SNPs and STRs in forensic medicine. A strategy for kinship evaluation.

Arch Med Sadowej Kryminol. 2017;67(3):226-240

Authors: Pontes L, Sousa JC, Medeiros R

Abstract
Some emerging technologies are used as strategies for the analyses of single nucleotide polymorphisms (SNPs) that have attracted much interest in recent years, applied to various scientific areas. They have been extensively used as markers to identify genes that underlie complex diseases and also to realize the potential of pharmacogenomics in relation to different drug responses. Additionally, SNPs have been shown to be very useful in forensic genetics resolving all kinds of legal problems, namely crime cases, disaster victim identification and paternity and kinship investigation testing. The low mutation rate of SNPs, makes these markers very suitable for relationship testing. In the great majority of the cases, analyses with the widely used sets of STR markers provide powerful statistical evidence but some of them remain with ambiguous results. Those include cases with complex pedigrees or cases with some problems, like mutations, that are inherent to the use of STRs. At this time several forensic laboratories are using SNPs especially to complement the study of STRs in some of their casework cases. This paper intends to analyze some of our casework examples and to providea data update on the joint use of STRs and autosomal SNPs in the evaluation and kinship calculation, one of the strategies currently used for this purpose, namely reviewing and comparing results published by various working groups.

PMID: 29460612 [PubMed - in process]

Research directions in the clinical implementation of pharmacogenomics - An Overview of US programs and projects.

Clin Pharmacol Ther. 2018 Feb 20;:

Authors: Volpi S, Bult C, Chisholm RL, Deverka PA, Ginsburg GS, Jacob HJ, Kasapi M, McLeod HL, Roden DM, Williams MS, Green ED, Lyman Rodriguez L, Aronson S, Cavallari LH, Denny JC, Dressler L, Johnson JA, Klein TE, Steven Leeder J, Piquette-Miller M, Perera M, Rasmussen-Torvik LJ, Rehm HL, Ritchie MD, Skaar TC, Wagle N, Weinshilboum R, Weitzel KW, Wildin R, Wilson J, Manolio TA, Relling MV

Abstract
Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here, we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them. This article is protected by copyright. All rights reserved.

PMID: 29460415 [PubMed - as supplied by publisher]

Pharmacogenetic information in clinical guidelines - the European perspective.

Clin Pharmacol Ther. 2018 Feb 20;:

Authors: Swen JJ, Nijenhuis M, van Rhenen M, de Boer-Veger NJ, Buunk AM, Houwink EJF, Mulder H, Rongen GA, van Schaik RHN, van der Weide J, Wilffert B, Deneer VHM, Guchelaar HJ, Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association (KNMP)

PMID: 29460273 [PubMed - as supplied by publisher]

Operationalizing the Reciprocal Engagement Model of Genetic Counseling Practice: a Framework for the Scalable Delivery of Genomic Counseling and Testing.

J Genet Couns. 2018 Feb 19;:

Authors: Schmidlen T, Sturm AC, Hovick S, Scheinfeldt L, Scott Roberts J, Morr L, McElroy J, Toland AE, Christman M, O'Daniel JM, Gordon ES, Bernhardt BA, Ormond KE, Sweet K

Abstract
With the advent of widespread genomic testing for diagnostic indications and disease risk assessment, there is increased need to optimize genetic counseling services to support the scalable delivery of precision medicine. Here, we describe how we operationalized the reciprocal engagement model of genetic counseling practice to develop a framework of counseling components and strategies for the delivery of genomic results. This framework was constructed based upon qualitative research with patients receiving genomic counseling following online receipt of potentially actionable complex disease and pharmacogenomics reports. Consultation with a transdisciplinary group of investigators, including practicing genetic counselors, was sought to ensure broad scope and applicability of these strategies for use with any large-scale genomic testing effort. We preserve the provision of pre-test education and informed consent as established in Mendelian/single-gene disease genetic counseling practice. Following receipt of genomic results, patients are afforded the opportunity to tailor the counseling agenda by selecting the specific test results they wish to discuss, specifying questions for discussion, and indicating their preference for counseling modality. The genetic counselor uses these patient preferences to set the genomic counseling session and to personalize result communication and risk reduction recommendations. Tailored visual aids and result summary reports divide areas of risk (genetic variant, family history, lifestyle) for each disease to facilitate discussion of multiple disease risks. Post-counseling, session summary reports are actively routed to both the patient and their physician team to encourage review and follow-up. Given the breadth of genomic information potentially resulting from genomic testing, this framework is put forth as a starting point to meet the need for scalable genetic counseling services in the delivery of precision medicine.

