Pharmacogenomics research and clinical implementation in Brazil.

Basic Clin Pharmacol Toxicol. 2018 Dec 27;:

Authors: Rodrigues-Soares F, Suarez-Kurtz G

Abstract
We searched Pubmed entries and the Lattes database for Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a Genome-Wide Association Study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renally transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atanazavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessment of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (e.g. HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (e.g. warfarin guidelines), "race" or ethnicity. This article is protected by copyright. All rights reserved.

PMID: 30589990 [PubMed - as supplied by publisher]

Pharmacotherapeutic strategies for standard treatment-resistant psoriasis.

Expert Opin Pharmacother. 2018 Dec 27;:1-12

Authors: Heath MS, Kolli SS, Dowling JR, Cline A, Feldman SR

Abstract
INTRODUCTION: Psoriasis management includes a variety of treatments including localized therapies and systemic treatments; however, many patients report inadequate clinical response and resistance to therapy. Currently there is no treatment algorithm that incorporates effective strategies to tackle the various barriers leading to resistance. Areas covered: The authors evaluate the scope of resistance, the reasons it occurs, and provide the reader with strategies for overcoming resistance in both localized and systemic therapies for psoriasis. Expert opinion: Refractory psoriasis involves modifiable and non-modifiable factors that warrant different approaches to maximize clinical response. Treatment-resistance to topical therapies may be due to poor adherence. Improving adherence involves incorporating patients' treatment preferences, improving the physician-patient relationship, and simplifying treatment regimens. Treatment-resistance to systemic therapies can be due to non-adherence but can also be due to ineffective dosing, development of anti-drug antibodies, and severe disease that necessitates multiple drugs. After addressing non-adherence, strategies to maximize systemic therapies include increasing the dosage, combining treatments, drug switching and incorporating pharmacogenetics.

PMID: 30589362 [PubMed - as supplied by publisher]

Effect of rifampin on enantioselective disposition and anti-hypertensive effect of benidipine.

Br J Clin Pharmacol. 2018 Dec 27;:

Authors: Sunwoo YE, Nguyen PTT, Chin MC, Ryu JY, Shon J, Shin JG

Abstract
AIMS: In vitro study showed that benidipine is exclusively metabolised by cytochrome P450 (CYP) 3A. This study evaluated the effect of rifampin on the enantioselective disposition and anti-hypertensive effect of benidipine.
METHODS: Benidipine (8 mg) was administered to healthy subjects with or without repeated rifampin dosing, in a crossover design. Plasma concentrations of (S)-(S)-(+)-α and (R)-(R)-(-)-α isomers of benidipine and blood pressure were measured for up to 24 h after dosing. In addition, CYP3A metabolic capacity was evaluated in each subject using oral clearance of midazolam.
RESULTS: The exposure of (S)-(S)-(+)-α-benidipine was greater than that of (R)-(R)-(-)-α-benidipine by approximately three-fold following single dose of benidipine. Repeated doses of rifampin significantly decreased the exposure of both isomers. Geometric mean ratios (GMRs) (95% CI) of Cmax and AUCinf for (S)-(S)-(+)-α-benidipine were 0.14 (0.10-0.18) and 0.12 (0.08-0.18), respectively. GMRs (95% CI) of Cmax and AUCinf for (R)-(R)-(-)-α-benidipine were 0.10 (0.06-0.17) and 0.10 (0.06-0.17), respectively. Oral clearances of both isomers were increased equally by approximately 10-fold. There were no significant differences in cardiovascular effect following benidipine administration between control and rifampin treatment. CYP3A activity using midazolam did not appear to correlate with oral clearance of benidipine.
CONCLUSIONS: After single administration of racemic benidipine, enantioselective disposition of (S)-(S)-(+)-α- and (R)-(R)-(-)-α-benidipine was observed. Treatments with rifampin significantly decreased the exposure of both isomers but appeared to marginally affect its blood pressure-lowering effect in healthy subjects. Impact of coadministration of rifampin on the treatment effects of benidipine should be assessed in hypertensive patients.

PMID: 30589098 [PubMed - as supplied by publisher]

Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.

