An epigenetic signature of adhesion molecules predicts poor prognosis of ovarian cancer patients.

Oncotarget. 2017 Aug 08;8(32):53432-53449

Authors: Chang PY, Liao YP, Wang HC, Chen YC, Huang RL, Wang YC, Yuan CC, Lai HC

Abstract
DNA methylation is a promising biomarker for cancer. The epigenetic effects of cell adhesion molecules may affect the therapeutic outcome and the present study examined their effects on survival in ovarian cancer. We integrated methylomics and genomics datasets in The Cancer Genome Atlas (n = 391) and identified 106 highly methylated adhesion-related genes in ovarian cancer tissues. Univariate analysis revealed the methylation status of eight genes related to progression-free survival. In multivariate Cox regression analysis, four highly methylated genes (CD97, CTNNA1, DLC1, HAPLN2) and three genes (LAMA4, LPP, MFAP4) with low methylation were significantly associated with poor progression-free survival. Low methylation of VTN was an independent poor prognostic factor for overall survival after adjustment for age and stage. Patients who carried any two of CTNNA1, DLC1 or MFAP4 were significantly associated with poor progression-free survival (hazard ratio: 1.59; 95% confidence interval: 1.23, 2.05). This prognostic methylation signature was validated in a methylomics dataset generated in our lab (n = 37, hazard ratio: 16.64; 95% confidence interval: 2.68, 103.14) and in another from the Australian Ovarian Cancer Study (n = 91, hazard ratio: 2.43; 95% confidence interval: 1.11, 5.36). Epigenetics of cell adhesion molecules is related to ovarian cancer prognosis. A more comprehensive methylomics of cell adhesion molecules is needed and may advance personalized treatment with adhesion molecule-related drugs.

PMID: 28881822 [PubMed - in process]

Correlation of HAMP gene polymorphisms and expression with the susceptibility and length of hospital stays in Taiwanese children with Kawasaki disease.

Oncotarget. 2017 Aug 01;8(31):51859-51868

Authors: Huang YH, Yang KD, Hsu YW, Lu HF, Wong HS, Yu HR, Kuo HC, Huang FC, Lo MH, Hsieh KS, Chen SF, Chang WC, Kuo HC

Abstract
Kawasaki disease (KD) is a form of systemic vasculitis. Regarding its pathogenesis, HAMP gene encoding hepcidin, which is significant for iron metabolism, has a vital function. In this study, we recruited a total of 381 KD patients for genotyping. Data from 997 subjects (500 subjects from cohort 1; 497 subjects from cohort 2) were used for analysis. Using TaqMan allelic discrimination, we determined five tag SNPs (rs916145, rs10421768, rs3817623, rs7251432, and rs2293689). Treatment outcome data related to such clinical phenotypes as coronary artery lesions (CAL), coronary artery aneurysms (CAA), and intravenous immunoglobulin (IVIG) effects were also collected. Furthermore, we measured plasma hepcidin levels with an enzyme-linked immunosorbent assay. We found that HAMP gene polymorphism (rs7251432, and rs2293689) was significantly correlated with KD risk and that plasma hepcidin levels both before and after IVIG treatment had a significantly positive correlation with length of hospital stays (R = 0.217, p = 0.046 and R = 0.381, p < 0.0001, respectively). In contrast, plasma hepcidin levels has a negative correlation with KD patients' albumin levels (R = -0.27, p < 0.001) prior to IVIG treatment. This study's findings indicate that HAMP might have a role in the disease susceptibility, as well as its expressions correlated length of hospital stays, and albumin levels in Taiwanese children with KD.

PMID: 28881695 [PubMed - in process]

The pharmacogenomics of valproic acid.