PMID: 29460110 [PubMed - as supplied by publisher]

Leptospirosis in human: Biomarkers in host immune responses.

Microbiol Res. 2018 Mar;207:108-115

Authors: Vk C, Ty L, Wf L, Ywy WS, An S, S Z, A M

Abstract
Leptospirosis remains one of the most widespread zoonotic diseases caused by spirochetes of the genus Leptospira, which accounts for high morbidity and mortality globally. Leptospiral infections are often found in tropical and subtropical regions, with people exposed to contaminated environments or animal reservoirs are at high risk of getting the infection. Leptospirosis has a wide range of clinical manifestations with non-specific signs and symptoms and often misdiagnosed with other acute febrile illnesses at early stage of infection. Despite being one of the leading causes of zoonotic morbidity worldwide, there is still a gap between pathogenesis and human immune responses during leptospiral infection. It still remains obscure whether the severity of the infection is caused by the pathogenic properties of the Leptospira itself, or it is a consequence of imbalance host immune factors. Hence, in this review, we seek to summarize the past and present milestone findings on the biomarkers of host immune response aspects during human leptospiral infection, including cytokine and other immune mediators. A profound understanding of the interlink between virulence factors and host immune responses during human leptospirosis is imperative to identify potential biomarkers for diagnostic and prognostic applications as well as designing novel immunotherapeutic strategies in future.

PMID: 29458845 [PubMed - in process]

[Molecular aspects of vasoprotective peptide KED activity during atherosclerosis and restenosis].

Adv Gerontol. 2016;29(4):646-650

Authors: Kozlov KL, Bolotov II, Linkova NS, Drobintseva AO, Khavinson VK, Dyakonov MM, Kozina LS

Abstract
Peptide KED (Lys-Glu-Asp) has vasoprotective effects and is effective substance in treatment of of atherosclerosis and other cardio-vascular disorders in elderly people. One of the probable mechanisms of biological activity of this peptide is epigenetic genes regulation. These genes can coding proteins, which are markers of endothelium functional activity. The goal of investigation was to study the KED peptide effect on signal molecules expression in normal, atherosclerotic and restenotic endothelium in vitro. It was shown, that KED peptide has normalized endothelin-1 expression, which increased during atherosclerosis and restenosis. KED peptide also restorates cells interactions by connexin expression. Geroprotective effect of KED peptide is realized by increasing of sirtuin1 expression, which has took part in DNA reparation.

PMID: 28539025 [PubMed - indexed for MEDLINE]

Leveraging the Learning Health Care Model to Improve Equity in the Age of Genomic Medicine.

Learn Health Syst. 2018 Jan;2(1):

Authors: Blizinsky KD, Bonham VL

Abstract
To fully achieve the goals of a genomics-enabled learning health care system, purposeful efforts to understand and reduce health disparities and improve equity of care are essential. This paper highlights three major challenges facing genomics-enabled learning health care systems, as they pertain to ancestrally diverse populations: inequality in the utility of genomic medicine; lack of access to pharmacogenomics in clinical care; and inadequate incorporation of social and environmental data into the electronic health care record (EHR). We advance a framework that can not only be used to directly improve care for all within the learning health system, but can also be used to focus on the needs to address racial and ethnic health disparities and improve health equity.

PMID: 29457138 [PubMed]

Effects of Cytochrome P450 Single Nucleotide Polymorphisms on Methadone Metabolism and Pharmacodynamics.

Biochem Pharmacol. 2018 Feb 16;:

Authors: Ahmad T, Valentovic MA, Rankin GO

Abstract
Methadone is a synthetic, long-acting opioid with a single chiral center forming two enantiomers, (R)-methadone and (S)-methadone, each having specific pharmacological actions. Concentrations of (R)- and (S)-methadone above therapeutic levels have the ability to cause serious, life-threatening, and fatal side effects. This toxicity can be due in part to the pharmacogenetics of an individual, which influences the pharmacokinetic and pharmacodynamic properties of the drug. Methadone is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, predominately by CYP2B6, followed by CYP3A4, 2C19, 2D6, and to a lesser extent, CYP2C18, 3A7, 2C8, 2C9, 3A5, and 1A2. Single nucleotide polymorphisms (SNPs) located within CYPs have the potential to play an important role in altering methadone metabolism and pharmacodynamics. Several SNPs in the CYP2B6, 3A4, 2C19, 2D6, and 3A5 genes result in increases in methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance. In particular, carriers of CYP2B6∗6/∗6 may have a greater risk for detrimental adverse effects, as methadone metabolism and clearance are diminished in these individuals. CYP2B6∗4, on the other hand, has been observed to decrease plasma concentrations of methadone due to increased methadone clearance. The involvement, contribution, and understanding the role of SNPs in CYP2B6, and other CYP genes, in methadone metabolism can improve the therapeutic uses of methadone in patient outcome and the development of personalized medicine.

PMID: 29458047 [PubMed - as supplied by publisher]

Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation.

Br J Clin Pharmacol. 2018 Feb 19;:

Authors: Ueshima S, Hira D, Kimura Y, Fujii R, Tomitsuka C, Yamane T, Tabuchi Y, Ozawa T, Itoh H, Ohno S, Horie M, Terada T, Katsura T

Abstract
AIMS: This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolising enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban.
METHODS: Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2, and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using non-linear mixed effect modelling (NONMEM™) program.
RESULTS: The non-linear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70 mL/min) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06 L/h. When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7 L.
CONCLUSION: The present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are considered to be intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions.

PMID: 29457840 [PubMed - as supplied by publisher]

Novel approach for CES1 genotyping: integrating single nucleotide variants and structural variation.

Pharmacogenomics. 2018 Feb 19;:

Authors: Bjerre D, Berg Rasmussen H

Abstract
AIM: Development of a specific procedure for genotyping of CES1A1 (CES1) and CES1A2, a hybrid of CES1A1  and the pseudogene CES1P1.
MATERIALS & METHODS: The number of CES1A1 and CES1A2  copies and that of CES1P1  were determined using real-time PCR. Long range PCRs followed by secondary PCRs allowed sequencing of single nucleotide variants in CES1A1 and CES1A2. Results & conlusion: A procedure consisting of two main steps was developed. Its first main step, the copy number determination, informed about presence of CES1A2 . This information enabled choice of PCR in the second main step, which selectively amplified CES1A1 and, if present, also CES1A2, for subsequent sequencing. Examination of 501 DNA samples suggested that our procedure is specific with potential for personalization of drug treatments.

PMID: 29457755 [PubMed - as supplied by publisher]

Kinase-targeted cancer therapies: progress, challenges and future directions.

Mol Cancer. 2018 Feb 19;17(1):48

Authors: Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HPV

Abstract
The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.

PMID: 29455673 [PubMed - in process]

Systematic Cell-Based Phenotyping of Missense Alleles.

Methods Mol Biol. 2017;1601:215-228

Authors: Thormählen AS, Runz H

Abstract
Sequencing of the protein-coding genome, the exome, has proven powerful to unravel links between genetic variation and disease for both Mendelian and complex conditions. Importantly, however, the increasing number of sequenced human exomes and mapping of disease-associated alleles is accompanied by a simultaneous, yet exponential increase in the overall number of rare and low frequency alleles identified. For most of these novel alleles, biological consequences remain unknown since reliable experimental approaches to better characterize their impact on protein function are only slowly emerging.Here we review a scalable, cell-based strategy that we have recently established to systematically profile the biological impact of rare and low frequency missense variants in vitro. By applying this approach to missense alleles identified through cohort-level exome sequencing in the low-density lipoprotein receptor (LDLR) we are able to distinguish rare alleles that predispose to familial hypercholesterolemia and myocardial infarction from alleles without obvious impact on LDLR levels or functions. We propose that systematic implementation of such and similar strategies will significantly advance our understanding of the protein-coding human genome and how rare and low frequency genetic variation impacts on health and disease.

PMID: 28470529 [PubMed - indexed for MEDLINE]

Donor and recipient P450 gene polymorphisms influence individual pharmacological effects of tacrolimus in Chinese liver transplantation patients.

