Deglycosylation of wogonoside enhances its anticancer potential.

J Cancer Res Ther. 2018 Sep;14(Supplement):S594-S599

Authors: Wang CZ, Wan JY, Zhang CF, Lu F, Chen L, Yuan CS

Abstract
Introduction: Scutellaria baicalensis is commonly used in Asia as an herbal medicine to treat a variety of ailments, including cancer. Wogonoside, one major constituent of S. baicalensis, can be primarily converted to wogonin through deglycosylation via enteric microbiome metabolism.
Materials and Methods: The antiproliferative effects of the glycoside (wogonoside) and its deglycosylated compound (wogonin) on a panel of human cancer cell lines from the most common solid tumors were evaluated using the MTS colorimetric assay. Cell cycle and apoptosis were determined using flow cytometry. Enzymatic activities of caspases were measured, and the interactions of wogonin and caspases were explored by a docking analysis.
Results: Wogonoside did not have obvious antiproliferative effects on the cancer cells. In contrast, wogonin showed significant antiproliferative activities on all the tested cancer cells. Wogonin arrested the cells in the G1 phase and significantly induced cell apoptosis. The compound also activated the expression of caspases 3 and 9. The docking results suggest that the compound forms hydrogen bonds with Phe250 and Ser251, and π-π interactions with Phe256 in caspase 3, and with Asp228 in caspase 9.
Conclusions: After wogonoside deglycosylation, wogonin significantly enhanced its anticancer potential as a potent anticancer compound derived from S. baicalensis.

PMID: 30249874 [PubMed - indexed for MEDLINE]

A New Approach towards Minimizing the Risk of Misdosing Warfarin Initiation Doses.

Comput Math Methods Med. 2018;2018:5340845

Authors: Sharabiani A, Nutescu EA, Galanter WL, Darabi H

Abstract
It is a challenge to be able to prescribe the optimal initial dose of warfarin. There have been many studies focused on an efficient strategy to determine the optimal initial dose. Numerous clinical, genetic, and environmental factors affect the warfarin dose response. In practice, it is common that the initial warfarin dose is substantially different from the stable maintenance dose, which may increase the risk of bleeding or thrombosis prior to achieving the stable maintenance dose. In order to minimize the risk of misdosing, despite popular warfarin dose prediction models in the literature which create dose predictions solely based on patients' attributes, we have taken physicians' opinions towards the initial dose into consideration. The initial doses selected by clinicians, along with other standard clinical factors, are used to determine an estimate of the difference between the initial dose and estimated maintenance dose using shrinkage methods. The selected shrinkage method was LASSO (Least Absolute Shrinkage and Selection Operator). The estimated maintenance dose was more accurate than the original initial dose, the dose predicted by a linear model without involving the clinicians initial dose, and the values predicted by the most commonly used model in the literature, the Gage clinical model.

PMID: 29861781 [PubMed - indexed for MEDLINE]

Cost-Effectiveness Analysis of Genotype-Guided Treatment Allocation in Patients with Alcohol Use Disorders Using Naltrexone or Acamprosate, Using a Modeling Approach.

Eur Addict Res. 2018 Nov 01;24(5):245-254

Authors: Sluiter RL, Kievit W, van der Wilt GJ, Schene AH, Teichert M, Coenen MJH, Schellekens A

Abstract
Alcohol use disorders (AUD) are a major contributor to the global burden of disease, and have huge societal impact. Some studies show that AUD patients carrying the G-allele of the OPRM1 variant c.118A>G respond better to naltrexone, resulting in reduced relapse rates compared to carriers of the AA genotype. Genotype-guided treatment allocation of these patients carrying a G-allele to naltrexone could potentially improve the treatment outcome. However, cost-effectiveness of this strategy should be investigated before considering clinical implementation. We, therefore, evaluated costs and Quality-Adjusted Life-Years (QALYs), using a modelling approach, from an European perspective, of genotype-guided treatment allocation (G-allele carriers receiving naltrexone; AA homozygotes acamprosate or naltrexone) compared to standard care (random treatment allocation to acamprosate or naltrexone), by using a Markov model. Genotype-guided treatment allocation resulted in incremental costs of EUR 66 (95% CI -28 to 149) and incremental effects of 0.005 QALYs (95% CI 0.000-0.011) per patient (incremental cost-effectiveness ratio of EUR 13,350 per QALY). Sensitivity analyses showed that the risk ratio to relapse after treatment allocation had the largest impact on the cost-effectiveness. Depending on the willingness to pay for a gain of one QALY, probabilities that the intervention is cost-effective varies between 6 and 79%. In conclusion, pharmacogenetic treatment allocation of AUD patients to naltrexone, based on OPRM1 genotype, can be a cost-effective strategy, and could have potential individual and societal benefits. However, more evidence on the impact of genotype-guided treatment allocation on relapse is needed to substantiate these conclusions, as there is contradictory evidence about the effectiveness of OPRM1 genotyping.