J Hum Genet. 2017 Sep 07;:

Authors: Zhu MM, Li HL, Shi LH, Chen XP, Luo J, Zhang ZL

Abstract
Valproic acid is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. Adverse effects of valproic acid are rare, but hepatotoxicity is severe in particular in those younger than 2 years old and polytherapy. During valproic acid treatment, it is difficult for prescribers to predict its individual response. Recent advances in the field of pharmacogenomics have indicated variants of candidate genes that affect valproic acid efficacy and safety. In this review, a large number of candidate genes that influence valproic acid pharmacokinetics and pharmacodynamics are discussed, including metabolic enzymes, drug transporters, neurotransmitters and drug targets. Furthermore, pharmacogenomics is an important tool not only in further understanding of interindividual variability but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.Journal of Human Genetics advance online publication, 7 September 2017; doi:10.1038/jhg.2017.91.

PMID: 28878340 [PubMed - as supplied by publisher]

Pathogen lineage-based genome-wide association study identified CD53 as susceptible locus in tuberculosis.

J Hum Genet. 2017 Sep 07;:

Authors: Omae Y, Toyo-Oka L, Yanai H, Nedsuwan S, Wattanapokayakit S, Satproedprai N, Smittipat N, Palittapongarnpim P, Sawanpanyalert P, Inunchot W, Pasomsub E, Wichukchinda N, Mushiroda T, Kubo M, Tokunaga K, Mahasirimongkol S

Abstract
Tuberculosis (TB) is known to be affected by host genetic factors. We reported a specific genetic risk factor through a genome-wide association study (GWAS) that focused on young age onset TB. In this study, we further focused on the heterogeneity of Mycobacterium tuberculosis (M. tb) lineages and assessed its possible interaction with age at onset on host genetic factors. We identified the pathogen lineage in 686 Thai TB cases and GWAS stratified by both infected pathogen lineage information and age at onset revealed a genome-wide significant association of one single-nucleotide polymorphism (SNP) on chromosome 1p13, which was specifically associated with non-Beijing lineage-infected old age onset cases (P=2.54E-08, OR=1.74 (95% CI=1.43-2.12)), when we compared them to the population-matched healthy controls. This SNP locates near the CD53 gene, which encodes a leukocyte surface glycoprotein. Interestingly, the expression of CD53 was also correlated with the patients' active TB status. This is the first report of a pathogen lineage-based genome-wide association study. The results suggested that host genetic risk in TB is depended upon the pathogen genetic background and demonstrate the importance of analyzing the interaction between host and pathogen genomes in TB.Journal of Human Genetics advance online publication, 7 September 2017; doi:10.1038/jhg.2017.82.

PMID: 28878339 [PubMed - as supplied by publisher]

Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin.

Nat Genet. 2016 Sep;48(9):1055-1059

Authors: Zhou K, Yee SW, Seiser EL, van Leeuwen N, Tavendale R, Bennett AJ, Groves CJ, Coleman RL, van der Heijden AA, Beulens JW, de Keyser CE, Zaharenko L, Rotroff DM, Out M, Jablonski KA, Chen L, Javorský M, Židzik J, Levin AM, Williams LK, Dujic T, Semiz S, Kubo M, Chien HC, Maeda S, Witte JS, Wu L, Tkáč I, Kooy A, van Schaik RHN, Stehouwer CDA, Logie L, MetGen Investigators, DPP Investigators, ACCORD Investigators, Sutherland C, Klovins J, Pirags V, Hofman A, Stricker BH, Motsinger-Reif AA, Wagner MJ, Innocenti F, 't Hart LM, Holman RR, McCarthy MI, Hedderson MM, Palmer CNA, Florez JC, Giacomini KM, Pearson ER

Abstract
Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

PMID: 27500523 [PubMed - indexed for MEDLINE]

SULT1A1 copy number variation: ethnic distribution analysis in Indian population.

