of orally administered drugs. Several CYP enzymes have been identified in the small intestine of Caucasians, but intestinal CYP enzymes have not been reported in the Japanese population, except for CYP3A4 and CYP2C19. In this study, we evaluated the CYP2D6 metabolic capacity by measurement of CYP2D6 mRNA and protein levels and activity in the small intestine of Japanese individuals. Normal jejunal tissues were obtained from 31 patients who had undergone pancreaticoduodenectomy, and the CYP2D6*10 variant was identified in these tissues. CYP2D6 mRNA and CYP2D6 protein levels were analyzed using real-time reverse transcription-polymerase chain reaction and Western blotting, respectively. Bufuralol 1'-hydroxylation, a marker of CYP2D6 activity, was analyzed using high-performance liquid chromatography. Frequencies of the CYP2D6*1/*1, *1/*10, and *10/*10 genotypes in the jejunal tissue were 29.0% (n = 9), 35.5% (n = 11), and 35.5% (n = 11), respectively. CYP2D6 protein and activity levels did not differ significantly between the genotypes. A positive correlation was found between CYP2D6 protein and activity levels. Furthermore, CYP2D6 protein levels and activity in the small intestine were significantly lower than those in the liver. These findings suggest that the metabolic capacity of CYP2D6 in the small intestine of the Japanese population has a relatively small effect on drug metabolism.

PMID: 28626197 [PubMed - as supplied by publisher]

Pitfalls and Opportunities for Epigenomic Analyses Focused on Disease Diagnosis, Prognosis, and Therapy.

Trends Pharmacol Sci. 2017 Jun 15;:

Authors: Lauschke VM, Ivanov M, Ingelman-Sundberg M

PMID: 28625497 [PubMed - as supplied by publisher]

Pharmacogenetics in obstetric anesthesia.

Best Pract Res Clin Anaesthesiol. 2017 Mar;31(1):23-34

Authors: Landau R, Smiley R

Abstract
The 21st century has been billed as the era of "precision/personalized medicine." Genetic investigation of clinical syndromes may guide therapy as well as reveal previously unknown biological or pharmacological pathways that may result in novel drug therapies. Several clinical issues in obstetrics and obstetric anesthesiology have been targets for genetic investigations. These include evaluation of the genetic effects on preterm labor and the progression of labor, spinal anesthesia-induced hypotension and the response to medications used to treat hypotension, and the effect of gene variants on pain and analgesic responses. Most studies have examined specific single nucleotide polymorphisms. Findings have revealed modest effects of genetic variation without tangible impact on current clinical practice. Over the next decade, increased availability of whole exome and genome sequencing, epigenetics, large genetic databases, computational biology and other information technology, and more rapid methods of real-time genotyping may increase the impact of genetics in the clinical arena of obstetrics and obstetric anesthesia.

PMID: 28625302 [PubMed - in process]

Role of the N-acetylation polymorphism in solithromycin metabolism.

Pharmacogenomics. 2017 Jun;18(8):765-772

Authors: Hein DW, Doll MA

Abstract
AIM: Solithromycin is a new macrolide antibiotic for the potential treatment of bacterial pneumonia.
MATERIALS & METHODS: Solithromycin N-acetylation by human NAT1 and NAT2 was investigated following recombinant expression in yeast and in cryopreserved human hepatocytes from rapid, intermediate and slow acetylators.
RESULTS: Solithromycin exhibited over twofold higher affinity for recombinant human NAT2 than NAT1. Apparent maximum velocities for the N-acetylation of solithromycin catalyzed by the NAT2 allozyme associated with rapid acetylators were significantly (p < 0.01) higher than by the NAT2 allozymes associated with slow acetylators. Robust gene dose responses (rapid>intermediate>slow acetylators) were exhibited in cryopreserved human hepatocytes in situ following incubation with 100 μM solithromycin.
CONCLUSION: Solithromycin is N-acetylated by human NAT1 and NAT2 and the role of the NAT2 acetylation polymorphism on solithromycin metabolism may be concentration dependent.

PMID: 28625123 [PubMed - in process]

Identification of Potential Plasma Biomarkers for Nonalcoholic Fatty Liver Disease by Integrating Transcriptomics and Proteomics in Laying Hens.