Circulation. 2018 Nov 20;:

Authors: Sabater-Lleal M, Huffman JE, de Vries PS, Marten J, Mastrangelo MA, Song C, Pankratz N, Ward-Caviness CK, Yanek LR, Trompet S, Delgado GE, Guo X, Bartz TM, Martinez-Perez A, Germain M, de Haan HG, Ozel AB, Polasek O, Smith AV, Eicher JD, Reiner AP, Tang W, Davies NM, Stott DJ, Rotter JI, Tofler GH, Boerwinkle E, de Maat MPM, Kleber ME, Welsh P, Brody JA, Chen MH, Vaidya D, Soria JM, Suchon P, van Hylckama Vlieg A, Desch KC, Kolcic I, Joshi PK, Launer LJ, Harris TB, Campbell H, Rudan I, Becker DM, Li JZ, Rivadeneira F, Uitterlinden AG, Hofman A, Franco OH, Cushman M, Psaty BM, Morange PE, McKnight B, Chong MR, Fernandez-Cadenas I, Rosand J, Lindgren A, Gudnason V, Wilson JF, Hayward C, Ginsburg D, Fornage M, Rosendaal FR, Souto JC, Becker LC, Jenny NS, März W, Jukema JW, Dehghan A, Trégouët DA, Morrison AC, Johnson AD, O'Donnell CJ, Strachan DP, Lowenstein CJ, Smith NL, INVENT Consortium; MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC)

Abstract
BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.
METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.
RESULTS: We identified 13 novel genome-wide significant (p≤2.5x10-8) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.
CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

PMID: 30586737 [PubMed - as supplied by publisher]

Classic challenges and emerging approaches to medication therapy in older adults.

Discov Med. 2018 Oct;26(143):137-146

Authors: Alagiakrishnan K, Mah D, Padwal R

Abstract
Prescribing medications safely and effectively in older adults is a complex process. This review discusses challenges with medication prescribing in older adults and outlines a holistic approach to medication management in older adults. Well-known challenges including the alterations in pharmacokinetics and pharmacodynamics that often occur with aging are discussed. Other classic concerns including polypharmacy, potentially inappropriate medication use, prescribing cascades, suboptimal prescribing, paradoxical harm and unintended consequences of medications, and drug interactions are reviewed. Newer approaches, including deprescribing, pharmacogenomics, and the future potential for senolytic therapy are also discussed. All healthcare providers should consider these challenges when prescribing medications in older adults. Choosing a drug that fits both a patient's pathophysiology and biology, avoiding drugs with significant side effects, titrating doses, and deprescribing are all critical in optimizing medication therapy.

PMID: 30586537 [PubMed - in process]

MALAT1: a potential biomarker in cancer.

Cancer Manag Res. 2018;10:6757-6768

Authors: Li ZX, Zhu QN, Zhang HB, Hu Y, Wang G, Zhu YS

Abstract
Purpose: The research of long non-coding RNAs (lncRNAs) has become a new passion with the discovery of abundant new lncRNAs and extensive investigation of their roles in various diseases, especially in cancers. Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) emerges as a hotspot, which has been reported to be involved in dysregulation of cell signaling and closely correlated with cancer development, progression, and response to therapy. This review is a brief update of the current knowledge related to the role of MALAT1 in cancer-associated molecular pathways and pathophysiology and possible determinants for MALAT1 to function as a biomarker, aiming to stimulate the basic investigation of lncRNA MALAT1 as well as its translation to clinical applications.
Methods: We have selected vast literature from electronic databases including studies associated with its clinical significance and the pivotal functions in cancer processes such as cell proliferation, apoptosis, metastasis, immunity, angiogenesis, and drug resistance.
Results: Studies have shown that aberrant expression of MALAT1 is related to cancer pathophysiology with the potential to be translated clinically and MALAT1 can regulate cancer processes by interacting with molecules, such as proteins, RNAs and DNAs, and further altering different signal pathways.
Conclusion: MALAT1 lncRNA promises to be a potential biomarker for cancer diagnosis as well as prognosis. Additionally, it might be a therapeutic target for human cancers.