Ann Hum Biol. 2017 Sep 06;:1-13

Authors: Almal S, Padh H

Abstract
Cytosolic sulfotransferases (SULTs) are phase II detoxification enzymes involved in metabolism of numerous xenobiotics, drugs, and endogenous compounds. Interindividual variation in sulfonation capacity is important for determining an individual's response to xenobiotics. SNPs in SULTs, mainly SULT1A1 have been associated with cancer risk and also with response to therapeutic agents. Copy number variation (CNVs) in SULT1A1 is found to be correlated with altered enzyme activity. This short report primarily focuses on CNV in SULT1A1 and its distribution among different ethnic populations around the globe. Frequency distribution of SULT1A1 copy number (CN) in 157 healthy Indian individuals was assessed using florescent-based quantitative PCR assay. A range of 1 to >4 copies, with a frequency of SULT1A1 CN = 2 (64.9%) the highest, was observed in our (Indian) population. Upon comparative analysis of frequency distribution of SULT1A1 CN among diverse population groups, a statistically significant difference was observed between Indians (our data) and African-American (AA) (p= 0.0001) and South African (Tswana) (p< 0.0001) populations. Distribution of CNV in the Indian population was found to be similar to that in European-derived populations of America and Japan. In conclusion, CNV of SULT1A1 varies significantly among world populations and may be one of the determinants of health and diseases.

PMID: 28875717 [PubMed - as supplied by publisher]

ABCB1 gene polymorphism associated with clinical factors can predict drug-resistant tuberculosis.

Clin Sci (Lond). 2017 Aug 01;131(15):1831-1840

Authors: Pontual Y, Pacheco VSS, Monteiro SP, Quintana MSB, Costa MJM, Rolla VC, de Castro L

Abstract
Polymorphism in the ABCB1 gene encoding P-glycoprotein, a transmembrane drug efflux pump, contributes to drug resistance and has been widely studied. However, their association with rifampicin and ethambutol resistance in tuberculosis (TB) patients is still unclear. Genotype/allele/haplotype frequencies in c.1236C > T (rs1128503), c.2677G > T/A (rs2032582), and c.3435C > T (rs1045642) were obtained from 218 patients. Of these, 80 patients with rifampicin and/or ethambutol resistance were selected as the case group and 138 patients were selected for the control group through the results of their culture and drug-sensitive tests. Patients aged <18 years and HIV-positive serologic tests were excluded. ABCB1 polymorphisms were determined using a PCR direct-sequencing approach, and restriction fragment length polymorphism (RFLP). A nomogram was constructed to simulate a combined prediction of the probability of anti-TB drug resistance, with factors including genotype c.1236C > T (rs1128503) (P=0.02), clinical form (P=0.03), previous treatment (P=0.01), and skin color (P=0.03), contributing up to 90% chance of developing anti-TB drug resistance. Considering genotype analyses, CT (rs1128503) demonstrated an increased chance of anti-TB drug resistance (odds ratio (OR): 2.34, P=0.02), while the analyses for ethambutol resistance revealed an association with a rare A allele (rs2032582) (OR: 12.91, P=0.01), the haplotype TTC (OR: 5.83, P=0.05), and any haplotype containing the rare A allele (OR: 7.17, P=0.04). ABCB1 gene polymorphisms in association with others risk factors contribute to anti-TB drug resistance, mainly ethambutol. The use of the nomogram described in the present study could contribute to clinical decision-making prior to starting TB treatment.

PMID: 28572401 [PubMed - indexed for MEDLINE]

The novel carboxylesterase 1 variant c.662A>G may decrease the bioactivation of oseltamivir in humans.