J Nutr. 2017 Mar;147(3):293-303

Authors: Tsai MT, Chen YJ, Chen CY, Tsai MH, Han CL, Chen YJ, Mersmann HJ, Ding ST

Abstract
Background: Prevalent worldwide obesity is associated with increased incidence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. The identification of noninvasive biomarkers for NAFLD is of recent interest. Because primary de novo lipogenesis occurs in chicken liver as in human liver, adult chickens with age-associated steatosis resembling human NAFLD is an appealing animal model.Objective: The objective of this study was to screen potential biomarkers in the chicken model for NAFLD by transcriptomic and proteomic analysis.Methods: Hy-Line W-36 laying hens were fed standard feed from 25 to 45 wk of age to induce fatty liver. They were killed every 4 wk, and liver and plasma were collected at each time point to assess fatty liver development and for transcriptomic and proteomic analysis. Next, selected biomarkers were confirmed in additional experiments by providing supplements of the hepatoprotective nutrients betaine [300, 600, or 900 parts per million (ppm) in vivo; 2 mM in vitro] or docosahexaenoic acid (DHA; 1% in vivo; 100 μM in vitro) to 30-wk-old Hy-Line W-36 laying hens for 4 mo and to Hy-Line W-36 chicken primary hepatocytes with oleic acid-induced steatosis. Liver or hepatocyte lipid contents and the expression of biomarkers were then examined.Results: Plasma acetoacetyl-CoA synthetase (AACS), dipeptidyl-peptidase 4 (DPP4), glutamine synthetase (GLUL), and glutathione S-transferase (GST) concentrations are well-established biomarkers for NAFLD. Selected biomarkers had significant positive associations with hepatic lipid deposition (P < 0.001). Betaine (900 ppm in vivo; 2 mM in vitro) and DHA (1% in vivo; 100 μM in vitro) supplementation both resulted in lower steatosis accompanied by the reduced expression of selected biomarkers in vivo and in vitro (P < 0.05).Conclusion: This study used adult laying hens to identify biomarkers for NAFLD and indicated that AACS, DPP4, GLUL, and GST could be considered to be potential diagnostic indicators for NAFLD in the future.

PMID: 28077733 [PubMed - indexed for MEDLINE]

Impact of VKORC1 gene polymorphisms on warfarin maintenance dosage: A novel systematic review and meta-analysis of 53 studies.

Int J Clin Pharmacol Ther. 2017 Apr;55(4):304-321

Authors: Tang W, Shi QP, Ding F, Yu ML, Hua J, Wang YX

Abstract
OBJECTIVE: To analyze the correlation between <i>VKORC1</i> gene polymorphisms and warfarin maintenance dosage, as well as the correlation of dosage of warfarin with age and ethnicity.
METHODS: We retrieved related studies published between January 2000 and March 2016 from PubMed, Embase, the Cochrane Library, Web of Science, VIP, CNKI, and Wan Fang data. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data and crosscheck data. Then, RevMan5.3 software was used to perform a meta-analysis.
RESULTS: 53 studies were included in the meta-analysis. The most prevalent genotypes were -1639 AA, 1173 TT, and 3730 GG in both Asian and Caucasians, but the distribution frequencies of all three were higher in Asians than in Caucasians. The meta-analysis showed that compared with homozygous <i>VKORC1</i>-1639 AA carriers, carriers of type GA, GG, and G (GA + GG) required 45% (95% confidence interval (CI) 42 - 49), 77% (95% CI 70 - 84), and 51% (95% CI 47 - 55) higher warfarin doses, respectively. Carriers of type CC, TC, and C (CC + TC) required 83% (95% CI 73 - 92), 26% (95% CI 23 - 29), and 53% (95% CI 44 - 62) higher warfarin doses, respectively, compared to homozygous <i>VKORC1</i> 1173 TT carriers. Carriers of type AA, GA, and A (AA + GA) required 40% (95% CI 29 - 51), 25% (95% CI 17 - 33), and 33% (95% CI 21 - 45) higher warfarin doses, respectively, compared to carriers of the homozygous <i>VKORC1</i> 3730 GG polymorphism (all p < 0.05). Subgroup analysis showed that Asian patients aged ≤ 60 years carrying 1173 CC, TC, and C genotypes required 28%, 39%, and 22% higher warfarin doses, respectively, compared with patients aged > 60 years. Caucasian patients aged > 60 years carrying -1639 GA, GG and G genotypes needed 24%, 39%, and 37% lower warfarin doses, respectively, compared with patients aged ≤ 60 years. These differences were statistically significant (p < 0.05).
CONCLUSIONS: Our study showed that the relationship between <italic>VKORC1</italic> gene polymorphisms and warfarin maintenance dose differs between individuals, and that individuals with different ages and ethnicities require different doses of warfarin. Caucasians carriers of genotype -1639 GG, G and 1173 CC, TC, C required a higher mean daily warfarin doses compared with Asian patients. Therefore, in order to achieve optimal treatment and lowest risk, <i>VKORC1</i> gene polymorphism detection is suggested.
.