PMID: 30384381 [PubMed - as supplied by publisher]

A multi-gene expression profile panel for predicting liver metastasis: An algorithmic approach.

PLoS One. 2018;13(11):e0206400

Authors: Shah K, Patel S, Mirza S, Rawal RM

Abstract
BACKGROUND & AIM: Liver metastasis has been found to affect outcome in prostate, pancreatic and colorectal cancers, but its role in lung cancer is unclear. The 5 year survival rate remains extensively low owing to intrinsic resistance to conventional therapy which can be attributed to the genetic modulators involved in the pathogenesis of the disease. Thus, this study aims to generate a model for early diagnosis and timely treatment of liver metastasis in lung cancer patients.
METHODS: mRNA expression of 15 genes was quantified by real time PCR on lung cancer specimens with (n = 32) and without (n = 30) liver metastasis and their normal counterparts. Principal Component analysis, linear discriminant analysis and hierarchical clustering were conducted to obtain a predictive model. The accuracy of the models was tested by performing Receiver Operating Curve analysis.
RESULTS: The expression profile of all the 15 genes were subjected to PCA and LDA analysis and 5 models were generated. ROC curve analysis was performed for all the models and the individual genes. It was observed that out of the 15 genes only 8 genes showed significant sensitivity and specificity. Another model consisting of the selected eight genes was generated showing a specificity and sensitivity of 90.0 and 96.87 respectively (p <0.0001). Moreover, hierarchical clustering showed that tumors with a greater fold change lead to poor prognosis.
CONCLUSION: Our study led to the generation of a concise, biologically relevant multi-gene panel that significantly and non-invasively predicts liver metastasis in lung cancer patients.

PMID: 30383826 [PubMed - in process]

Functional Genomics.

Adv Exp Med Biol. 2018;1102:11-30

Authors: Goh HH, Ng CL, Loke KK

Abstract
Functional genomics encompasses diverse disciplines in molecular biology and bioinformatics to comprehend the blueprint, regulation, and expression of genetic elements that define the physiology of an organism. The deluge of sequencing data in the postgenomics era has demanded the involvement of computer scientists and mathematicians to create algorithms, analytical software, and databases for the storage, curation, and analysis of biological big data. In this chapter, we discuss on the concept of functional genomics in the context of systems biology and provide examples of its application in human genetic disease studies, molecular crop improvement, and metagenomics for antibiotic discovery. An overview of transcriptomics workflow and experimental considerations is also introduced. Lastly, we present an in-house case study of transcriptomics analysis of an aromatic herbal plant to understand the effect of elicitation on the biosynthesis of volatile organic compounds.

PMID: 30382566 [PubMed - in process]

Clinical implications of APOE genotyping for late-onset Alzheimer's disease (LOAD) risk estimation: a review of the literature.

J Neural Transm (Vienna). 2018 Oct 31;:

Authors: Marshe VS, Gorbovskaya I, Kanji S, Kish M, Müller DJ

Abstract
Alzheimer's disease is a genetically complex neurodegenerative disorder representing the leading cause of dementia. Advances in personal genomics are increasing the public uptake of genetic susceptibility testing for complex diseases such as late-onset Alzheimer's disease (LOAD). For LOAD, the discovery of the major risk ε4 allele of the APOE gene has prompted a debate on the ethics and utility of presymptomatic (i.e., predictive) testing. Although the mechanistic contribution of APOE to disease onset remains uncertain, presymptomatic genetic testing provides a relative risk of developing LOAD. Presymptomatic testing for complex disorders, such as LOAD is much less conclusive than early-onset Alzheimer's disease (EOAD) which follows a Mendelian inheritance pattern. Given the lack of preventive strategies available for EOAD or LOAD, APOE genotyping offers limited clinical utility, thus, raising ethical and practical questions. We conducted a systematic search of five electronic databases or primary studies published during January 2008-January 2018 which investigated practical and ethical issues of presymptomatic APOE genotyping for LOAD risk estimation. We identified 31 articles which suggested that APOE genotyping for LOAD susceptibility provides potential benefits to at-risk patients and can guide changes in positive health-related behaviors. However, other individuals may experience test-related anxiety, depression and psychological distress. Future research should focus on developing an integrated risk assessment tool to enhance the utility of APOE genotyping. Furthermore, empirical research is required to understand actual psychological and social implications associated with testing.

PMID: 30382407 [PubMed - as supplied by publisher]

Genetic Loci Determining Total Immunoglobulin E Levels from Birth through Adulthood.

Allergy. 2018 Oct 31;:

Authors: Yao TC, Chung RH, Lin CY, Tsai PC, Chang WC, Yeh KW, Tsai MH, Liao SL, Hua MC, Lai SH, Chen LC, Chang SW, Yu YW, Hsu JY, Chang SC, Cheng WC, Hu D, Hong X, Burchard EG, Wang X, Tzeng JY, Tsai HJ, Huang JL

PMID: 30378687 [PubMed - as supplied by publisher]

Chemical Pharmacotherapy for the Treatment of Orthostatic Hypotension.

Expert Opin Pharmacother. 2018 Oct 30;:

Authors: Cheshire WP

Abstract
INTRODUCTION: Orthostatic hypotension (OH) is a common yet often overlooked condition. Particularly debilitating is neurogenic orthostatic hypotension (nOH) caused by deficient neurotransmission of norepinephrine, which is the primary neurotransmitter released at sympathetic peripheral vascular nerve terminals in response to orthostatic stress. Areas covered: In this review, the author summarizes and critiques established and emerging pharmacologic approaches for the management of nOH. Two drugs are currently approved. Midodrine, an α1-adrenoreceptor agonist, acts on capacitance vessels to increase peripheral vascular tone, thus increases arterial pressure. Droxidopa, an orally administered prodrug of norepinephrine, increases circulating norepinephrine levels, causing peripheral vasoconstriction and increases standing blood pressure. Preliminary studies support the selective use of several off-label drugs in difficult cases. All of these drugs can potentially unmask or exacerbate neurogenic supine hypertension (nSH), which occurs in about half of patients with nOH. Expert opinion: Chemical pharmacotherapy of nOH is best individualized to the needs and condition of each patient and guided by the underlying pathophysiology, severity of orthostatic incapacity, and minimization of comorbidities such as nSH. The goal of therapy is to maintain cerebral perfusion and increase the patient's ability to engage in upright daily activities. Advances in pharmacogenetics and ambulatory devices hold promise.

PMID: 30376728 [PubMed - as supplied by publisher]

Metformin transporter pharmacogenomics: insights into drug disposition - where are we now?

Expert Opin Drug Metab Toxicol. 2018 Oct 30;:

Authors: Chan P, Shao L, Tomlinson B, Zhang Y, Liu ZM

Abstract
INTRODUCTION: Metformin is recommended as first line treatment for type 2 diabetes (T2D) by all major diabetes guidelines. With appropriate usage it is safe and effective overall, but its efficacy and tolerability show considerable variation between individuals. It is a substrate for several drug transporters and polymorphisms in these transporter genes have shown effects on metformin pharmacokinetics and pharmacodynamics. Areas covered: This article provides a review of the current status of the influence of transporter pharmacogenomics on metformin efficacy and tolerability. The transporter variants identified to have an important influence on the absorption, distribution and elimination of metformin, particularly those in organic cation transporter 1 (OCT1, gene SLC22A1), are reviewed. Expert opinion: Candidate gene studies have shown that genetic variations in SLC22A1 and other drug transporters influence the pharmacokinetics, glycemic responses and gastrointestinal intolerance to metformin, although results are somewhat discordant. Conversely, genome-wide association studies of metformin response have identified signals in the pharmacodynamic pathways rather than the transporters involved in metformin disposition. Currently, pharmacogenomic testing to predict metformin response and tolerability may not have a clinical role, but with additional data from larger studies and availability of safe and effective alternative antidiabetic agents, this is likely to change.