PLoS One. 2017;12(4):e0176320

Authors: Oh J, Lee S, Lee H, Cho JY, Yoon SH, Jang IJ, Yu KS, Lim KS

Abstract
BACKGROUND: Human carboxylesterase 1 (CES1) is a serine esterase that hydrolyses various exogenous and endogenous compounds including oseltamivir, a prodrug used to treat influenza. A novel CES1 c.662A>G single nucleotide polymorphism (SNP) was predicted to decrease CES1 enzymatic activity in an in silico analysis. This study evaluated the effect of the c.662A>G SNP on the pharmacokinetics (PK) of oseltamivir in humans.
METHODS: A single oral dose of oseltamivir at 75 mg was administered to 20 healthy subjects, 8 heterozygous c.662A>G carriers (c.662AG) and 12 non-carriers (c.662AA). The concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate, were measured in plasma and urine using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were calculated using a noncompartmental method. The geometric mean ratios (GMR, c.662AG to c.662AA) of the PK parameters and their 90% confidence intervals (CI) were calculated.
RESULTS: The systemic exposure to oseltamivir, as assessed by the AUC0-48h of oseltamivir, was increased by 10% in c.662AG subjects, whereas the AUC0-48h of oseltamivir carboxylate was 5% lower in c.662AG subjects. The GMR and 90% CI of the metabolic ratio (AUC0-48h, Oseltamivir carboxylate/AUC0-48h, Oseltamivir) was 0.87 (0.66-1.14). The amount of unchanged oseltamivir excreted in the urine was increased by 15% in subjects with the c.662AG genotype.
CONCLUSIONS: This result suggests that CES1 enzymatic activity may be decreased in these heterozygous allele carriers, although further studies are warranted to investigate the clinical implications of this genetic variation on CES1 substrate drugs.
TRIAL REGISTRATION: ClinicalTtrials.gov NCT01902342.

PMID: 28437488 [PubMed - indexed for MEDLINE]

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.

Nat Genet. 2017 Mar;49(3):416-425

Authors: Wain LV, Shrine N, Artigas MS, Erzurumluoglu AM, Noyvert B, Bossini-Castillo L, Obeidat M, Henry AP, Portelli MA, Hall RJ, Billington CK, Rimington TL, Fenech AG, John C, Blake T, Jackson VE, Allen RJ, Prins BP, Understanding Society Scientific Group, Campbell A, Porteous DJ, Jarvelin MR, Wielscher M, James AL, Hui J, Wareham NJ, Zhao JH, Wilson JF, Joshi PK, Stubbe B, Rawal R, Schulz H, Imboden M, Probst-Hensch NM, Karrasch S, Gieger C, Deary IJ, Harris SE, Marten J, Rudan I, Enroth S, Gyllensten U, Kerr SM, Polasek O, Kähönen M, Surakka I, Vitart V, Hayward C, Lehtimäki T, Raitakari OT, Evans DM, Henderson AJ, Pennell CE, Wang CA, Sly PD, Wan ES, Busch R, Hobbs BD, Litonjua AA, Sparrow DW, Gulsvik A, Bakke PS, Crapo JD, Beaty TH, Hansel NN, Mathias RA, Ruczinski I, Barnes KC, Bossé Y, Joubert P, van den Berge M, Brandsma CA, Paré PD, Sin DD, Nickle DC, Hao K, Gottesman O, Dewey FE, Bruse SE, Carey DJ, Kirchner HL, Geisinger-Regeneron DiscovEHR Collaboration, Jonsson S, Thorleifsson G, Jonsdottir I, Gislason T, Stefansson K, Schurmann C, Nadkarni G, Bottinger EP, Loos RJ, Walters RG, Chen Z, Millwood IY, Vaucher J, Kurmi OP, Li L, Hansell AL, Brightling C, Zeggini E, Cho MH, Silverman EK, Sayers I, Trynka G, Morris AP, Strachan DP, Hall IP, Tobin MD

Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

PMID: 28166213 [PubMed - indexed for MEDLINE]

Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.

Nat Genet. 2017 Feb;49(2):186-192

Authors: Luo Y, de Lange KM, Jostins L, Moutsianas L, Randall J, Kennedy NA, Lamb CA, McCarthy S, Ahmad T, Edwards C, Serra EG, Hart A, Hawkey C, Mansfield JC, Mowat C, Newman WG, Nichols S, Pollard M, Satsangi J, Simmons A, Tremelling M, Uhlig H, Wilson DC, Lee JC, Prescott NJ, Lees CW, Mathew CG, Parkes M, Barrett JC, Anderson CA

Abstract
To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ∼12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.

PMID: 28067910 [PubMed - indexed for MEDLINE]

Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.