PMID: 30584369 [PubMed]

Association of C35T polymorphism in dihydrofolate reductase gene with toxicity of methotrexate in rheumatoid arthritis patients.

Expert Opin Drug Metab Toxicol. 2018 Dec 24;:

Authors: Vejnović D, Milić V, Popović B, Damnjanović T, Maksimović N, Bunjevački V, Krajinović M, Novaković I, Damjanov N, Jekić B

Abstract
BACKGROUND: Methotrexate, a folate analogue, is the most commonly used disease-modifying drug in the treatment of rheumatoid arthritis. However, high interindividual differences in drug response are present among RA patients.
RESEARCH DESIGN AND METHODS: In a group of 234 RA patients treated with MTX we investigated whether rs1650697 polymorphism in DHFR gene may have impact on MTX efficacy and/or adverse drug effects (ADEs). Relative DAS28 values (rDAS28) were used for MTX therapy estimation and all adverse drug events were recorded. Patients were genotyped for selected polymorphism by real-time PCR method.
RESULTS: According to the EULAR criteria after 6 months of MTX therapy 196 patients (83.8 %) were classified as responders, (25 (10.7 %) were good and 171 (73.1 %) were moderate) and 38 patients (16.2 %) as non-responders. ADEs were observed in 55 patients (23.5 %).
CONCLUSIONS: Our results showed that the presence of T allele might be protective against MTX hepatotoxicity measured by transaminaze levels (p=0.05). Furthermore, among patients who also received low-dose corticosteroids we have found a lower rDAS values in patients with CC genotype (p=0.039).

PMID: 30583708 [PubMed - as supplied by publisher]

Confirmation practice in pharmacogenetic testing; how good is good enough?

Clin Chim Acta. 2018 Dec 21;:

Authors: Lunenburg CATC, Guchelaar HJ, van Schaik RHN, Neumaier M, Swen JJ

Abstract
Pharmacogenetic testing is increasingly implemented in routine diagnostics. However, quality control measures, in particular confirmation practices e.g. the use of two independent genotyping techniques, are subject of debate and there are no clear guidelines. The aim of the current paper is to discuss the current practice in confirmation testing in the field of pharmacogenetics and draw attention to this situation. DPYD genotyping is used as a case example to highlight the importance of assigning the correct genotype. Current confirmation practices in laboratories are explored through a survey. Substantial heterogeneity was observed with 54% of the laboratories applying different forms of confirmation practice. Finally, we evaluated over 10 years of genotyping results from two large genotyping facilities, which both use a second, independent genotyping technique. Discrepancies between tests were identified in 9 patients (0.01%), possibly due to allele dropout. We feel that a second, independent technique is useful for genetic tests with a high clinical impact, such as DPYD testing. Guidelines can help to align confirmatory laboratory practices for pharmacogenetics, which may need to be specified per gene and test.

PMID: 30582901 [PubMed - as supplied by publisher]

PATJ Low Frequency Variants Are Associated with Worse Ischemic Stroke Functional Outcome: A Genome-Wide Meta-Analysis.

Circ Res. 2018 Oct 15;:

Authors: Mola-Caminal M, Carrera C, Soriano-Tárraga C, Giralt Steinhauer E, Diaz-Navarro RM, Tur S, Jiménez C, Medina-Dols A, Cullell N, Torres-Aguila NP, Muiño E, Rodri Guez-Campello A, Ois A, Cuadrado-Godia E, Vivanco-Hidalgo RM, Hernandez-Guillamon M, Sole M, Delgado P, Bustamante A, Garcia-Berrocoso T, Mendioroz M, Castellanos M, Serena J, Martí-Fàbregas J, Segura T, Serrano-Heras G, Obach V, Ribo M, Molina CA, Álvarez-Sabín J, Palomeras Soler EP, Freijo MDM, Font MA, Rosand J, Rost NS, Gallego-Fabrega C, Lee JM, Heitsch L, Ibanez L, Cruchaga C, Phuah CL, Lemmens R, Thijs VNS, Lindgren A, Maguire JM, Rannikmae K, Sudlow CL, Jern C, Stanne TM, Lorentzen E, Muñoz-Narbona LA, Davalos A, Lopez-Cancio E, Worrall BB, Woo D, Kittner SJ, Mitchell BD, Montaner J, Roquer J, Krupinski JA, Estivill X, Rabionet R, Vives-Bauza C, Fernandez-Cadenas I, Jiménez-Conde J