PMID: 30375241 [PubMed - as supplied by publisher]

The impacts of dopamine D2 receptor polymorphism and antipsychotic dosage on dopamine supersensitivity psychosis in schizophrenia.

Schizophr Res. 2017 12;190:182-183

Authors: Takase M, Kanahara N, Oda Y, Niitsu T, Watanabe H, Iyo M

PMID: 28285026 [PubMed - indexed for MEDLINE]

Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients.

Sci Rep. 2017 02 08;7:42192

Authors: Tang J, Liu R, Zhang YL, Liu MZ, Hu YF, Shao MJ, Zhu LJ, Xin HW, Feng GW, Shang WJ, Meng XG, Zhang LR, Ming YZ, Zhang W

Abstract
Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the "derivation cohort" to develop dose-prediction algorithm, while the remaining 20% constituted the "validation cohort" to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.

PMID: 28176850 [PubMed - indexed for MEDLINE]

Interactions Between ABCB1 Genotype and Preoperative Statin Use Impact Clinical Outcomes Among Breast Cancer Patients.

Front Oncol. 2018;8:428

Authors: Tryggvadottir H, Huzell L, Gustbée E, Simonsson M, Markkula A, Jirström K, Rose C, Ingvar C, Borgquist S, Jernström H

Abstract
Multiple clinical trials investigate statins' effects in breast cancer. The ABCB1 genotype appears to influence statin response and toxicity in the cardiovascular setting. This exploratory study aimed to investigate the interplay between preoperative statin use, ABCB1 genotype, and tumor-specific expression of the statin target 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in breast cancer. Preoperative statin use, ABCB1 C3435T genotype, and HMGCR expression in relation to outcome were analyzed in 985 primary breast cancer patients from a population-based prospective cohort in Sweden from 2002 to 2012. Preoperative statin use (n = 80) was not associated with ABCB1 C3435T genotype (n = 576), HMGCR expression (n = 848), or clinical outcomes. ABCB1 C3435T TT-carriers had lower risk of breast cancer events than any C-carriers (adjusted hazard ratio (HRadj) 0.74; 95%CI 0.49, 1.12), but only in non-statin users (P interactio n = 0.042). Statin users with TT genotype had higher risk of distant metastasis (HRadj 4.37; 95%CI 1.20, 15.91; P interaction = 0.009) and shorter overall survival than other patients (HRadj 3.77; 95%CI 1.37, 10.39; P interactio n = 0.019). In conclusion, there were nominally significant interactions between ABCB1 genotype and preoperative statin use on clinical outcomes, while preoperative statin use was not associated with outcomes. Since this is an exploratory study of the impact of the ABCB1 genotype in relation to statin use and clinical outcomes in the breast cancer setting, the results should be interpreted with caution and warrant replication in an independent cohort, preferably in a randomized setting. Since statin use is common in breast cancer patients, it would be of interest to further elucidate the clinical impact of the ABCB1 genotype in breast cancer.

PMID: 30370250 [PubMed]

Synergetic Inhibition of Human Colorectal Cancer Cells by Combining Polyyne-Enriched Fraction from Oplopanax elatus and Irinotecan.