Nat Genet. 2017 Feb;49(2):256-261

Authors: de Lange KM, Moutsianas L, Lee JC, Lamb CA, Luo Y, Kennedy NA, Jostins L, Rice DL, Gutierrez-Achury J, Ji SG, Heap G, Nimmo ER, Edwards C, Henderson P, Mowat C, Sanderson J, Satsangi J, Simmons A, Wilson DC, Tremelling M, Hart A, Mathew CG, Newman WG, Parkes M, Lees CW, Uhlig H, Hawkey C, Prescott NJ, Ahmad T, Mansfield JC, Anderson CA, Barrett JC

Abstract
Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

PMID: 28067908 [PubMed - indexed for MEDLINE]

Leveraging human genetics to guide drug target discovery.

Trends Cardiovasc Med. 2017 Jul;27(5):352-359

Authors: Stitziel NO, Kathiresan S

Abstract
Identifying appropriate molecular targets is a critical step in drug development. Despite many advantages, the traditional tools of observational epidemiology and cellular or animal models of disease can be misleading in identifying causal pathways likely to lead to successful therapeutics. Here, we review some favorable aspects of human genetics studies that have the potential to accelerate drug target discovery. These include using genetic studies to identify pathways relevant to human disease, leveraging human genetics to discern causal relationships between biomarkers and disease, and studying genetic variation in humans to predict the potential efficacy and safety of inhibitory compounds aimed at molecular targets. We present some examples taken from studies of plasma lipids and coronary artery disease to highlight how human genetics can accelerate therapeutics development.

PMID: 27686272 [PubMed - indexed for MEDLINE]

Maximal expected benefits from lowering cholesterol in primary prevention for a high-risk population.

Curr Med Res Opin. 2016 Dec;32(12):1955-1958

Authors: Fanton-Aita F, Matteau A, Iliza AC, Mitchell D, Guertin JR, Dubois A, Dubé MP, Tardif JC, LeLorier J

Abstract
AIMS: The objective of this study was to estimate the maximal clinical benefit that could be reasonably expected from a cholesterol-lowering intervention.
MATERIALS AND METHODS: We used a hypothetical population at high risk of cardiovascular disease events from three risk assessment models including the Framingham risk function, the Score Canada and the Pooled Cohort Risk Assessment Equations. Our source population were all 55-year-old smoking men with diabetes, hypertension and low HDL. From this population, we identified two different subpopulations named "high" and "low", referring to their cholesterol levels which were set at 8.60 and 4.14 mmol/L respectively. Both subpopulations were identified for each risk assessment model in order to estimate the maximal impact of lowering cholesterol on cardiovascular disease events.
RESULTS: Our extrapolations estimated that the maximal theoretical efficacy of a cholesterol-lowering intervention corresponds to a risk ratio ranging between 0.46 and 0.66 over a 10-year period. The number of events prevented during this period were between 21 and 29 per 100 patients which corresponds to a number needed to treat varying from 3.47 to 4.76.
CONCLUSIONS: Our estimation showed the maximal clinical benefit that could be reasonably expected by an intervention that would lower total cholesterol in high-risk patients.

PMID: 27648984 [PubMed - indexed for MEDLINE]

Characterization of 22 Antituberculosis Drugs for Inhibitory Interaction Potential on Organic Anionic Transporter Polypeptide (OATP)-Mediated Uptake.

