Association between 28 single nucleotide polymorphisms and type 2 diabetes mellitus in the Kazakh population: a case-control study.

BMC Med Genet. 2017 Jul 24;18(1):76

Authors: Sikhayeva N, Iskakova A, Saigi-Morgui N, Zholdybaeva E, Eap CB, Ramanculov E

Abstract
BACKGROUND: We evaluated the associations between single nucleotide polymorphisms and different clinical parameters related to type 2 diabetes mellitus (T2DM), obesity risk, and metabolic syndrome (MS) in a Kazakh cohort.
METHODS: A total of 1336 subjects, including 408 T2DM patients and 928 control subjects, were recruited from an outpatient clinic and genotyped for 32 polymorphisms previously associated with T2DM and obesity-related phenotypes in other ethnic groups. For association studies, the chi-squared test or Fisher's exact test for binomial variables were used. Logistic regression was conducted to explore associations between the studied SNPs and the risk of developing T2DM, obesity, and MS, after adjustments for age and sex.
RESULTS: After excluding four SNPs due to Hardy-Weinberg disequilibrium, significant associations in age-matched cohorts were found betweenT2DM and the following SNPs: rs9939609 (FTO), rs13266634 (SLC30A8), rs7961581 (TSPAN8/LGR5), and rs1799883 (FABP2). In addition, examination of general unmatched T2DM and control cohorts revealed significant associations between T2DM and SNPsrs1799883 (FABP2) and rs9939609 (FTO). Furthermore, polymorphisms in the FTO gene were associated with increased obesity risk, whereas polymorphisms in the FTO and FABP2 genes were also associated with the risk of developing MS in general unmatched cohorts.
CONCLUSION: We confirmed associations between polymorphisms within the SLC30A8, TSPAN8/LGR5, FABP2, and FTO genes and susceptibility to T2DM in a Kazakh cohort, and revealed significant associations with anthropometric and metabolic traits. In particular, FTO and FABP2 gene polymorphisms were significantly associated with susceptibility to MS and obesity in this cohort.

PMID: 28738793 [PubMed - in process]

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pharmacogenomics

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Antistaphylococcal Activity of Selected Thiourea Derivatives.

Pol J Microbiol. 2017 Jan 02;65(4):451-460

Authors: Stefańska J, Stępień K, Bielenica A, Wrzosek M, Struga M

Abstract
Five of thiourea derivatives were prepared using as a starting compound 3-(trifluoromethyl)aniline, 4-chloro-3-nitroaniline, 1,3-thiazol-2-amine, 2H-1,2,3-triazol-4-amine and commercial isothiocyanates. All compounds were evaluated in vitro for antimicrobial activity. Derivatives 2 and 3 showed the highest inhibition against Gram-positive cocci (standard and hospital strains). The observed MIC values were in the range of 0.5-8 μg/ml. The products effectively inhibited the formation of biofilms of methicillin-resistant and standard strains of Staphylococcus epidermidis. Inhibitory activity of thioureas 2 and 3 against Staphylococcus aureus topoisomerase IV was studied. The examined compounds were nongenotoxic.

PMID: 28735329 [PubMed - in process]

Biological age is better than chronological as predictor of 3-month outcome in ischemic stroke.

Neurology. 2017 Jul 21;:

Authors: Soriano-Tárraga C, Mola-Caminal M, Giralt-Steinhauer E, Ois A, Rodríguez-Campello A, Cuadrado-Godia E, Gómez-González A, Vivanco-Hidalgo RM, Fernández-Cadenas I, Cullell N, Roquer J, Jiménez-Conde J

