Exemestane potency is unchanged by common nonsynonymous polymorphisms in CYP19A1: results of a novel anti-aromatase activity assay examining exemestane and its derivatives.

Pharmacol Res Perspect. 2017 Jun;5(3):e00313

Authors: Peterson A, Xia Z, Chen G, Lazarus P

Abstract
Exemestane (EXE) treats estrogen receptor positive (ER+) breast cancer in postmenopausal women by inhibiting the estrogen-synthesizing cytochrome P450 CYP19A1. Variability in the severity and incidence of side effects as well as overall drug efficacy may be partially explained by genetic factors, including nonsynonymous variation in CYP19A1, also known as aromatase. The present study identified phase I EXE metabolites in human liver microsomes (HLM) and investigated mechanisms that may alter the extent of systemic estrogen deprivation in EXE-treated women with breast cancer, including whether functional polymorphisms in aromatase cause differential inhibition by EXE and whether EXE metabolites possess anti-aromatase activity. The potency of EXE and ten of its derivatives was measured with HEK293-overexpressed wild type aromatase (CYP19A1*1) using a rapid novel UPLC tandem mass spectrometry method. Of the ten compounds assayed, five were poor inhibitors (IC 50 ˃ 50 μmol/L) of wild type aromatase while five others, including the major metabolite, 17β-dihydroexemestane (17β-DHE), exhibited moderate potency, with IC 50 values ranging between 1.2 and 7.1 μmol/L. The anti-aromatase activity of EXE was also tested with two common allozymes, aromatase(Thr201Met) (CYP19A1*3) and aromatase(Arg264Cys) (CYP19A1*4). Differential inhibition of variant aromatase is unlikely to account for variable clinical outcomes as EXE-mediated inhibition of aromatase(Thr201Met) (IC 50 = 0.86 ± 0.12 μmol/L) and aromatase(Arg264Cys) (IC 50 = 1.7 ± 0.65 μmol/L) did not significantly differ from wild type (IC 50 = 0.92 ± 0.17 μmol/L). Although less potent than the parent drug, these results suggest that active metabolites may contribute to the therapeutic mechanism of EXE.

PMID: 28603632 [PubMed - in process]

Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies.

Pharmgenomics Pers Med. 2017;10:197-204

Authors: Yamamoto-Furusho JK

Abstract
Inflammatory bowel disease (IBD) is a chronic and heterogeneous disorder characterized by remitting and relapsing periods of activity. Pharmacogenetics refers to the study of the effect of inheritance on individual variation in drug responses. Several drug-related markers in IBD patients have been identified in order to predict the response to medical treatment including biological therapy as well as the reduction of adverse events. In the future, the treatment of IBD should be personalized in its specific profile to provide the most efficacious treatment with lack of adverse events.

PMID: 28603427 [PubMed - in process]

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance.

Mol Cell Biol. 2016 Nov 01;36(21):2715-2727

Authors: Garbacz WG, Lu P, Miller TM, Poloyac SM, Eyre NS, Mayrhofer G, Xu M, Ren S, Xie W

Abstract
The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome.

PMID: 27528620 [PubMed - indexed for MEDLINE]

EBV infection and MSI status significantly influence the clinical outcomes of gastric cancer patients.

Clin Chim Acta. 2017 Jun 07;:

Authors: Shen H, Zhong M, Wang W, Liao P, Yin X, Rotroff D, Knepper TC, Mcleod HL, Zhou C, Xie S, Li W, Xu B, He Y

Abstract
BACKGROUND: Epstein-Barr virus (EBV) and microsatellite instability (MSI) are associated with the carcinogenesis of many kinds of tumors, including gastric cancer (GC). However, the impact of EBV and MSI status on the prognosis of stage II and III GC is still unclear. The aim of this study was to find out the prognostic value of EBV and MSI status in a population of GC patients from Southern China.
METHODS: Patients were genotyped for EBV infection based on the detection of EBV DNA from the formalin-fixed paraffin-embedded (FFPE) specimens. Sequentially, MSI status was measured by direct sequencing. Clinical characteristics and overall survival (OS) were analyzed in 202 GC patients. Additionally, the association of EBV and MSI status with chemotherapy-based toxicity was analyzed in 324 GC patients.
RESULTS: The survival analysis revealed EBV+ patients had a poorer OS than EBV- patients (HR=1.75, 95% CI: 1.08-2.82, FDR p=0.04). This survival advantage for EBV- patients was also found in patients <60y (FDR p=0.04) and patient with stage III disease (FDR p=0.04).
CONCLUSIONS: EBV infection and MSI status are associated with overall survival of gastric cancer patients. However, traditional chemotherapy showed no difference on outcome of patients in EBV and MSI subgroups.