Antimicrob Agents Chemother. 2016 May;60(5):3096-105

Authors: Parvez MM, Jung JA, Shin HJ, Kim DH, Shin JG

Abstract
We investigated the inhibitory interaction potential of 22 currently marketed antituberculosis (TB) drugs on organic anion-transporting polypeptide 1B1 (OATP1B1)-, OATP2B1-, and OATP1B3-mediated uptake using in vitro Xenopus oocytes and HEK cells. Rifabutin, ethambutol, amoxicillin, linezolid, p-amino salicylic acid, and rifapentine exhibited mild to moderate inhibitory effects on OATP-mediated uptake of estrone-3 sulfate, estradiol 17β-d-glucuronide, and rosuvastatin. The 50% inhibitory concentration (IC50) values of rifabutin, amoxicillin, ethambutol, p-amino salicylic acid, and linezolid were 35.4, 36.2, 57.6, 72.6, and 65.9 μM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B1 (OATP1B1) and 28.8, 28.9, 53.9, 31.5, and 61.0 μM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B3 (OATP1B3). Streptomycin and linezolid showed greater inhibition of organic anionic transporter polypeptide 2B1 (OATP2B1)-mediated uptake, with IC50 values of 33.2 and 35.6 μM, respectively, along with mild inhibition of other drugs. Furthermore, rifabutin, amoxicillin, and rifapentine significantly inhibited OATP1B1-mediated rosuvastatin uptake, with IC50 values of 12.3, 13.0, and 11.0 μM, respectively, which showed a similar profile to estrone-3 sulfate uptake. The calculated R values ([I]u inlet,max/Ki, where [I]u inlet,max represents the maximum estimated inhibitor concentration inlet to the liver and Ki is the inhibition constant) as the drug-drug interaction (DDI) indexes of PAS, ethambutol, and amoxicillin were 26.1, 6.5, and 4.3 for OATP1B1 and 52.0, 8.0, and 4.6 for OATP1B3, and those for streptomycin, amikacin, and linezolid were 5.0, 4.2, and 4.4 for OATP2B1, respectively, suggesting a higher possibility of in vivo DDIs. This study is the first comprehensive report to show the novel inhibitory potential of 22 marketed anti-TB drugs on OATP-mediated uptake, providing evidence for future in vivo clinical DDI studies.

PMID: 26976869 [PubMed - indexed for MEDLINE]

Pharmacogenetics of Aldo-keto Reductase 1C (AKR1C) Enzymes.

Expert Opin Drug Metab Toxicol. 2017 Sep 05;:

Authors: Alshogran OY

Abstract
INTRODUCTION: Genetic variation in metabolizing enzymes contributes to variable drug response and disease risk. Aldo-keto reductase type 1C (AKR1C) comprises a sub-family of reductase enzymes that play critical roles in the biotransformation of various drug substrates and endogenous compounds such as steroids. Several single nucleotide polymorphisms have been reported among AKR1C encoding genes, which may affect the functional expression of the enzymes. Areas covered: This review highlights and comprehensively discusses previous pharmacogenetic reports that have examined genetic variations in AKR1C and their association with disease development, drug disposition, and therapeutic outcomes. The article also provides information about the effect of AKR1C genetic variants on enzyme function in vitro. Expert opinion: The current evidence that links the effect of AKR1C gene polymorphisms to disease progression and development is inconsistent and needs further validation, despite of the tremendous knowledge available. Information about association of AKR1C genetic variants and drug efficacy, safety, and pharmacokinetics is limited, thus, future studies that advance our understanding about these relationships and their clinical relevance are needed. It is imperative to achieve consistent findings before the potential translation and adoption of AKR1C genetic variants can be used in clinical practice.

PMID: 28871815 [PubMed - as supplied by publisher]

Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects.

Sci Rep. 2017 Sep 04;7(1):10391

Authors: Gomez-Sanchez CI, Carballo JJ, Riveiro-Alvarez R, Soto-Insuga V, Rodrigo M, Mahillo-Fernandez I, Abad-Santos F, Dal-Ré R, Ayuso C

Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in which a significant proportion of patients do not respond to treatment. The objective of this study was to examine the role of genetic risk variants in the response to treatment with methylphenidate (MPH). The effectiveness of MPH was evaluated based on variations in the CGI-S and CGAS scales over a 12-month treatment period using linear mixed effects models. A total of 208 ADHD patients and 34 polymorphisms were included in the analysis. For both scales, the response was associated with time, extended-release MPH/both formulations, and previous MPH treatment. For the CGI-S scale, response was associated with SLC6A3 rs2550948, DRD4 promoter duplication, SNAP25 rs3746544, and ADGRL3 rs1868790. Interactions between the response over time and SLC6A3 and DRD2 were found in the CGI-S and CGAS scales, respectively. The proportion of the variance explained by the models was 18% for the CGI-S and 22% for the CGAS. In this long-term study, the effects of SLC6A3, DRD4, SNAP25, and ADGRL3 on response to treatment reflect those observed in previous studies. In addition, 2 previously unreported interactions with response to treatment over a 12-month period were found (SLC6A3 and DRD2).