Abstract
OBJECTIVE: To analyze the effect of age-related DNA methylation changes in multiple cytosine-phosphate-guanine (CpG) sites (biological age [b-age]) on patient outcomes at 3 months after an ischemic stroke.
METHODS: We included 511 patients with first-ever acute ischemic stroke assessed at Hospital del Mar (Barcelona, Spain) as the discovery cohort. Demographic and clinical data, including chronological age (c-age), vascular risk factors, initial stroke severity, recanalization treatment, and previous and 3-month modified Rankin Scale (p-mRS and 3-mRS, respectively) were registered. B-age was estimated with an algorithm, based on DNA methylation in 71 CpGs. Bivariate analysis determined variables associated with 3-mRS for inclusion in ordinal multivariate analysis.
RESULTS: After ordinal regressions for 3-month ischemic stroke outcome (3-mRS), b-age was associated with outcome (odds ratio 1.04 [95% confidence interval 1.01-1.07]), nullifying c-age. Stepwise regression kept b-age, basal NIH Stroke Scale, sex, p-mRS, and recanalization treatment as better explanatory variables, instead of c-age. These results were successfully replicated in an independent cohort.
CONCLUSIONS: B-age, estimated by DNA methylation, is an independent predictor of ischemic stroke outcome regardless of chronological years.

PMID: 28733340 [PubMed - as supplied by publisher]

In silico pharmacogenetic approach: The natalizumab case study.

Toxicol Appl Pharmacol. 2017 Jul 18;:

Authors: Cavaliere F, Montanari E, Emerson A, Buschini A, Cozzini P

Abstract
Natalizumab is a humanized monoclonal antibody to α4β1 integrin and is approved for the treatment of Multiple Sclerosis. In patients there is a great variation in drug response and there is much evidence that genetic contributors play an important role in defining an individual's susceptibility. Natalizumab binds to α4-residues Gln-152, Lys-201, Lys256, and these seem to be essential for its activity. Studies on a range of species in disease model have showed a loss of reactivity when any one of those three residues were different to human. Based on these animal studies, we thought that the single nucleotide polymorphism in the ITGA4 human gene causing a lysine to arginine transversion at amino acid position 256 require further investigations in the context of individual drug susceptibility. So, the aim of our study was to investigate the association between this genetic polymorphism and the resistance to natalizumab. We had applied molecular dynamics simulation to study the possible conformational changes induced by Lys256Arg transversion on the overall structure of integrin and we have analyzed the binding affinities of natalizumab in the non-mutated and mutated structures through HINT score. We found that this SNP does not affect the VLA4-natalizumab interaction. Instead, the binding affinities are slightly higher in the mutated complex than in the wild-type. We reported one of the first work in which MD simulation was applied in the pharmacogenetic context, and this approach is rapid and cost effective, since a population survey is carried out only after the positive prediction of simulation.

PMID: 28733203 [PubMed - as supplied by publisher]

Polymorphisms in cytochrome P450 oxidoreductase and its effect on drug metabolism and efficacy.

Pharmacogenet Genomics. 2017 Jul 20;:

Authors: Gong L, Zhang CM, Lv JF, Zhou HH, Fan L

Abstract
Cytochrome P450 oxidoreductase (POR) has played a potential role in the metabolism of drugs and steroids by supplying electrons to microsomal cytochrome P450 (CYP) enzymes. More than 200 different POR mutations and polymorphisms causing more than 130 amino acid changes in the POR protein have been reported since 2004. A503V is a common amino acid sequence variant encoded by POR*28, whereas A287P and R457H are the most common disease-causing mutations in Europeans and Asians, respectively. Polymorphisms in the POR gene can affect POR activity, CYP-mediated drug metabolism activities, and the efficacy of several clinically used drugs. The effects of POR variants on CYP activities are substrate dependent. In this review, recent research on the effects of POR genetic polymorphisms on drug metabolism and therapy has been summarized and discussed, which can contribute to the rational use of drugs in clinic and the development of personalized medicine.

PMID: 28731962 [PubMed - as supplied by publisher]

Drug discovery and development for rare genetic disorders.