PMID: 28601671 [PubMed - as supplied by publisher]

Pharmacogenetics-based optimisation of atazanavir treatment: potential role of new genetic predictors.

Drug Metab Pers Ther. 2017 May 24;32(2):115-117

Authors: Falvella FS, Ricci E, Cheli S, Resnati C, Cozzi V, Cattaneo D, Gervasoni C, Clementi E, Galli M, Riva A

PMID: 28599374 [PubMed - in process]

Identifying "super responders" in pulmonary arterial hypertension.

Pulm Circ. 2017 Apr-Jun;7(2):300-311

Authors: Halliday SJ, Hemnes AR

Abstract
Pharmacotherapeutic options for pulmonary arterial hypertension (PAH) have increased dramatically in the last two decades and along with this have been substantial improvements in survival. Despite these advances, however, PAH remains a progressive and ultimately fatal disease for most patients and only epoprostenol has been shown to improve survival in a randomized control trial. Clinical observations of the heterogeneity of treatment response to different classes of medications across the phenotypically diverse PAH population has led to the identification of patients who derive significantly more benefit from certain medications than the population mean, the so-called "super responders." This was first recognized among PAH patients with acute vasodilator response during invasive hemodynamic testing, a subset of whom have dramatically improved survival when treated with calcium channel blocker (CCB) therapy. Retrospective studies have now suggested a sex discrepancy in response to endothelin receptor antagonists (ERA) and phosphodiesterase inhibitors, and more recently a few studies have found genomic associations with response to CCBs and ERAs. With increasing availability of "omics" technologies, recognition of these "super responders," combined with careful clinical and molecular phenotyping, will lead to advances in pharmacogenomics, precision medicine, and continued improvements in survival among PAH patients.

PMID: 28597766 [PubMed - in process]

Distribution of CYP2C19 polymorphisms in Mongolian and Han nationals and the choice of specific antiplatelet drugs.

Int J Clin Pharm. 2017 Jun 09;:

Authors: Li J, Wang Y, Wang H

Abstract
Background Individualized medication reviews may improve our understanding of the distribution of CYP2C19 polymorphisms in ethnic populations. Objective To evaluate differences in CYP2C19 gene polymorphisms between Mongolian and Han nationals and determine the effect of adjustments of antiplatelet treatments according to the genetic profile in patients undergoing percutaneous coronary intervention (PCI). Setting Prospective, observational, single-center study. Methods 397 patients diagnosed with acute coronary syndrome were enrolled. Additionally, 186 patients undergoing PCI were given different treatments according to their CYP2C19 genotypes. Patients with the genotype of an extensive metabolizers (EMs; *1/*1) were co-administered aspirin 100 mg/day and clopidogrel 75 mg/day, following a loading dose of 300 mg; intermediate metabolizers (IMs; e.g., *1/*2 and *1/*3) and poor metabolizers (PMs; e.g., *2/*2 and *2/*3) were administered a loading dose of 180 mg ticagrelor, followed by a maintenance dose of 90 mg twice a day. Results In Mongolians, 60.79% of patients were EMs, which was significantly higher than that in Han nationals (P = 0.002). In Han individuals, 62.14% of patients were IMs and PMs, which was significantly higher than that in Mongolians (P < 0.05). Three patients died, and the frequency of adverse events during follow-up was significantly higher in patients given conventional treatment than in patients given tailored treatment (P = 0.039). However, differences in metabolism subtypes did not affect the incidence of adverse reactions. Conclusions There were differences in CYP2C19 polymorphisms between Mongolians and Hans. Effective, safe therapy was achieved by tailoring antiplatelet drug therapy based on genotype.

PMID: 28597175 [PubMed - as supplied by publisher]

Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior.