PMID: 28871191 [PubMed - in process]

A systematic review and critical appraisal of gene polymorphism association studies in medication-overuse headache.

Cephalalgia. 2017 Jan 01;:333102417728244

Authors: Cargnin S, Viana M, Sances G, Tassorelli C, Terrazzino S

Abstract
Purpose of review Medication-overuse headache is a secondary chronic headache disorder, evolving from an episodic primary headache type, caused by the frequent and excessive use of headache symptomatic drugs. While gene polymorphisms have been deeply investigated as susceptibility factors for migraine, little attention has been paid to medication-overuse headache genetics. In the present study we conducted a systematic review to identify, appraise and summarize the current findings of gene polymorphism association studies in medication-overuse headache. Methods A comprehensive literature search was conducted on PubMed and Web of Knowledge databases of primary studies that met the diagnostic criteria for medication-overuse headache according to the temporally-relevant Classification of Headache Disorder of the International Headache Society. Results A total of 17 candidate gene association studies focusing on medication-overuse headache were finally included in the qualitative review. Among these, 12 studies investigated the role of common gene polymorphisms as risk factors for medication-overuse headache susceptibility, six studies focused on the relationship with clinical features of medication-overuse headache patients, and four studies evaluated their role as determinants of clinical outcomes in medication-overuse headache patients. Conclusion Results of single studies show a potential role of polymorphic variants of the dopaminergic gene system or of other genes related to drug-dependence pathways as susceptibility factors for disease or as determinants of monthly drug consumption, respectively. In this systematic review, we summarize the findings of gene polymorphism association studies in medication-overuse headache and discuss the methodological issues that need to be addressed in the design of future studies.

PMID: 28870085 [PubMed - as supplied by publisher]

Mori cortex prevents kidney damage through inhibiting expression of inflammatory factors in the glomerulus in streptozocin-induced diabetic rats.

Iran J Basic Med Sci. 2017 Jun;20(6):715-721

Authors: Ma L, Ni H, Zou X, Yuan Y, Luo C, Liu B, Wang F, Xi Y, Chu Y, Xu P, Qiu X, Li S, Bu S

Abstract
OBJECTIVES: It has been widely reported that Mori cortex extract (MCE) is used for the treatment of diabetes mellitus in traditional medicine. The present study was designed to investigate its mechanism of action in the treatment of diabetic nephropathy (DN). We assessed whether MCE preventive treatment ameliorates kidney damage in high-fat diet and streptozotocin (STZ)-induced type 2 diabetic rats.
MATERIALS AND METHODS: Rats were fed a high-fat diet and injected with STZ. MCE was given to rats daily at 10 g/kg. Fasting blood glucose (FBG) and postprandial plasma glucose were measured. Blood and urine biochemical parameters, renal tissue morphology, and inflammation were investigated.
RESULTS: Prevention with MCE significantly decreased FBG and homoeostasis model assessment (HOMA) of IR (HOMA-IR) levels and increased insulin levels in diabetic rats. MCE prevention significantly decreased levels of KW/BW, BUN, Cr, and 24 hr urinary protein. MCE inhibited glomerular basement membrane thickening, tubular epithelial cell hypertrophy, and glomerular capillary dilation. MCE also prevented the disappearance of bowman's space and renal tubular lumen and decreased collagen deposition in rat kidney. Moreover, MCE reduced the levels of inflammatory factors (MCP-1 and TNF-α) and fibrosis factors (collagen IV and fibronectin).
CONCLUSION: MCE prevents DN through inhibition of inflammation and fibrosis in a rat model. It might provide a safe and effective way to prevent DN.

PMID: 28868127 [PubMed]

Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children with Cerebral Palsy.