Nutr Cancer. 2018 Oct 29;:1-11

Authors: Wang J, Shao L, Wang CZ, Zhou HH, Yuan CS, Huang WH

Abstract
Although irinotecan is an important anticancer drug for treating colorectal cancer, its dose-dependent side effects limited its clinical application. Thus, it's important to develop low-toxic candidates to enhance the efficacy of irinotecan. Polyynes from genus Oplopanax were reported to possess potential anticancer effects on colorectal cancer. Hereby, we evaluated the synergetic inhibition of human colorectal cancer cells by combining polyyne-enriched fraction from Oplopanax elatus (the dichloromethane fraction of Oplopanax elatus, OED) and irinotecan. The results showed that 5 μg/ml of OED combined with 40 μM of irinotecan possessed significant synergetic inhibition on SW-480 cells with a combination index (CI) of 0.56. Besides, the percentage of apoptotic cells was significantly increased from 69.57% (40 μM of irinotecan) or 72.7% (5 μg/ml of OED) to 95.6% after treatment of OED combined with irinotecan (OCI), suggesting OED and irinotecan possess the synergistic apoptotic effect (P < 0.01). Furthermore, Caspase-3 was significantly activated in OCI group (P < 0.05). Besides, the percentage of apoptotic cells of OED or/and irinotecan significantly decreased after inhibition of caspase-3. These data indicated that OED could enhance antiproliferative effects of irinotecan on colorectal cancer cells, which was related with induction of apoptosis and regulations of activity of caspase-3.

PMID: 30372160 [PubMed - as supplied by publisher]

Genetic Variants Associated With Plasma Lipids Are Associated With the Lipid Response to Niacin.

J Am Heart Assoc. 2018 Oct 02;7(19):e03488

Authors: Tuteja S, Qu L, Vujkovic M, Dunbar RL, Chen J, DerOhannessian S, Rader DJ

Abstract
Background Niacin is a broad-spectrum lipid-modulating drug, but its mechanism of action is unclear. Genome-wide association studies have identified multiple loci associated with blood lipid levels and lipoprotein (a). It is unknown whether these loci modulate response to niacin. Methods and Results Using data from the AIM - HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL /High Triglycerides and Impact on Global Health Outcomes) trial (n=2054 genotyped participants), we determined whether genetic variations at validated loci were associated with a differential change in plasma lipids and lipoprotein (a) 1 year after randomization to either statin+placebo or statin+niacin in a variant-treatment interaction model. Nominally significant interactions ( P<0.05) were found for genetic variants in MVK , LIPC , PABPC 4, AMPD 3 with change in high-density lipoprotein cholesterol; SPTLC 3 with change in low-density lipoprotein cholesterol; TOM 1 with change in total cholesterol; PDXDC 1 and CYP 26A1 with change in triglycerides; and none for lipoprotein (a). We also investigated whether these loci were associated with cardiovascular events. The risk of coronary disease related death was higher in the minor allele carriers at the LIPC locus in the placebo group (odds ratio 2.08, 95% confidence interval 1.11-3.90, P=0.02) but not observed in the niacin group (odds ratio 0.89, 95% confidence interval 0.48-1.65, P=0.7); P-interaction =0.02. There was a greater risk for acute coronary syndrome (odds ratio 1.85, 95% confidence interval 1.16-2.77, P=0.02) and revascularization events (odds ratio 1.64, 95% confidence interval 1.2-2.22, P=0.002) in major allele carriers at the CYP 26A1 locus in the placebo group not seen in the niacin group. Conclusions Genetic variation at loci previously associated with steady-state lipid levels displays evidence for lipid response to niacin treatment. Clinical Trials Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00120289.

PMID: 30371334 [PubMed - in process]

No association between G1359A CB1 polymorphisms and pain in young northeastern Mexicans.

Pharmacogenomics. 2018 Oct 29;:

Authors: Rodríguez-Rodríguez IA, Fernandez-Quiroga KA, Morales-San Claudio PD, Balderas-Rentería I, González-Santiago O

Abstract
AIM: Recent studies show an association between the endocannabinoid system and pain. In this study, we analyzed the association between two CNR1 gene polymorphisms and pain perception in a northeast Mexican population.
METHODS: Genotypic and allelic frequencies were obtained for both polymorphisms. Pain threshold, tolerance and perception were measured using the cold pressor task.
RESULTS: No significant association between the polymorphisms and pain perception was found (p > 0.05).
CONCLUSION: Genotypic and allelic frequencies for both polymorphisms were reported for the first time in a Mexican population; however, our results suggest that there is not a significant association between these and pain.

PMID: 30371142 [PubMed - as supplied by publisher]

Postviral atopic airway disease: pathogenesis and potential avenues for intervention.