Hum Mol Genet. 2016 Dec 15;25(24):5472-5482

Authors: Cornelis MC, Kacprowski T, Menni C, Gustafsson S, Pivin E, Adamski J, Artati A, Eap CB, Ehret G, Friedrich N, Ganna A, Guessous I, Homuth G, Lind L, Magnusson PK, Mangino M, Pedersen NL, Pietzner M, Suhre K, Völzke H, Swiss Kidney Project on Genes in Hypertension (SKIPOGH) team, Bochud M, Spector TD, Grabe HJ, Ingelsson E

Abstract
Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify potential adverse or beneficial effects of caffeine on health. We conducted a genome-wide association study (GWAS) of plasma caffeine, paraxanthine, theophylline, theobromine and paraxanthine/caffeine ratio among up to 9,876 individuals of European ancestry from six population-based studies. A single SNP at 6p23 (near CD83) and several SNPs at 7p21 (near AHR), 15q24 (near CYP1A2) and 19q13.2 (near CYP2A6) met GW-significance (P < 5 × 10-8) and were associated with one or more metabolites. Variants at 7p21 and 15q24 associated with higher plasma caffeine and lower plasma paraxanthine/caffeine (slow caffeine metabolism) were previously associated with lower coffee and caffeine consumption behavior in GWAS. Variants at 19q13.2 associated with higher plasma paraxanthine/caffeine (slow paraxanthine metabolism) were also associated with lower coffee consumption in the UK Biobank (n = 94 343, P < 1.0 × 10-6). Variants at 2p24 (in GCKR), 4q22 (in ABCG2) and 7q11.23 (near POR) that were previously associated with coffee consumption in GWAS were nominally associated with plasma caffeine or its metabolites. Taken together, we have identified genetic factors contributing to variation in caffeine metabolism and confirm an important modulating role of systemic caffeine levels in dietary caffeine consumption behavior. Moreover, candidate genes identified encode proteins with important clinical functions that extend beyond caffeine metabolism.

PMID: 27702941 [PubMed - indexed for MEDLINE]

Using Prescription Patterns in Primary Care to Derive New Quality Indicators for Childhood Community Antibiotic Prescribing.

Pediatr Infect Dis J. 2016 Dec;35(12):1317-1323

Authors: de Bie S, Kaguelidou F, Verhamme KM, De Ridder M, Picelli G, Straus SM, Giaquinto C, Stricker BH, Bielicki J, Sharland M, Sturkenboom MC, ARPEC study

Abstract
BACKGROUND: To describe patterns of antibiotic outpatient use in 3 European countries, including 2 new pediatric-specific quality indicators (QIs).
METHODS: A cohort study was conducted, 2001-2010, using electronic primary care records of 2,196,312 children up to 14 (Pedianet, Italy) or 18 years (The Health Improvement Network, United Kingdom; Integrated Primary Care Information database, The Netherlands) contributing 12,079,620 person-years. Prevalence rates of antibiotic prescribing per year were calculated and antibiotics accounting (drug utilization) for 90% of all antibiotic prescriptions were identified (drug utilization 90% method). The ratio between users of broad to narrow-spectrum penicillins, cephalosporins and macrolides (B/N ratio) and 2 pediatric-specific QIs: the proportion of amoxicillin users (amoxicillin index) and the ratio between users of amoxicillin to broad-spectrum penicillins, cephalosporins and macrolides (A/B ratio) were determined.
RESULTS: The overall annual prevalence of antibiotic prescriptions was 18.0% in the Netherlands, 36.2% in the United Kingdom and 52.0% in Italy. Use was maximal in the first years of life. The number of antibiotics accounting for the drug utilization 90% was comparable. The B/N ratio varied widely from 0.3 to 74.7. The amoxicillin index was highest in the Netherlands and the United Kingdom (50-60%), lowest in Italy (30%) and worsened over time in the United Kingdom and Italy. The A/B ratio in 2010 was 0.3 in Italy, 1.7 in the Netherlands and 5.4 in the United Kingdom.
CONCLUSIONS: The patterns of antibiotic prescribing varied highly with age and country. The pediatric-specific QIs combined with the total prevalence rate of use provide a clear picture of the trends of community childhood antibiotic prescribing, allowing monitoring of the impact of policy interventions.

PMID: 27626915 [PubMed - indexed for MEDLINE]

Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond.