PM R. 2017 Aug 31;:

Authors: McLaughlin MJ, He Y, Brunstrom-Hernandez J, Thio LL, Carleton BC, Ross CJD, Gaedigk A, Lewandowski A, Dai H, Jusko WJ, Leeder JS

Abstract
BACKGROUND: Pharmacogenomic variability can contribute to differences in pharmacokinetics and clinical responses. Pediatric patients with cerebral palsy (CP) with genetic variations have not been studied for these potential differences.
OBJECTIVE: To determine the genetic sources of variation in oral baclofen clearance and clinical responses.
DESIGN: Pharmacogenomic add-on study to determine variability in oral baclofen clearance and clinical responses.
SETTING: Multicenter study based in academic pediatric cerebral palsy clinics.
PARTICIPANTS: 49 patients with CP who had participated in an oral baclofen Pharmacokinetic/Pharmacodynamic (PK/PD) study.
METHODS: or Interventions: From 53 participants in a PK/PD trial, 49 underwent genetic analysis of 307 key genes and 4,535 single-nucleotide polymorphisms (SNPs) involved in drug absorption, distribution, metabolism and excretion. Associations between genotypes and phenotypes of baclofen disposition (weight-corrected and allometrically scaled clearance) and clinical endpoints (improvement from baseline in mean hamstring Modified Tardieu Scale (MTS) scores from baseline for improvement of R1 spastic catch) were determined by univariate analysis with correction for multiple testing by false discovery rate (FDR).
MAIN OUTCOME MEASUREMENTS: Primary outcome measures were the genotypic and phenotypic variability of oral baclofen in allometrically scaled clearance and change in the MTS angle compared to baseline.
RESULTS: After univariate analysis of the data, the SNP of ABCC9 (rs11046232, heterozygous AT vs. the reference TT genotype) was associated with a 2-fold increase in oral baclofen clearance (Mean 0.51 ± Standard Deviation 0.05 L/hr/kg for the AT genotype vs. 0.25 ± 0.07 L/hr/kg for the TT genotype, adjusted p<.001). Clinical responses were associated with decreased spasticity by MTS in allelic variants with SNPs ABCC12, SLC28A1, and PPARD.
CONCLUSIONS: Genetic variation in ABCC9 impacting oral baclofen clearance highlights the need for continued studies of genetic polymorphisms to better characterize variable drug response in children with CP. Single nucleotide polymorphisms in ABCC12, SLC28A1, and PPARD were associated with varied responses, which warrants further investigation to determine their effect on spasticity.

PMID: 28867665 [PubMed - as supplied by publisher]

Muscle Lim Protein and Myosin Binding Protein C form a complex regulating muscle differentiation.

Biochim Biophys Acta. 2017 Aug 31;:

Authors: Arvanitis DA, Vafiadaki E, Papalouka V, Sanoudou D

Abstract
Muscle Lim Protein (MLP) is a protein with multiple functional roles in striated muscle physiology and pathophysiology. Herein, we demonstrate that MLP directly binds to slow, fast, and cardiac myosin-binding protein C (MyBP-C) during myogenesis, as shown by yeast two-hybrid, and a range of protein-protein interaction assays. The minimal interacting domains involve MLP inter-LIM and MyBP-C C4. The interaction is sensitive to cytosolic Ca(2+) concentrations changes and to MyBP-C phosphorylation by PKA or CaMKII. Confocal microscopy of differentiating myoblasts showed MLP and MyBP-C colocalization during myoblast differentiation. Suppression of the complex formation with recombinant MyBP-C C4 peptide overexpression, inhibited myoblast differentiation by 65%. Suppression of both MLP and MyBP-C expression in myoblasts by siRNA revealed negative synergistic effects on differentiation. The MLP/MyBP-C complex modulates the actin activated myosin II ATPase activity in vitro, which could interfere with sarcomerogenesis and myofilaments assembly during differentiation. Our data demonstrate a critical role of the MLP/MyBP-C complex during early myoblast differentiation. Its absence in muscles with mutations or aberrant expression of MLP or MyBP-C could be directly implicated in the development of cardiac and skeletal myopathies.

PMID: 28867610 [PubMed - as supplied by publisher]