Expert Rev Clin Immunol. 2018 Oct 27;:

Authors: Hussain SA, Mejias A, Ramilo O, Peeples ME, Grayson MH

Abstract
INTRODUCTION: In early childhood, wheezing due to lower respiratory tract illness is often associated with infection by commonly known respiratory viruses such as respiratory syncytial virus (RSV) and human rhinovirus (RV). How respiratory viral infections lead to wheeze and/or asthma is an area of active research. Areas covered: This review provides an updated summary of the published information on the development of post-viral induced atopy and asthma and the mechanisms involved. We focus on the contribution of animal models in identifying pathways that may contribute to atopy and asthma following respiratory virus infection, different polymorphisms that have been associated with asthma development, and current options for disease management and potential future interventions. Expert commentary: Currently there are no prophylactic therapies that prevent infants infected with respiratory viruses from developing asthma or atopy. Neither are there curative therapies for patients with asthma. Therefore, a better understanding of genetic factors and other associated biomarkers in respiratory viral induced pathogenesis is important for developing effective personalized therapies.

PMID: 30370798 [PubMed - as supplied by publisher]

Gene Expression Signature for Prediction of Golimumab Response in a Phase 2a Open-Label Trial of Patients With Ulcerative Colitis.

Gastroenterology. 2018 10;155(4):1008-1011.e8

Authors: Telesco SE, Brodmerkel C, Zhang H, Kim LL, Johanns J, Mazumder A, Li K, Baribaud F, Curran M, Strauss R, Paxson B, Plevy S, Davison T, Knight L, Dibben S, Schreiber S, Sandborn W, Rutgeerts P, Siegel CA, Reinisch W, Greenbaum LE

Abstract
Golimumab, a tumor necrosis factor antagonist, is an effective treatment for patients with moderate-to-severe ulcerative colitis (UC); however, more than 50% of initial responders lose their response to the drug within the first year of therapy. A gene expression signature identified in colon biopsies collected before treatment was associated with response to infliximab, and was subsequently refined to associate with mucosal healing in response to golimumab. We performed a phase 2a open-label study of 103 golimumab-treated patients with moderate-to-severe UC to test whether the baseline gene expression signature could be used to predict which patients would achieve mucosal healing, clinical response, and clinical remission at weeks 6 and 30 of treatment. The gene expression signature identified patients who went on to achieve mucosal healing at treatment week 6 with an area under the receiver operating characteristic curve (AUCROC) of 0.688 (P = .002) and at week 30 with an AUCROC of 0.671 (P = .006). The signature identified patients with mucosal healing with 87% sensitivity, but only 34% specificity, limiting its clinical utility. The baseline gene expression signature did not identify patients who went on to achieve clinical remission or clinical response with statistical significance. Further studies are needed to identify biomarkers that can be used to predict which patients with UC will respond to treatment with anti-tumor necrosis factor agents. ClinicalTrials.gov no: NCT01988961.

PMID: 29981298 [PubMed - indexed for MEDLINE]

Replication of the pharmacogenetic effect of rs678849 on buprenorphine efficacy in African-Americans with opioid use disorder.

Pharmacogenomics J. 2018 Oct 27;:

Authors: Crist RC, Phillips KA, Furnari MA, Moran LM, Doyle GA, McNicholas LF, Cornish JW, Kampman KM, Preston KL, Berrettini WH

Abstract
Many patients with opioid use disorder do not have successful outcomes during treatment but the underlying reasons are not well understood. An OPRD1 variant (rs678849) was previously associated with methadone and buprenorphine efficacy in African-Americans with opioid use disorder. The objective of this study was to determine if the effect of rs678849 on opioid use disorder treatment outcome could be replicated in an independent population. Participants were recruited from African-American patients who had participated in previous studies of methadone or buprenorphine treatment at the outpatient treatment research clinic of the NIDA Intramural Research Program in Baltimore, MD, USA between 2000 and 2017. Rs678849 was genotyped retrospectively, and genotypes were compared with urine drug screen results from the previous studies for opioids other than the one prescribed for treatment. Genotypes were available for 24 methadone patients and 55 buprenorphine patients. After controlling for demographics, the effect of rs678849 genotype was significant in the buprenorphine treatment group (RR = 1.69, 95% confidence interval (CI) 1.59-1.79, p = 0.021). Buprenorphine patients with the C/C genotype were more likely to have opioid-positive drug screens than individuals with the C/T or T/T genotypes, replicating the original pharmacogenetic finding. The effect of genotype was not significant in the methadone group (p = 0.087). Thus, the genotype at rs678849 is associated with buprenorphine efficacy in African-Americans being treated for opioid use disorder. This replication suggests that rs678849 genotype may be a valuable pharmacogenetic marker for deciding which opioid use disorder medication to prescribe in this population.