PLoS Pathog. 2016 Jul;12(7):e1005763

Authors: Van Voorhis WC, Adams JH, Adelfio R, Ahyong V, Akabas MH, Alano P, Alday A, Alemán Resto Y, Alsibaee A, Alzualde A, Andrews KT, Avery SV, Avery VM, Ayong L, Baker M, Baker S, Ben Mamoun C, Bhatia S, Bickle Q, Bounaadja L, Bowling T, Bosch J, Boucher LE, Boyom FF, Brea J, Brennan M, Burton A, Caffrey CR, Camarda G, Carrasquilla M, Carter D, Belen Cassera M, Chih-Chien Cheng K, Chindaudomsate W, Chubb A, Colon BL, Colón-López DD, Corbett Y, Crowther GJ, Cowan N, D'Alessandro S, Le Dang N, Delves M, DeRisi JL, Du AY, Duffy S, Abd El-Salam El-Sayed S, Ferdig MT, Fernández Robledo JA, Fidock DA, Florent I, Fokou PV, Galstian A, Gamo FJ, Gokool S, Gold B, Golub T, Goldgof GM, Guha R, Guiguemde WA, Gural N, Guy RK, Hansen MA, Hanson KK, Hemphill A, Hooft van Huijsduijnen R, Horii T, Horrocks P, Hughes TB, Huston C, Igarashi I, Ingram-Sieber K, Itoe MA, Jadhav A, Naranuntarat Jensen A, Jensen LT, Jiang RH, Kaiser A, Keiser J, Ketas T, Kicka S, Kim S, Kirk K, Kumar VP, Kyle DE, Lafuente MJ, Landfear S, Lee N, Lee S, Lehane AM, Li F, Little D, Liu L, Llinás M, Loza MI, Lubar A, Lucantoni L, Lucet I, Maes L, Mancama D, Mansour NR, March S, McGowan S, Medina Vera I, Meister S, Mercer L, Mestres J, Mfopa AN, Misra RN, Moon S, Moore JP, Morais Rodrigues da Costa F, Müller J, Muriana A, Nakazawa Hewitt S, Nare B, Nathan C, Narraidoo N, Nawaratna S, Ojo KK, Ortiz D, Panic G, Papadatos G, Parapini S, Patra K, Pham N, Prats S, Plouffe DM, Poulsen SA, Pradhan A, Quevedo C, Quinn RJ, Rice CA, Abdo Rizk M, Ruecker A, St Onge R, Salgado Ferreira R, Samra J, Robinett NG, Schlecht U, Schmitt M, Silva Villela F, Silvestrini F, Sinden R, Smith DA, Soldati T, Spitzmüller A, Stamm SM, Sullivan DJ, Sullivan W, Suresh S, Suzuki BM, Suzuki Y, Swamidass SJ, Taramelli D, Tchokouaha LR, Theron A, Thomas D, Tonissen KF, Townson S, Tripathi AK, Trofimov V, Udenze KO, Ullah I, Vallieres C, Vigil E, Vinetz JM, Voong Vinh P, Vu H, Watanabe NA, Weatherby K, White PM, Wilks AF, Winzeler EA, Wojcik E, Wree M, Wu W, Yokoyama N, Zollo PH, Abla N, Blasco B, Burrows J, Laleu B, Leroy D, Spangenberg T, Wells T, Willis PA

Abstract
A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

PMID: 27467575 [PubMed - indexed for MEDLINE]

Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort.

Int J Cancer. 2016 Oct 15;139(8):1731-9

Authors: Chin YM, Tan LP, Abdul Aziz N, Mushiroda T, Kubo M, Mohd Kornain NK, Tan GW, Khoo AS, Krishnan G, Pua KC, Yap YY, Teo SH, Lim PV, Nakamura Y, Lum CL, Malaysian NPC Study Group, Ng CC

Abstract
Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome toward NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene p values derived from differential expression values from GEO2R. Our study identified NPC association in the gene ontology (GO) axonemal dynein complex pathway (pGWAS-GSEA  = 1.98 × 10(-2) ; pExpr-GSEA  = 1.27 × 10(-24) ; pBonf-Combined  = 4.15 × 10(-21) ). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (pAmpliSeq-GSEA  = 6.56 × 10(-4) ). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort.

PMID: 27236004 [PubMed - indexed for MEDLINE]

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FOXP3 inhibits cancer stem cell self-renewal via transcriptional repression of COX2 in colorectal cancer cells.