Am J Med Genet A. 2017 Jul 21;:

Authors: Sun W, Zheng W, Simeonov A

Abstract
Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed. Rare diseases are usually genetic diseases; hence, employing pharmacogenetics to develop treatments and using whole genome sequencing to identify the etiologies for such diseases are appropriate strategies to exploit. Beginning with high throughput screening of small molecules, the benefits and challenges of target-based and phenotypic screens are discussed. Explanations and examples of drug repurposing are given; drug repurposing as an approach to quickly move programs to clinical trials is evaluated. Consideration is given to the category of biologics which include gene therapy, recombinant proteins, and autologous transplants. Disease models, including animal models and induced pluripotent stem cells (iPSCs) derived from patients, are surveyed. Finally, the role of biomarkers in drug discovery and development, as well as clinical trials, is elucidated.

PMID: 28731526 [PubMed - as supplied by publisher]

Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort.

Pharmacogenomics J. 2017 Jul;17(4):393

Authors: Dodgen TM, De J Labuschagne C, van Schalkwyk A, Steffens FE, Gaedigk A, Cromarty AD, Alessandrini M, Pepper MS

Abstract
This corrects the article DOI: 10.1038/tpj.2015.76.

PMID: 28729716 [PubMed - in process]

Mechanistic Multi-Tissue Modeling of GILZ Regulation: Integrating Circadian Gene Expression with Receptor-Mediated Corticosteroid Pharmacodynamics.

J Pharmacol Exp Ther. 2017 Jul 20;:

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

Abstract
The glucocorticoid-induced leucine zipper (GILZ) is an important mediator of anti-inflammatory corticosteroid action. The pharmacokinetic/pharmacodynamic/pharmacogenomic effects of acute and chronic methylprednisolone (MPL) dosing on the tissue-specific dynamics of GILZ expression were examined in rats. A mechanism-based model was developed to investigate and integrate the role of MPL and circadian rhythms on the transcriptional enhancement of GILZ in multiple tissues. Animals received a single 50 mg/kg intramuscular bolus or a seven-day 0.3 mg/kg/h subcutaneous infusion of MPL and were euthanized at several time-points. An additional group of rats were euthanized at several times and served as 24-h light/dark (circadian) controls. Plasma MPL and corticosterone concentrations were measured by high-performance liquid chromatography. The expression of GILZ and glucocorticoid receptor (GR) mRNA was quantified in tissues using qRT-PCR. The pharmacokinetics of MPL were described using a two-compartment model. Mild-to-robust circadian oscillations in GR and GILZ mRNA expression were characterized in lung, muscle, and adipose tissues and modeled using Fourier harmonic functions. Acute MPL dosing caused significant down-regulation (40-80%) in GR mRNA and enhancement of GILZ mRNA expression (500-1080%) in the tissues examined. While GILZ returned to its rhythmic baseline following acute dosing, a new steady-state was observed upon enhancement by chronic dosing. The model captured the complex dynamics in all tissues and for both dosing regimens. The model quantitatively integrates physiological mechanisms such as circadian processes and GR tolerance phenomena, which control the tissue-specific regulation of GILZ by corticosteroids. These studies characterize GILZ as a pharmacodynamic marker of corticosteroid actions in several tissues.

PMID: 28729456 [PubMed - as supplied by publisher]

Dysregulation of miR-223 constitutes a promising biomarker that informs about clinical outcomes of acute liver failure.

Clin Sci (Lond). 2017 Aug 01;131(15):2059-2062

Authors: Lauschke VM

Abstract
In this issue of Clinical Science, Schueller et al. [Clin. Sci. (2017) 131, 1971-1987] evaluated the role of miR-223 across multiple etiologies of acute and chronic liver insults in murine models and clinical samples. The authors find that while miR-223 is not mechanistically involved in liver injury, its intracellular levels in hepatocytes are increased upon hepatic damage in a broad panel of mechanistically distinct injury models. Furthermore, the authors provide evidence that circulating miR-223 levels provide a promising minimally invasive biomarker for acute liver failure (ALF) that defines a distinct subset of ALF cases and correlates with clinical outcomes. Combined, the highlighted study suggests that miR-223 constitutes a promising biomarker whose clinical validity and utility warrant further investigations.