Abstract
RATIONALE: Ischemic stroke (IS) is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome.
OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest genome-wide association study (GWAS) in IS recovery to date.
METHODS AND RESULTS: A 12-cohort, two-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent IS cases. Functional outcome was recorded using 3-month modified Rankin Scale (mRS). Analyses were adjusted for confounders such as discharge NIHSS. A gene-based burden test was performed. The discovery phase (n=1,225) was followed by open (n=2,482) and stringent joint-analyses (n=1,791). Those cohorts with mRS recorded at timepoints other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, beta=0·40, p=1·70x10-9).
CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

PMID: 30582445 [PubMed - as supplied by publisher]

Factors influencing hepatic metabolism of antihypertensive drugs: impact on clinical response.

Expert Opin Drug Metab Toxicol. 2018 Dec 24;:1-13

Authors: Höcht C, Bertera FM, Santander Plantamura Y, Parola L, Del Mauro JS, Polizio AH

Abstract
INTRODUCTION: Although main antihypertensive drugs are able to efficiently reduce blood pressure, only a third of treated hypertensive patients achieve optimal blood pressure control. Extensive interpatient variability on drug metabolism and oral disposition of blood pressure lowering drugs can contribute to this failure in hypertension management. Areas covered: The aim of the present review is to update the knowledge on the features of hepatic metabolism of the main antihypertensive agents, including β-blockers, calcium channel blockers, angiotensin receptor blockers, and angiotensin converting enzyme inhibitors. The factors that contribute to the large interindividual variability of main antihypertensive drugs are also covered. Expert opinion: The variability of plasma concentration of antihypertensive drugs due to the involvement of hepatic metabolism can contribute to the inadequate control of blood pressure in the daily clinical practice. Genotype screening of specific hepatic drug-metabolizing enzymes may contribute to optimize dose selection and to increase the rate of blood pressure control in patients treated with specific β-blockers, calcium channel blockers, and angiotensin receptor blockers.

PMID: 30582386 [PubMed - as supplied by publisher]

The role of genetics and genomics in clinical psychiatry.

Dialogues Clin Neurosci. 2018 Sep;20(3):169-177

Authors: Hoehe MR, Morris-Rosendahl DJ

Abstract
The enormous successes in the genetics and genomics of many diseases have provided the basis for the advancement of precision medicine. Thus, the detection of genetic variants associated with neuropsychiatric disorders, as well as treatment outcome, has raised growing expectations that these findings could soon be translated into the clinic to improve diagnosis, the prediction of disease risk and individual response to drug therapy. In this article, we will provide an introduction to the search for genes involved in psychiatric illness and summarize the present findings in major psychiatric disorders. We will review the genetic variants in genes encoding drug metabolizing enzymes and specific drug targets which were found to be associated with variable drug response and severe side effects. We will evaluate the clinical translatability of these findings, whether there is currently any role for genetic testing and in this context, make valuable sources of information available to the clinician seeking guidance and advice in this rapidly developing field of psychiatric genetics.

PMID: 30581286 [PubMed - in process]

PHARMACOGENETIC EFFECTS OF METHOTREXATE (MTX) IN UKRAINIAN PATIENTS DEPENDING ON THE MTHFR GENOTYPES (CLINICAL CASES).