Oncotarget. 2017 May 18;:

Authors: Liu S, Zhang C, Zhang K, Gao Y, Wang Z, Li X, Cheng G, Wang S, Xue X, Li W, Zhang W, Zhang Y, Xing X, Li M, Hao Q

Abstract
Colon cancer stem cell (cCSC) is considered as the seed cell of colon cancer initiation and metastasis. Cyclooxygenase-2 (COX2), a downstream target of NFκB, is found to be essential in promoting cancer stem cell renewal. However, how COX2 is dysregulated in cCSCs is largely unknown. In this study, we found that the expression of transcription factor FOXP3 was much lower in the spheroids than that in the parental tumor cells. Overexpression of FOXP3 significantly decreased the numbers of spheres, reduced the side population. Accordingly, FOXP3 expression decreased the tumor size and weight in the xenograft model. The tumor inhibitory effects of FOXP3 were rarely seen when COX2 was additionally knocked down. Mechanically, FOXP3 transcriptionally repressed COX2 expression via interacting with and thus inhibiting p65 activity on the putative NFκB response elements in COX2 promoter. Taken together, we here revealed possible involvement of FOXP3 in regulating cCSC self-renewal via tuning COX2 expression, and thus providing a new target for the eradication of colon cancer stem cells.

PMID: 28591725 [PubMed - as supplied by publisher]

Alternative drug sensitivity metrics improve preclinical cancer pharmacogenomics.

Nat Biotechnol. 2017 Jun 07;35(6):500-502

Authors: Hafner M, Niepel M, Sorger PK

PMID: 28591115 [PubMed - in process]

Associations between serum 25(OH)D concentrations and prevalent asthma among children living in communities with differing levels of urbanization: a cross-sectional study.

Asthma Res Pract. 2017;3:5

Authors: Pollard SL, Lima JJ, Romero K, Tarazona-Meza C, Mougey E, Tomaino K, Malpartida-Guzmán G, Hansel NN, Checkley W, GASP Study Investigators

Abstract
BACKGROUND: Prior evidence suggests that vitamin D deficiency may increase the risk of asthma and atopy and impair pulmonary function in children.
METHODS: In this cross-sectional analysis nested in a case-control study, we analyzed serum 25(OH)D concentrations in 413 children with asthma and 471 children without asthma living in two geographically adjacent study communities (Pampas and Villa El Salvador). We measured total and antigen-specific IgE levels, pulmonary function, asthma control, and exhaled nitric oxide.
RESULTS: Mean 25(OH)D concentrations were 25.2 ng/mL (SD 10.1) in children with asthma and 26.1 ng/mL (SD 13.7) in children without asthma (p = 0.28). Vitamin D deficiency (25(OH)D < 20 ng/ml) was more common in Pampas than in Villa El Salvador (52.7% vs. 10.5%; p < 0.001). In the overall study population, a 10 ng/ml decrease in serum 25(OH)D concentrations was not significantly associated with odds of asthma (OR 1.09, 95% CI: 0.94 to 1.25). However, vitamin D deficiency was associated with a 1.6-fold increase in odds of asthma in the overall cohort (95% CI: 1.14 to 2.25). After stratifying by site, a 10 ng/mL decrease in serum 25(OH)D concentrations was associated with 18% higher odds of having asthma in Pampas (OR = 1.18, 95% CI 1.02 to 1.38), whereas there was no significant association between 25(OH)D concentrations and asthma in Villa El Salvador (OR = 0.95, 95% CI 0.87 to 1.05). Combined data from these geographically adjacent populations suggests a possible threshold for the relationship between 25(OH)D levels and asthma at approximately 27.5 ng/ml. Serum 25(OH)D concentrations were not clearly associated with asthma control, total serum IgE, atopy, or airway inflammation.
CONCLUSION: Serum 25(OH)D concentrations were inversely associated with asthma in one study community with a high prevalence of deficiency. Studies are needed to investigate a possible threshold 25(OH)D concentration after which higher vitamin D levels show no further benefit for asthma.

PMID: 28588900 [PubMed - in process]

KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment.