PMID: 28729435 [PubMed - in process]

Expression of CYP4V2 in human THP1 macrophages and its transcriptional regulation by peroxisome proliferator-activated receptor gamma.

Toxicol Appl Pharmacol. 2017 Jul 17;:

Authors: Yi M, Shin JG, Lee SJ

Abstract
Because macrophages respond to a variety of pathological and pharmacological reagents, understanding the role of P450s in macrophages is important for therapeutic intervention. There has been a lack of research on CYP4 in macrophages, but fatty acid accumulation and lipid trafficking in macrophages have been suggested to be a main cause of atherosclerosis. All human CYP4 genes (n=12) were screened in THP1 macrophages by gene-specific reverse transcriptase-polymerase chain reaction (RT-PCR). Only CYP4V2 exhibited strong expression of both mRNA and protein. Expression levels of both CYP4V2 mRNA and protein were significantly reduced after treatment with peroxisome proliferator-activated receptor gamma (PPARγ) antagonist GW9662. However, the expression levels of CYP4V2 were not changed by PPARα antagonist (GW6471) and liver X receptor alpha antagonist (22-S hydroxycholesterol). A metabolite of the CYP4V2 enzyme, 12-hydroxydodecanoic acid, was detected in THP1 macrophages, and this metabolite was significantly decreased after treatment with the PPARγ inhibitor GW9662 (>80% decreased, p<0.05). In summary, fatty acid metabolizing protein CYP4V2 was identified in human THP1 macrophages, and its expression was regulated by PPARγ. Further study is required to understand the role of CYP4V2 with regard to fat accumulation in the activated macrophage and atherosclerotic plaque development.

PMID: 28729181 [PubMed - as supplied by publisher]

Extracellular purines' action on glomerular albumin permeability in isolated rat glomeruli: insights into the pathogenesis of albuminuria.

Am J Physiol Renal Physiol. 2016 Jul 01;311(1):F103-11

Authors: Kasztan M, Piwkowska A, Kreft E, Rogacka D, Audzeyenka I, Szczepanska-Konkel M, Jankowski M

Abstract
Purinoceptors (adrengeric receptors and P2 receptors) are expressed on the cellular components of the glomerular filtration barrier, and their activation may affect glomerular permeability to albumin, which may ultimately lead to albuminuria, a well-established risk factor for the progression of chronic kidney disease and development of cardiovascular diseases. We investigated the mechanisms underlying the in vitro and in vivo purinergic actions on glomerular filter permeability to albumin by measuring convectional albumin permeability (Palb) in a single isolated rat glomerulus based on the video microscopy method. Primary cultured rat podocytes were used for the analysis of Palb, cGMP accumulation, PKG-Iα dimerization, and immunofluorescence. In vitro, natural nucleotides (ATP, ADP, UTP, and UDP) and nonmetabolized ATP analogs (2-meSATP and ATP-γ-S) increased Palb in a time- and concentration-dependent manner. The effects were dependent on P2 receptor activation, nitric oxide synthase, and cytoplasmic guanylate cyclase. ATP analogs significantly increased Palb, cGMP accumulation, and subcortical actin reorganization in a PKG-dependent but nondimer-mediated route in cultured podocytes. In vivo, 2-meSATP and ATP-γ-S increased Palb but did not significantly affect urinary albumin excretion. Both agonists enhanced the clathrin-mediated endocytosis of albumin in podocytes. A product of adenine nucleotides hydrolysis, adenosine, increased the permeability of the glomerular barrier via adrenergic receptors in a dependent and independent manner. Our results suggest that the extracellular nucleotides that stimulate an increase of glomerular Palb involve nitric oxide synthase and cytoplasmic guanylate cyclase with actin reorganization in podocytes.

PMID: 27076649 [PubMed - indexed for MEDLINE]

Genetic Variants of Cytochrome CYP2D6 in Two Mixed Chilean Populations.