Int Immunopharmacol. 2018 Feb 14;57:18-24

Authors: Liu J, Ouyang Y, Chen D, Yao B, Lin D, Li Z, Zang Y, Liu H, Fu X

Abstract
The immunosuppressant drug tacrolimus (Tac) used for the prevention of immunological rejection is a metabolic substrate of cytochrome P450 enzymes. This study was designed to evaluate the short-term and long-term potential influence of single-nucleotide polymorphisms (SNPs) in CYP450 genes of liver transplant (LT) recipients as well as the donors on individual pharmacological effects of Tac and to guide individualized-medication from the perspective of pharmacogenomics. Twenty-one SNPs of the CYP450 gene were genotyped for both recipients and donors in 373 LT patients receiving Tac-based immunosuppressants. The Tac concentration/dosage ratio (C/D) was evaluated from the initial medication until one year after LT. The C/D ratio was significantly higher when the donor and/or recipient genotype of CYP3A5 rs776746 was G/G or rs15524 was T/T or rs4646450 was C/C all through one year after transplantation. Comparing the effect of donor gene variants of rs776746, rs15524, and rs4646450 on Tac C/D ratios with the recipients, statistically significant differences were found between the donor T/T group and the recipient T/T group in rs15524 at 1 month and 6 months, and at 6 months, the donor C/C group differed from the recipient C/C group in rs4646450. In conclusion, rs776746, rs15524, and rs4646450 of CYP3A5 had a significant influence on Tac pharmacological effects for both the initial use and long-term use. The donor liver genotype and the recipient intestine genotype contribute almost equally in the short-term, but the donor genotype had a greater effect than the recipient genotype at 6 months. Personalized Tac treatment after LT should be based on the CYP3A5 genotype.

PMID: 29454235 [PubMed - as supplied by publisher]

Sequential analysis in neonatal research-systematic review.

Eur J Pediatr. 2018 Feb 16;:

Authors: Lava SAG, Elie V, Ha PTV, Jacqz-Aigrain E

Abstract
As more new drugs are discovered, traditional designs come at their limits. Ten years after the adoption of the European Paediatric Regulation, we performed a systematic review on the US National Library of Medicine and Excerpta Medica database of sequential trials involving newborns. Out of 326 identified scientific reports, 21 trials were included. They enrolled 2832 patients, of whom 2099 were analyzed: the median number of neonates included per trial was 48 (IQR 22-87), median gestational age was 28.7 (IQR 27.9-30.9) weeks. Eighteen trials used sequential techniques to determine sample size, while 3 used continual reassessment methods for dose-finding. In 16 studies reporting sufficient data, the sequential design allowed to non-significantly reduce the number of enrolled neonates by a median of 24 (31%) patients (IQR - 4.75 to 136.5, p = 0.0674) with respect to a traditional trial. When the number of neonates finally included in the analysis was considered, the difference became significant: 35 (57%) patients (IQR 10 to 136.5, p = 0.0033).
CONCLUSION: Sequential trial designs have not been frequently used in Neonatology. They might potentially be able to reduce the number of patients in drug trials, although this is not always the case. What is known: • In evaluating rare diseases in fragile populations, traditional designs come at their limits. About 20% of pediatric trials are discontinued, mainly because of recruitment problems. What is new: • Sequential trials involving newborns were infrequently used and only a few (n = 21) are available for analysis. • The sequential design allowed to non-significantly reduce the number of enrolled neonates by a median of 24 (31%) patients (IQR - 4.75 to 136.5, p = 0.0674).

PMID: 29453599 [PubMed - as supplied by publisher]

Vitamin D pathway genetic variants are able to influence sofosbuvir and its main metabolite pharmacokinetics in HCV mono-infected patients.

Infect Genet Evol. 2018 Feb 13;:

Authors: Cusato J, De Nicolò A, Boglione L, Favata F, Ariaudo A, Pinna SM, Carcieri C, Guido F, Avataneo V, Cariti G, Di Perri G, D'Avolio A

Abstract
Vitamin D levels and genetic variants were associated with drug outcome/toxicity and concentrations. The plasma exposure of GS-331007, the main sofosbuvir metabolite, has been related to SVR. We evaluated the impact of polymorphisms in genes (CYP27B1, CYP24A1, VDBP and VDR) related to vitamin D pathway on sofosbuvir and GS-331007 plasma levels in HCV mono-infected patients at one month of treatment. Polymorphisms were investigated through real-time PCR; drug plasma quantification was performed through a UHPLC-MS/MS method. GS-331007 levels were associated with CYP24A1rs2248359 and VDRCdx2 variants in all the analyzed patients and linear regression analysis showed that sex, body mass index, HCV genotype, baseline estimated glomerular filtration rate, VDRCdx2AG/GG and CYP27B1-1260TT genotypes significantly predict concentrations. We performed sub-analyses considering the HCV genotype and the concomitant drug, identifying polymorphisms associated with GS-331007 concentrations. This is the first study focusing on vitamin D pathway gene variants and DAAs concentrations, but further studies are required.