BMC Med Genet. 2017 Jun 06;18(1):64

Authors: Song J, Yang Y, Mauvais-Jarvis F, Wang YP, Niu T

Abstract
BACKGROUND: Type 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic β cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic β cells that regulates insulin production and processing. Because mutations of these genes could affect insulin secretion stimulated by sulfonylureas, the aim of this study is to assess associations between molecular variants of KCNJ11, ABCC8 and TCF7L2 genes and response to sulfonylurea treatment and to predict their potential functional effects.
METHODS: Based on a comprehensive literature search, we found 13 pharmacogenetic studies showing that single nucleotide polymorphisms (SNPs) located in KCNJ11: rs5219 (E23K), ABCC8: rs757110 (A1369S), rs1799854 (intron 15, exon 16 -3C/T), rs1799859 (R1273R), and TCF7L2: rs7903146 (intron 4) were significantly associated with responses to sulfonylureas. For in silico bioinformatics analysis, SIFT, PolyPhen-2, PANTHER, MutPred, and SNPs3D were applied for functional predictions of 36 coding (KCNJ11: 10, ABCC8: 24, and TCF7L2: 2; all are missense), and HaploReg v4.1, RegulomeDB, and Ensembl's VEP were used to predict functions of 7 non-coding (KCNJ11: 1, ABCC8: 1, and TCF7L2: 5) SNPs, respectively.
RESULTS: Based on various in silico tools, 8 KCNJ11 missense SNPs, 23 ABCC8 missense SNPs, and 2 TCF7L2 missense SNPs could affect protein functions. Of them, previous studies showed that mutant alleles of 4 KCNJ11 missense SNPs and 5 ABCC8 missense SNPs can be successfully rescued by sulfonylurea treatments. Further, 3 TCF7L2 non-coding SNPs (rs7903146, rs11196205 and rs12255372), can change motif(s) based on HaploReg v4.1 and are predicted as risk factors by Ensembl's VEP.
CONCLUSIONS: Our study indicates that a personalized medicine approach by tailoring sulfonylurea therapy of T2D patients according to their genotypes of KCNJ11, ABCC8, and TCF7L2 could attain an optimal treatment efficacy.

PMID: 28587604 [PubMed - in process]

Is There a Role for Genomics in the Management of Hypertension?

Int J Mol Sci. 2017 May 26;18(6):

Authors: Burrello J, Monticone S, Buffolo F, Tetti M, Veglio F, Williams TA, Mulatero P

Abstract
Hypertension (HTN) affects about 1 billion people worldwide and the lack of a single identifiable cause complicates its treatment. Blood pressure (BP) levels are influenced by environmental factors, but there is a strong genetic component. Linkage analysis has identified several genes involved in Mendelian forms of HTN and the associated pathophysiological mechanisms have been unravelled, leading to targeted therapies. The majority of these syndromes are due to gain-of-function or loss-of-functions mutations, resulting in an alteration of mineralocorticoid, glucocorticoid, or sympathetic pathways. The diagnosis of monogenic forms of HTN has limited practical implications on the population and a systematic genetic screening is not justifiable. Genome-wide linkage and association studies (GWAS) have identified single nucleotide polymorphisms (SNPs), which influence BP. Forty-three variants have been described with each SNP affecting systolic and diastolic BP by 1.0 and 0.5 mmHg, respectively. Taken together Mendelian inheritance and all GWAS-identified HTN-associated variants explain 2-3% of BP variance. Epigenetic modifications, such as DNA methylation, histone modification and non-coding RNAs, have become increasingly recognized as important players in BP regulation and may justify a further part of missing heritability. In this review, we will discuss how genetics and genomics may assist clinicians in managing patients with HTN.

PMID: 28587112 [PubMed - in process]

Development and Initial Assessment of a Patient Education Video about Pharmacogenetics.

J Pers Med. 2017 May 25;7(2):

Authors: Mills R, Ensinger M, Callanan N, Haga SB

Abstract
As few patient-friendly resources about pharmacogenetics are currently available, we aimed to create and assess a patient educational video on pharmacogenetic testing. A primary literature and resources review was conducted to inform the content and the format of the video. The educational video was then created using a commercially available animation program and pilot tested in focus groups of the general public and by an online survey of pharmacists. Emerging themes from the focus groups and survey indicate a desire for appropriate risk contextualization and specific examples when pharmacogenetic testing may be beneficial. Focus group participants also expressed a preference for a video with live action, and more text to reinforce concepts. Pharmacists generally felt that the video was understandable for patients and relevant for decision-making regarding testing. Using this initial feedback and the identification of important concepts to include in pharmacogenetics educational tools, we plan to revise the video, perform additional evaluations, and publish the video for public use in the future.