Hum Hered. 2017 Jul 21;82(1-2):16-20

Authors: Acuña M, Pinto E, Olivares P, Ríos C

Abstract
OBJECTIVES: It is known that the interindividual and interethnic variability of the genetic polymorphisms of CYP2D6 plays an important role in the presentation of adverse drug reactions and concerning lack of therapeutic effects in humans. However, there are few data available from mixed populations of Latin America, including the Chilean. The aim of this study was therefore to estimate the frequencies of CYP2D6 variants in two samples of hospitals from the northern (Hospital San José, HSJ) and eastern (Clínica Las Condes, CLC) parts of Santiago, Chile, with different degrees of Amerindian admixture (HSJ: 34.5%; CLC: 15.9%).
METHODS: We used polymerase chain reaction followed by restriction endonuclease digestion (PCR-RFLP) to genotype 7 CYP2D6 alleles in 250 healthy unrelated individuals of Chilean Mestizo background. The detection of allele CYP2D6*5 and the duplication of this gene was performed by long-PCR.
RESULTS: The degrees of Amerindian admixture are reflected in the observed frequencies of the CYP2D6*1 (HSJ: 58.26%; CLC: 41.06%), CYP2D6*2 (HSJ: 28.10%; CLC: 40.65%), and CYP2D6*4 (HSJ: 8.26%; CLC: 12.60%) alleles; the frequencies of CYP2D6*1 (p = 0.0002) and CYP2D6*2 (p = 0.0036) are significantly different between the samples. Four individuals (CLC: 0.41%; HSJ: 1.24%) could not be assigned to a genotype. We identified 3.25% of the genotypes which predict a poor metabolizer phenotype in CLC and 1.65% in HSJ.
CONCLUSION: Our data indicate ethnic group-dependent genetic differences in the vulnerability to treatment with the large variety of drugs metabolized by the enzyme CYP2D6.

PMID: 28728153 [PubMed - as supplied by publisher]

Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits: a Genetics of Diabetes Audit and Research Tayside study.

Pharmacogenet Genomics. 2017 Jul 19;:

Authors: Soto-Pedre E, Siddiqui MK, Doney AS, Palmer CNA, Pearson ER, Leese GP

Abstract
OBJECTIVE: Replication of associations in genome-wide association studies is desirable to ensure that such signals are potentially clinically meaningful. This study aimed to replicate associations of selected single-nucleotide polymorphisms (SNPs) with hypothyroidism and serum thyroid-stimulating hormone (TSH) using electronic medical records (EMRs).
PATIENTS AND METHODS: A cross-sectional study was carried out among patients of European Caucasian ethnicity from the Genetics of Diabetes Audit and Research Tayside recruited in Tayside (Scotland, UK). EMRs (biochemistry, prescribing, hospital admissions and demographics) were used to ascertain patients with hypothyroidism and their controls as well as average serum TSH concentration, and linked to genetic biobank data. Genetic tests of association were performed using logistic and linear regression models.
RESULTS: We analysed 1703 cases of hypothyroidism and 9457 controls. All four SNPs located on chromosome 9 at FOXE1 were associated with hypothyroidism with similar effect estimates (odds ratio=0.75-0.76, P<5e-08). Also, loci on chromosomes 1 (PTPN22), six (HLA-E/HLA-C) and 12 (SH2B3) were replicated. For serum TSH, we confirmed 12 SNPs previously reported at PDE8B, CAPZB, PDE10A, LOC105371356, NR3C2, VEGFA, IGFBP5, INSR, PRDM11, NFIA, ITPK1 and ABO. Overall, these SNPs accounted for 6.8% of the serum TSH variation (P<1e-04).
CONCLUSION: EMRs linked to genomic data in large populations enable validation of genome-wide association studies discoveries without additional genotyping costs. Our replication confirmed at genome-wide significance the association of loci at FOXE1 with hypothyroidism, and PDE8B, CAPZB and PDE10A with serum TSH. A total of 12 SNPs seemed to explain nearly 7% of the serum TSH variation.