Georgian Med News. 2018 Jun;(279):111-117

Authors: Fedota O, Roschenyuk L, Tyzhnenko T, Merenkova I, Vorontsov V

Abstract
The aim of the study is an evaluation the influence of MTHFR gene polymorphisms in the response to MTX in Ukrainian patients. The study group included unrelated Ukrainian patients with dermatoses - psoriasis vulgaris, psoriasis arthritis, psoriasis erythrodermic, atopic dermatitis, scleroderma, eczema, flat lichen and ectopic pregnancy. The materials for this study are based on the accumulated data from clinical observations of different reactions of patients with dermatoses and ectopic pregnancies when using methotrexate as the basic therapy according protocols. The analysis of the results obtained in the retrospective study indicated that MTX-treated patients had shown a different parameters depending on genotypes or haplotypes of MTHFR gene. After the treatment in the group of patients, carriers of CC genotype on C677T polymorphism of MTHFR gene, who received methotrexate, the normal levels of transaminases were observed. Probably, patients with the CCAA genotype are the fast metabolizers and could take methotrexate and other medications without complications for a long time. In the presented study, alpha-amylase levels in patients with CC and CT genotypes of C677T MTHFR gene before MTX treatment were normal or lower than normal. We found out that the level of amylase was significantly, almost 2 times, increased after treatment with MTX in patients with CCAA haplotype of MTHFR gene. Thus, the study of the association of polymorphisms of the MTHFR gene with a response to MTX has shown that the decrease in the therapeutic effect and the appearance of side effects in different genotypes is in the following relationship: CCAA <CTAA <CTAC. The main idea of future research is the search for ways to increase the effectiveness of therapy in patients, taking into account the pathophysiological processes and the genotypes of one-carbon metabolism genes for successful treatment.

PMID: 30035732 [PubMed - indexed for MEDLINE]

Pharmacokinetic-Pharmacodynamic interaction associated with venlafaxine-XR remission in patients with major depressive disorder with history of citalopram / escitalopram treatment failure.

J Affect Disord. 2018 Dec 17;246:62-68

Authors: Ahmed AT, Biernacka JM, Jenkins G, Rush AJ, Shinozaki G, Veldic M, Kung S, Bobo WV, Hall-Flavin DK, Weinshilboum RM, Wang L, Frye MA

Abstract
BACKGROUND: The purpose of this study was to identify specific pharmacokinetic (PK) and pharmacodynamics (PD) factors that affect the likelihood of treatment remission with a serotonin norepinephrine reuptake inhibitor (SNRI) in depressed patients whose initial selective serotonin reuptake inhibitor (SSRI) failed.
METHODS: Multiple logistic regression modeling of PK and PD variation hypothesized to contribute to SNRI (i.e. duloxetine or venlafaxine) treatment remission in prior SSRI (i.e. citalopram or escitalopram) failure was conducted on 139 subjects from the Pharmacogenomics Research Network (PGRN) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies. Depressive symptoms were assessed with the Quick Inventory of Depressive Symptomatology Clinician-rated (QIDS-C16).
RESULTS: Venlafaxine-XR remission was associated with a significant interaction between CYP2D6 ultra-rapid metabolizer (URM) phenotype and SLC6A4 5-HTTLPR L/L genotype. A similar significant interaction effect was observed between CYP2D6 URM and SLC6A2 G1287A GA genotype. Stratifying by transporter genotypes, venlafaxine-XR remission was associated with CYP2D6 URM in patients with SLC6A4 L/L (p = 0.001) and SLC6A2 G1287A GA genotypes.
LIMITATIONS: The primary limitation of this post hoc study was small sample size.
CONCLUSION: Our results suggest that CYP2D6 ultra-rapid metabolizer status contributes to venlafaxine-XR treatment remission in MDD patients; in particular, there is a PK-PD interaction with treatment remission associated with CYP2D6 URM phenotype and SLC6A4 5-HTTLPR L/L or SLC6A2 G1287A G/A genotype, respectively. These preliminary data are encouraging and support larger pharmacogenomics studies differentiating treatment response to mechanistically different antidepressants in addition to further PK-PD interactive analyses.

PMID: 30578947 [PubMed - as supplied by publisher]

HLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis.