PMID: 28587070 [PubMed - in process]

Influence of vitamin D and transforming growth factor β3 serum concentrations, obesity, and family history on the risk for uterine fibroids.

Fertil Steril. 2016 Dec;106(7):1787-1792

Authors: Ciebiera M, Włodarczyk M, Słabuszewska-Jóźwiak A, Nowicka G, Jakiel G

Abstract
OBJECTIVE: To evaluate the influence of 25-hydroxyvitamin D and transforming growth factor β3 (TGF-β3) serum concentrations, weight, and family history on the risk of developing uterine fibroids.
DESIGN: Retrospective cohort study.
SETTING: University hospital.
PATIENT(S): A total of 188 women, including patients admitted for uterine fibroid surgery (n = 105) as the study group and healthy women of similar age (n = 83) as controls.
INTERVENTION(S): Medical history and completion of specially designed questionnaire, transvaginal or transabdominal genital ultrasound scan, blood sampling, and measurement of vitamin D and TGF-β3 serum concentrations.
MAIN OUTCOME MEASURE(S): Evaluation of the impact of family history, vitamin D, and TGF-β3 serum concentrations on the risk of developing uterine fibroids.
RESULT(S): Mean 25-hydroxyvitamin D serum concentrations were 21.9 ± 8.9 ng/mL and 26.7 ± 11.9 ng/mL in patients with uterine fibroids and controls, respectively. The difference was statistically significant. The TGF-β3 serum concentrations in the fibroid-positive group ranged from 1.20 to 436.15 pg/mL (half the patients had concentrations >16.25 pg/mL). Concentrations in the control group ranged from 0.96 to 49.08 pg/mL (half the women had concentrations of >11.80 pg/mL). The differences were statistically significant. Higher body mass index (BMI) and positive family history were also found to be among the risk factors for uterine fibroids.
CONCLUSION(S): Our study confirmed higher BMI, positive family history, and lower vitamin D and higher TGF-β3 serum concentrations as risk factors for uterine fibroids.

PMID: 27743697 [PubMed - indexed for MEDLINE]

SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome.

J Am Heart Assoc. 2017 Jun 05;6(6):

Authors: Makarawate P, Chaosuwannakit N, Vannaprasaht S, Sahasthas D, Koo SH, Lee EJD, Tassaneeyakul W, Barajas-Martinez H, Hu D, Sawanyawisuth K

Abstract
BACKGROUND: Brugada syndrome (BrS) is an inherited primary arrhythmia disorder leading to sudden cardiac arrest. SCN5A, encoding the α-subunit of the cardiac sodium channel (Nav1.5), is the most common pathogenic gene of BrS. An implantable cardioverter defibrillator (ICD) is the standard treatment for secondary prevention. This study aimed to evaluate association of the SCN5A variant with this cardiac conduction disturbance and appropriate ICD shock therapy in Thai symptomatic BrS patients with ICD implants.
METHODS AND RESULTS: Symptomatic BrS patients diagnosed at university hospital were enrolled from 2008 to 2011. The primary outcome of the study was an appropriate ICD shock defined as having non-pacing-associated ICD shock after the occurrence of ventricular tachycardia or ventricular fibrillation. Associations between SCN5A polymorphisms, cardiac conduction disturbance, and potential confounding factors associated with appropriate ICD shock therapy were analyzed. All 40 symptomatic BrS patients (median age, 43 years) with ICD implantations were followed for 24 months. There were 16 patients (40%) who had the appropriate ICD shock therapy after ICD treatment. An independent factor associated with appropriate ICD shock therapy was SCN5A-R1193Q with an adjusted hazard ratio of 10.550 (95% CI, 1.631-68.232).
CONCLUSIONS: SCN5A-R1193Q is associated with cardiac conduction disturbances. It may be a genetic marker associated with ventricular arrhythmia leading to appropriate ICD shock therapy in symptomatic BrS patients with ICD treatment. Because of the small sample size of study population and the appropriate ICD shock outcome, further large studies are needed to confirm the results of this study.

PMID: 28584071 [PubMed - in process]