PMID: 28025970 [PubMed - indexed for MEDLINE]

Steady-state pharmacokinetics of mycophenolic acid in renal transplant patients: exploratory analysis of the effects of cyclosporine, recipients' and donors' ABCC2 gene variants, and their interactions.

Eur J Clin Pharmacol. 2017 Jun 18;:

Authors: Božina N, Lalić Z, Nađ-Škegro S, Borić-Bilušić A, Božina T, Kaštelan Ž, Trkulja V

Abstract
PURPOSE: The study aims to evaluate the impact of recipients' and donors' polymorphisms in multidrug resistance-associated protein 2 (MRP2) gene ABCC2 -24C>T and 1249G>A on disposition of mycophenolic acid (MPA) and their interaction with cyclosporine (CsA) (compared to tacrolimus, TAC) in stable de novo adult renal transplant patients of Croatian origin.
METHODS: A total of 68 recipient-donor pairs were genotyped. Steady-state pharmacokinetics of MPA was assessed by the model-independent method.
RESULTS: Adjusted for MPA formulation, renal function, type of calcineurin inhibitor and recipients' and donors' genotypes at the two loci, donors' A-allele at 1249G>A was associated with a reduced peak (29%) and early (AUC0-2, 33%) exposure and increased MPA clearance (26%). Donors' A-allele combined with CsA was associated with 78% higher MPA clearance, 49% lower early and 48% lower total exposure as compared to wild type homozygosity + TAC. Recipients' SNPs per se did not reflect on MPA disposition. However, A-allele at 1249G>A + CsA (compared to wild type + TAC) was associated with a numerically greater increase in MPA clearance (59 vs. 41%), reduction in total exposure (36 vs. 27%) and increase in absorption rate (C max/AUC) (56 vs. 37%) than observed for the main effect of CsA. Less pronounced effects were observed for the combination of variant allele at -24C>T and CsA.
CONCLUSION: Considering MPA disposition, data indicate: donors' ABCC2 1249G>A polymorphism increases clearance and reduces exposure; CsA increases clearance and reduces exposure by inhibiting MRP2 in the gut, the liver, and the kidney; donors' ABCC2 1249G>A polymorphism enhances the renal CsA effect, while recipients' polymorphism seems to enhance the liver and the gut CsA effects.

PMID: 28624888 [PubMed - as supplied by publisher]

The microbiome-gut-brain axis: implications for schizophrenia and antipsychotic induced weight gain.

Eur Arch Psychiatry Clin Neurosci. 2017 Jun 17;:

Authors: Kanji S, Fonseka TM, Marshe VS, Sriretnakumar V, Hahn MK, Müller DJ

Abstract
With the emergence of knowledge implicating the human gut microbiome in the development and regulation of several physiological systems, evidence has accumulated to suggest a role for the gut microbiome in psychiatric conditions and drug response. A complex relationship between the enteric nervous system, the gut microbiota and the central nervous system has been described which allows for the microbiota to influence and respond to a variety of behaviors and psychiatric conditions. Additionally, the use of pharmaceuticals may interact with and alter the microbiota to potentially contribute to adverse effects of the drug. The gut microbiota has been described in several psychiatric disorders including depression and anxiety, but only a few reports have discussed the role of the microbiome in schizophrenia. The following review examines the evidence surrounding the gut microbiota in behavior and psychiatric illness, the role of the microbiota in schizophrenia and the potential for antipsychotics to alter the gut microbiota and promote adverse metabolic events.

PMID: 28624847 [PubMed - as supplied by publisher]

KCNQ1 gene polymorphism is associated with glycaemic response to treatment with DPP-4 inhibitors.