J Allergy Clin Immunol. 2018 Dec 19;:

Authors: Dand N, Duckworth M, Baudry D, Russell A, Curtis CJ, Lee SH, Evans I, Mason KJ, Alsharqi A, Becher G, Burden AD, Goodwin RG, McKenna K, Murphy R, Perera GK, Rotarescu R, Wahie S, Wright A, Reynolds NJ, Warren RB, Griffiths CEM, Smith CH, Simpson MA, Barker JN, BADBIR study group, the BSTOP study group and the PSORT consortium

Abstract
BACKGROUND: Biologic therapies can be highly effective for the treatment of severe psoriasis but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness.
OBJECTIVE: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the two most commonly prescribed biologics for psoriasis, adalimumab (anti-TNFα) and ustekinumab (anti-IL12/23).
METHODS: The study utilises a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1,326 patients for whom PASI90 response status (90% reduction in psoriasis area and severity index) was observed after 3, 6 or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables.
RESULTS: HLA-C*06:02 negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time-points (most strongly at 6m: odds ratio (OR) = 2.95, P = 5.85×10-7) and the difference was greater in HLA-C*06:02 negative patients with psoriatic arthritis (PsA; OR = 5.98, P = 6.89×10-5). Biologic naive patients that were HLA-C*06:02 positive and PsA negative demonstrated significantly poorer response to adalimumab at 12m (OR = 0.31, P = 3.42×10-4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1.
CONCLUSION: This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.

PMID: 30578879 [PubMed - as supplied by publisher]

Role of CYP2B6 pharmacogenomics in bupropion-mediated smoking cessation.

J Clin Pharm Ther. 2018 Dec 21;:

Authors: Tran AX, Ho TT, Varghese Gupta S

Abstract
WHAT IS KNOWN AND OBJECTIVE: Pharmacogenomics holds promise in smoking cessation because of its potential to shed light on the complexity of drug metabolism and improve treatments using therapeutic agents. The cytochrome P450 2B6 gene (CYP2B6) encodes CYP2B6 enzyme that has been found to mediate the hydroxylation of bupropion, a smoking cessation aid. CYP2B6 exhibits a range of polymorphic variants that alter the pharmacokinetics and pharmacodynamics of bupropion. Genetic variations in CYP2B6 may influence the risk of adverse effects or efficacy of treatment with bupropion. The objective of this review was to investigate the influence of pharmacogenomics on smoking cessation therapy.
METHODS: A thorough literature search was conducted on PubMed, SCOPUS and EMBASE using keywords related to bupropion, smoking cessation, pharmacogenomics and CYP2B6. Research and review articles, case reports and clinical and preclinical studies pertinent to the research topic were identified, evaluated and summarized. Cited articles within the above-mentioned sources also provided pertinent information.
RESULTS: There is strong literature evidence to prove that CYP2B6 polymorphisms affect pharmacokinetic and pharmacodynamic properties of bupropion, thus affecting the therapeutic outcome of smoking cessation therapy.
WHAT IS NEW AND CONCLUSIONS: Complete understanding of pharmacogenetic variation of bupropion pharmacokinetics and pharmacodynamics will be beneficial for designing safer and more personalized smoking cessation therapy with improved outcomes.

PMID: 30578565 [PubMed - as supplied by publisher]

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

Nat Genet. 2019 Jan;51(1):51-62

Authors: Giri A, Hellwege JN, Keaton JM, Park J, Qiu C, Warren HR, Torstenson ES, Kovesdy CP, Sun YV, Wilson OD, Robinson-Cohen C, Roumie CL, Chung CP, Birdwell KA, Damrauer SM, DuVall SL, Klarin D, Cho K, Wang Y, Evangelou E, Cabrera CP, Wain LV, Shrestha R, Mautz BS, Akwo EA, Sargurupremraj M, Debette S, Boehnke M, Scott LJ, Luan J, Zhao JH, Willems SM, Thériault S, Shah N, Oldmeadow C, Almgren P, Li-Gao R, Verweij N, Boutin TS, Mangino M, Ntalla I, Feofanova E, Surendran P, Cook JP, Karthikeyan S, Lahrouchi N, Liu C, Sepúlveda N, Richardson TG, Kraja A, Amouyel P, Farrall M, Poulter NR, Understanding Society Scientific Group, International Consortium for Blood Pressure, Blood Pressure-International Consortium of Exome Chip Studies, Laakso M, Zeggini E, Sever P, Scott RA, Langenberg C, Wareham NJ, Conen D, Palmer CNA, Attia J, Chasman DI, Ridker PM, Melander O, Mook-Kanamori DO, Harst PV, Cucca F, Schlessinger D, Hayward C, Spector TD, Jarvelin MR, Hennig BJ, Timpson NJ, Wei WQ, Smith JC, Xu Y, Matheny ME, Siew EE, Lindgren C, Herzig KH, Dedoussis G, Denny JC, Psaty BM, Howson JMM, Munroe PB, Newton-Cheh C, Caulfield MJ, Elliott P, Gaziano JM, Concato J, Wilson PWF, Tsao PS, Velez Edwards DR, Susztak K, Million Veteran Program, O'Donnell CJ, Hung AM, Edwards TL