PMID: 30368523 [PubMed - as supplied by publisher]

The Integrating Pharmacogenetics in Clinical Care (I-PICC) Study: Protocol for a point-of-care randomized controlled trial of statin pharmacogenetics in primary care.

Contemp Clin Trials. 2018 Oct 24;:

Authors: Vassy JL, Brunette CA, Majahalme N, Advani S, MacMullen L, Hau C, Zimolzak AJ, Miller SJ

Abstract
BACKGROUND: The association between the SLCO1B1 rs4149056 variant and statin-associated muscle symptoms (SAMS) is well validated, but the clinical utility of its implementation in patient care is unknown.
DESIGN: The Integrating Pharmacogenetics in Clinical Care (I-PICC) Study is a pseudo-cluster randomized controlled trial of SLCO1B1 genotyping among statin-naïve primary care and women's health patients across the Veteran Affairs Boston Healthcare System. Eligible patients of enrolled primary care providers are aged 40-75 and have elevated risk of cardiovascular disease by American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Patients give consent by telephone in advance of an upcoming appointment, but they are enrolled only if and when their provider co-signs an order for SLCO1B1 testing, performed on a blood sample already collected in clinical care. Enrolled patients are randomly allocated to have their providers receive results through the electronic health record at baseline (PGx + arm) versus after 12 months (PGx- arm). The primary outcome is the change in low-density lipoprotein cholesterol (LDL-C) after one year. Secondary outcomes are concordance with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for simvastatin prescribing, concordance with ACC/AHA guidelines for statin use, and incidence of SAMS. With 408 patients, the study has >80% power to exclude a between-group LDL-C difference of 10 mg/dL (non-inferiority design) and to detect between-group differences of 15% in CPIC guideline concordance (superiority design).
CONCLUSION: The outcomes of the I-PICC Study will inform the clinical utility of preemptive SLCO1B1 testing in the routine practice of medicine, including its proposed benefits and unforeseen risks.

PMID: 30367991 [PubMed - as supplied by publisher]

Integrative approach identifies corticosteroid response variant in diverse populations with asthma.

J Allergy Clin Immunol. 2018 Oct 24;:

Authors: Levin AM, Gui H, Hernandez-Pacheco N, Yang M, Xiao S, Yang JJ, Hochstadt S, Barczak AJ, Eckalbar WL, Rynkowski D, Samedy LA, Kwok PY, Pino-Yanes M, Erle DJ, Lanfear DE, Burchard EG, Williams LK

Abstract
BACKGROUND: Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved non-white populations.
OBJECTIVE: To identify genetic predictors of ICS response in multiple population groups with asthma.
METHODS: The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n=244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (i.e., the combined effect of the SNP and SNP x ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in three additional groups - African Americans (n=803 and n=563) and Latinos (n=1,461). RNA-seq data from 408 asthma cases and 405 controls were used to examine whether genotype was associated with gene expression.
RESULTS: One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P=7.79x10-8) and was jointly associated with asthma exacerbations in three validation cohorts (P=0.023, P=0.029, and P=0.041). RNA-seq analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P=6.10x10-4). RNASE2 encodes eosinophil-derived neurotoxin (EDN), and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (i.e., high pre-treatment EDN levels or blood eosinophil counts).
CONCLUSION: We identified a variant, rs3827907, which appears to influence response to ICS treatment in multiple population groups, and likely mediates its effect through eosinophils.
CLINICAL IMPLICATIONS: African Americans and Latinos are disproportionately affected by asthma and its complications. Here we identify a pharmacogenomic variant that may assist in identifying individuals from these groups who will respond to ICS treatment.

PMID: 30367910 [PubMed - as supplied by publisher]