Diabetes Res Clin Pract. 2017 May 19;130:142-147

Authors: Gotthardová I, Javorský M, Klimčáková L, Kvapil M, Schroner Z, Kozárová M, Malachovská Z, Ürgeová A, Židzik J, Tkáč I

Abstract
AIMS: Only afew gene variants were associated with the response to dipeptidylpeptidase-4 inhibitors (DPP4I). KCNQ1 gene variants were previously related both to type 2 diabetes (T2D) and incretin effect. We hypothesized that T2D related KCNQ1 variants would be associated with smaller glucose-lowering effect of DDP4I.
METHODS: We performed a retrospective study in 137 Caucasian subjects with T2D who were followed for 6months after initiation of DPP4I treatment. Genotyping for KCNQ1 rs163184 and rs151290 was performed using PCR-HRMA and PCR-RFLP methods, respectively. The main clinical outcome was reduction in HbA1c (ΔHbA1c) after 6-month DPP4I treatment.
RESULTS: KCNQ1 rs163184 T>G variant was associated with the response to DPP4I treatment in genetic additive model (β=-0.30, p=0.022). For each G allele in the rs163184 genotype, we observed a 0.3% (3.3mmol/mol) less reduction in HbA1c during treatment with a DPP4I. Both the GG homozygotes and G-allele carriers had significantly smaller HbA1c reduction in comparison with the TT homozygotes.
CONCLUSIONS: KCNQ1 rs163184 T>G variant was associated with a reduced glycaemic response to DPP4I. The difference of 0.6% (6.5mmol/mol) in HbA1c reduction between the TT and GG homozygotes might be of clinical significance if replicated in further studies.

PMID: 28624668 [PubMed - as supplied by publisher]

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Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits.

PLoS One. 2017;12(6):e0179020

Authors: Pinsonneault JK, Frater JT, Kompa B, Mascarenhas R, Wang D, Sadee W

Abstract
Genetic variants of ESR1 have been implicated in multiple diseases, including behavioral disorders, but causative variants remain uncertain. We have searched for regulatory variants affecting ESR1 expression in human brain, measuring allelic ESR1 mRNA expression in human brain tissues with marker SNPs in exon4 representing ESR1-008 (or ESRα-36), and in the 3'UTR of ESR1-203, two main ESR1 isoforms in brain. In prefrontal cortex from subjects with bipolar disorder, schizophrenia, and controls (n = 35 each; Stanley Foundation brain bank), allelic ESR1 mRNA ratios deviated from unity up to tenfold at the exon4 marker SNP, with large allelic ratios observed primarily in bipolar and schizophrenic subjects. SNP scanning and targeted sequencing identified rs2144025, associated with large allelic mRNA ratios (p = 1.6E10-6). Moreover, rs2144025 was significantly associated with ESR1 mRNA levels in the Brain eQTL Almanac and in brain regions in the Genotype-Tissue Expression project. In four GWAS cohorts, rs2104425 was significantly associated with behavioral traits, including: hypomanic episodes in female bipolar disorder subjects (GAIN bipolar disorder study; p = 0.0004), comorbid psychological symptoms in both males and females with attention deficit hyperactivity disorder (GAIN ADHD, p = 0.00002), psychological diagnoses in female children (eMERGE study of childhood health, subject age ≥9, p = 0.0009), and traits in schizophrenia (e.g., grandiose delusions, GAIN schizophrenia, p = 0.0004). The first common ESR1 variant (MAF 12-33% across races) linked to regulatory functions, rs2144025 appears conditionally to affect ESR1 mRNA expression in the brain and modulate traits in behavioral disorders.

PMID: 28617822 [PubMed - in process]

[The association of the FAS/APO-1 (rs2234767) gene polymorphism with the risk and rapid progression of multiple sclerosis].

Zh Nevrol Psikhiatr Im S S Korsakova. 2017;117(2. Vyp. 2):10-13

Authors: Nochevnaya OM, Pereverzeva OV, Sokolova EA, Phillipenko ML, Zamyatina SV, Palaschenko AS, Zhdanova ES, Elchaninova SA, Smagina IV

Abstract
AIM: To evaluate the association of the FAS/APO-1 (rs2234767) gene polymorphism with the risk of multiple sclerosis and its progression dynamics.
MATERIAL AND METHODS: A case-control study included 100 patients with recurrent multiple sclerosis (MS), Russians from the Altai Territory, and 100 healthy volunteers. Real-time polymerase chain reaction was used to genotype the 1377G>A polymorphism in the promoter of the FAS/APO-1 (rs2234767) gene. Association of this polymorphism with the risk of multiple sclerosis and its progression was evaluated.
RESULTS: The G/А genotype and the А-allele were associated with the increased risk of multiple sclerosis. The G/А genotype and the А-allele were associated with the risk of high progression rate of the disease. The G/G genotype and the G-allele had a protective effect.
CONCLUSION: Predisposition to MS as well as to high progression rate are associated with the FAS/APO-1*G/А gene in Russians living in the Altai Territory. Further research is required to make the conclusion.

PMID: 28617356 [PubMed - in process]