PMID: 29452294 [PubMed - as supplied by publisher]

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors.

Int J Cancer. 2018 Feb 16;:

Authors: Liew PL, Huang RL, Weng YC, Fang CL, Hui-Ming Huang T, Lai HC

Abstract
Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type-specific epigenomics and its clinical significance remain uncertain. We analyzed the methylomic profiles of six benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs), and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis-coupled proton transport, proteolysis involved in the cellular protein catabolic process, and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma, and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC, or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second-generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous-type-specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC. This article is protected by copyright. All rights reserved.

PMID: 29451304 [PubMed - as supplied by publisher]

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.

Diabetologia. 2018 Feb 15;:

Authors: Habeb AM, Flanagan SE, Zulali MA, Abdullah MA, Pomahačová R, Boyadzhiev V, Colindres LE, Godoy GV, Vasanthi T, Al Saif R, Setoodeh A, Haghighi A, Haghighi A, Shaalan Y, International Neonatal Diabetes Consortium, Hattersley AT, Ellard S, De Franco E

Abstract
AIMS/HYPOTHESIS: Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes.
METHODS: We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire.
RESULTS: We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months (IQR 5-27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day.
CONCLUSIONS/INTERPRETATION: In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent.
DATA AVAILABILITY: SLC19A2 mutation details have been deposited in the Decipher database ( https://decipher.sanger.ac.uk/ ).

PMID: 29450569 [PubMed - as supplied by publisher]

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

Addict Behav Rep. 2017 Dec;6:8-14

Authors: Ettienne EB, Chapman E, Maneno M, Ofoegbu A, Wilson B, Settles-Reaves B, Clarke M, Dunston G, Rosenblatt K

Abstract
Introduction: Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes.
Methods: We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management.
Results: At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing.
Conclusion: Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

PMID: 29450233 [PubMed]

Therapeutic Lowering of Lipoprotein(a): A Role for Pharmacogenetics?

Circ Genom Precis Med. 2018 Feb;11(2):e002052

Authors: Boffa MB, Koschinsky ML

PMID: 29449330 [PubMed - in process]

A study on the genetic polymorphisms of CYP3A5 among the Orang Asli in Malaysia using next generation sequencing platform.

Ann Hum Biol. 2018 Feb 15;:1-12

Authors: Ang GY, Yu CY, Johari James R, Ahmad A, Abdul Rahman T, Mohd Nor F, Shaari SA, Ismail AI, Teh LK, Salleh MZ

Abstract
CYP3A5 is the predominant subfamily of biotransformation enzymes in the liver and the genetic variations in CYP3A5 are an important determinant of interindividual and interethnic differences in CYP3A-mediated drug disposition and response. This study aims to investigate the genetic polymorphisms of CYP3A5 among the Orang Asli in Peninsular Malaysia using next generation sequencing platform. Genomic DNAs were extracted from blood samples of the three main Orang Asli tribes and whole-genome sequencing was performed. A total of 61 single nucleotide polymorphisms were identified and all the SNPs were located in introns except rs15524 which is in the 3'UTR and 11 of these polymorphisms were novel. Two allelic variants and three genotypes were identified in the Orang Asli. The major allelic variant was the non-functional CYP3A5*3 (66.4%). The percentages of Orang Asli with CYP3A5*3/*3 (47.2%) and CYP3A5*1/*3 (38.1%) genotypes are more than twice the percentage of Orang Asli with CYP3A5*1/*1 (14.8%) genotype. Almost half of the Orang Asli harboured CYP3A5 non-expressor genotype (CYP3A5*3/*3). The predominance of the CYP3A5 non-expressor genotype among the Orang Asli was unraveled and the findings in this study may serve as a guide for the optimiszation of pharmacotherapy for the Orang Asli community.

PMID: 29447003 [PubMed - as supplied by publisher]