Abstract
In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

PMID: 30578418 [PubMed - in process]

Erratum for Parvez et al., "Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro".

Antimicrob Agents Chemother. 2019 Jan;63(1):

Authors: Parvez MM, Kaisar N, Shin HJ, Lee YJ, Shin JG

PMID: 30578406 [PubMed - in process]

Gene expression effects of lithium and valproic acid in a serotonergic cell line.

Physiol Genomics. 2018 Dec 21;:

Authors: Balasubramanian D, Pearson JF, Kennedy MA

Abstract
Valproic acid (VPA) and lithium are widely used in the treatment of bipolar disorder. However, the underlying mechanism of action of these drugs is not clearly understood. We used RNA-Seq analysis to examine the global profile of gene expression in a rat serotonergic cell line (RN46A) after exposure to these two mood stabilizer drugs. Numerous genes were differentially regulated in response to VPA (log2 fold change ≥ 1.0; i.e. odds ratio of ≥ 2, at FDR <5%), but only two genes ( Dynlrb2 and Cdyl2) showed significant differential regulation after exposure of the cells to lithium, with the same analysis criteria. Both of these genes were also regulated by VPA. Many of the differentially expressed genes had functions of potential relevance to mood disorders or their treatment, such as several serpin family genes (including neuroserpin), Nts (neurotensin), Maob (monoamine oxidase B) and Ap2b1, which is important for synaptic vesicle function. Pathway analysis revealed significant enrichment of Gene Ontology terms such as extracellular matrix (ECM) remodelling, cell adhesion and chemotaxis. This study in a cell line derived from the raphe nucleus has identified a range of genes and pathways that provide novel insights into potential therapeutic actions of the commonly used mood stabilizer drugs.

PMID: 30576260 [PubMed - as supplied by publisher]

Genetic advances in gout: potential applications in clinical practice.

Curr Opin Rheumatol. 2018 Dec 19;:

Authors: Tai V, Merriman TR, Dalbeth N

Abstract
PURPOSE OF REVIEW: Many novel genetic associations in the field of hyperuricaemia and gout have been described recently. This review discusses advances in gout genetics and their potential clinical applications.
RECENT FINDINGS: Genome-wide association studies have identified approximately 30 serum urate-associated loci, some of which represent targets for drug development in gout. Some genes implicated in initiating the inflammatory response to deposited crystals in gout flares have also been described. In addition, genetic studies have been used to understand the link between hyperuricaemia and other comorbidities, particularly cardiometabolic diseases. ABCG2 has been established as a key genetic determinant in the onset of gout, and plays a role in the progression and severity of disease. Recent pharmacogenetic studies have also demonstrated the association between ABCG2 and poor response to allopurinol, and the link between human leukocyte antigen-B58:01 genotype and adverse drug reactions to allopurinol.
SUMMARY: Advances in gout genetics have provided important molecular insights into disease pathogenesis, better characterized the pharmacogenetics of allopurinol, and raised the possibility of using genetic testing to provide personalized treatment for patients. Prospective studies are now needed to clarify whether genetic testing in gout provides further benefit when added to established clinical management.

PMID: 30575597 [PubMed - as supplied by publisher]

New steps in infliximab therapeutic drug monitoring in patients with inflammatory bowel diseases.

Br J Clin Pharmacol. 2018 Dec 21;:

Authors: Nemoz B, Ternant D, Bailly S, Gautier-Veyret E, Jourdil JF, Bonaz B, Stanke-Labesque F

PMID: 30575085 [PubMed - as supplied by publisher]