PMID: 28727628 [PubMed - as supplied by publisher]

Transcriptome Profiling of Patient-Specific Human iPSC-Cardiomyocytes Predicts Individual Drug Safety and Efficacy Responses In Vitro.

Cell Stem Cell. 2016 Sep 01;19(3):311-25

Authors: Matsa E, Burridge PW, Yu KH, Ahrens JH, Termglinchan V, Wu H, Liu C, Shukla P, Sayed N, Churko JM, Shao N, Woo NA, Chao AS, Gold JD, Karakikes I, Snyder MP, Wu JC

Abstract
Understanding individual susceptibility to drug-induced cardiotoxicity is key to improving patient safety and preventing drug attrition. Human induced pluripotent stem cells (hiPSCs) enable the study of pharmacological and toxicological responses in patient-specific cardiomyocytes (CMs) and may serve as preclinical platforms for precision medicine. Transcriptome profiling in hiPSC-CMs from seven individuals lacking known cardiovascular disease-associated mutations and in three isogenic human heart tissue and hiPSC-CM pairs showed greater inter-patient variation than intra-patient variation, verifying that reprogramming and differentiation preserve patient-specific gene expression, particularly in metabolic and stress-response genes. Transcriptome-based toxicology analysis predicted and risk-stratified patient-specific susceptibility to cardiotoxicity, and functional assays in hiPSC-CMs using tacrolimus and rosiglitazone, drugs targeting pathways predicted to produce cardiotoxicity, validated inter-patient differential responses. CRISPR/Cas9-mediated pathway correction prevented drug-induced cardiotoxicity. Our data suggest that hiPSC-CMs can be used in vitro to predict and validate patient-specific drug safety and efficacy, potentially enabling future clinical approaches to precision medicine.

PMID: 27545504 [PubMed - indexed for MEDLINE]

Influx transporter variants as predictors of cancer chemotherapy-induced toxicity: systematic review and meta-analysis.

Pharmacogenomics. 2016 Jul;17(10):1189-1205

Authors: Zaïr ZM, Singer DR

Abstract
AIM: Chemotherapeutic agents have been shown to increase lung patient survival, however their use may be limited by their serious adverse effects. We aimed to assess int impact of pharmacogenetic variation of influx transporters on inter-individual patient variation in adverse drug reactions.
PATIENTS & METHODS: We conducted a meta-analysis and systemic review and identified 16 publications, totaling 1510 patients, to be eligible for review.
RESULTS: Meta-analysis showed east-Asian patients expressing SLCO1B1 521T>C or 1118G>A to have a two- to fourfold increased risk of irinotecan-induced neutropenia but not diarrhea. American patients, expressing SLC19A1 IVS2(4935) G>A, were further associated with pemetrexed/gemcitabine-induced grade 3+ leukopenia.
CONCLUSION: Future studies should look to robust validation of SLCO1B1 and SLC19A1 as prognostic markers in the management of lung cancer patients.

PMID: 27380948 [PubMed - indexed for MEDLINE]

miRNAs: mediators of ErbB family targeted therapy resistance.

Pharmacogenomics. 2016 Jul;17(10):1175-1187

Authors: Adem BF, Bastos NR, Dias F, Teixeira AL, Medeiros R

Abstract
The ErbB/HER tyrosine kinase receptors family plays a key regulatory role in different cellular processes by activating several signaling pathways. In different tumor types, mutations or overexpression of the ErbB family members are a common feature, which led to the development of targeted therapies against this receptors. Although with this kind of treatment we are heading to a more personalized medicine, the development of acquired resistance is still an issue, therefore, several studies focused on discovering the mechanisms behind it. More recently, miRNAs have been described as important mediators of acquired resistance, specifically, acquired resistance to ErbB family targeted therapies. Ultimately, miRNA-based therapeutics using exosomes as a drug delivery model can revolutionize today's approach of cancer treatment.

PMID: 27359187 [PubMed - indexed for MEDLINE]

Systems analysis of the prostate transcriptome in African-American men compared with European-American men.

Pharmacogenomics. 2016 Jul;17(10):1129-1143

Authors: Hardiman G, Savage SJ, Hazard ES, Wilson RC, Courtney SM, Smith MT, Hollis BW, Halbert CH, Gattoni-Celli S

Abstract
AIM: African-Americans (AA) have increased prostate cancer risk and a greater mortality rate than European-Americans (EA). AA exhibit a high prevalence of vitamin D deficiency. We examined the global prostate transcriptome in AA and EA, and the effect of vitamin D3 supplementation.
PATIENTS & METHODS: Twenty-seven male subjects (ten AA and 17 EA), slated to undergo prostatectomy were enrolled in the study. Fourteen subjects received vitamin D3 (4000 IU daily) and 13 subjects received placebo for 2 months prior to surgery.
RESULTS: AA show higher expression of genes associated with immune response and inflammation.
CONCLUSION: Systems level analyses support the concept that Inflammatory processes may contribute to disease progression in AA. These transcripts can be modulated by a short course of vitamin D3 supplementation.

PMID: 27359067 [PubMed - indexed for MEDLINE]

SNPs in NRXN1 and CHRNA5 are associated to smoking and regulation of GABAergic and glutamatergic pathways.

Pharmacogenomics. 2016 Jul;17(10):1145-1158

Authors: Pérez-Rubio G, Pérez-Rodríguez ME, Fernández-López JC, Ramírez-Venegas A, García-Colunga J, Ávila-Moreno F, Camarena A, Sansores RH, Falfán-Valencia R

Abstract
AIM: To identify genetic variants associated with greater tobacco consumption in a Mexican population.
PATIENTS & METHODS: Daily smokers were classified as light smokers (LS; n = 742), heavy smokers (HS; n = 601) and nonsmokers (NS; n = 606). In the first stage, a genotyping microarray that included 347 SNPs in CHRNA2-CHRNA7/CHRNA10, CHRNB2-CHRNB4 and NRXN1 genes and 37 ancestry-informative markers was used to analyze 707 samples (187 HS, 328 LS and 192 NS). In the second stage, 14 SNPs from stage 1 were validated in the remaining samples (HS, LS and NS; n = 414 in each group) using real-time PCR. To predict the role of the associated SNPs, an in silico analysis was performed.
RESULTS: Two SNPs in NRXN1 and two in CHRNA5 were associated with cigarette consumption, while rs10865246/C (NRXN1) was associated with high nicotine addiction. The in silico analysis revealed that rs1882296/T had a high level of homology with Hsa-miR-6740-5p, which encodes a putative miRNA that targets glutamate receptor subunits (GRIA2, GRID2) and GABA receptor subunits (GABRG1, GABRA4, GABRB2), while rs1882296/C had a high level of homology with Hsa-miR-6866-5p, which encodes a different miRNA that targets GRID2 and GABRB2.
CONCLUSION: In a Mexican Mestizo population, greater consumption of cigarettes was influenced by polymorphisms in the NRXN1 and CHRNA5 genes. We proposed new hypotheses regarding the putative roles of miRNAs that influence the GABAergic and glutamatergic pathways in smoking addiction.

PMID: 27355804 [PubMed - indexed for MEDLINE]

Deep molecular response by IFN-α and dasatinib combination in a patient with T315I-mutated chronic myeloid leukemia.

Pharmacogenomics. 2016 Jul;17(10):1159-1163

Authors: Zhou L, Shi H, Jiang S, Ruan C, Liu H

Abstract
The T315I mutation is especially challenging as it confers resistance to all first- and second-generation tyrosine kinase inhibitors. We present here a chronic myeloid leukemia patient harboring the T315I and E255V BCR-ABL1 mutation successfully achieved deep molecular response with a combined treatment of dasatinib and IFN-α. To our knowledge, this is the second case of a T315I-bearing chronic myeloid leukemia patient displaying satisfactory response to the combination therapy of dasatinib and IFN-α.

PMID: 27347777 [PubMed - indexed for MEDLINE]