Implementation and Quality Control of Lung Cancer EGFR Genetic Testing by MALDI-TOF Mass Spectrometry in Taiwan Clinical Practice.

Sci Rep. 2016;6:30944

Authors: Su KY, Kao JT, Ho BC, Chen HY, Chang GC, Ho CC, Yu SL

Abstract
Molecular diagnostics in cancer pharmacogenomics is indispensable for making targeted therapy decisions especially in lung cancer. For routine clinical practice, the flexible testing platform and implemented quality system are important for failure rate and turnaround time (TAT) reduction. We established and validated the multiplex EGFR testing by MALDI-TOF MS according to ISO15189 regulation and CLIA recommendation in Taiwan. Totally 8,147 cases from Aug-2011 to Jul-2015 were assayed and statistical characteristics were reported. The intra-run precision of EGFR mutation frequency was CV 2.15% (L858R) and 2.77% (T790M); the inter-run precision was CV 3.50% (L858R) and 2.84% (T790M). Accuracy tests by consensus reference biomaterials showed 100% consistence with datasheet (public database). Both analytical sensitivity and specificity were 100% while taking Sanger sequencing as the gold-standard method for comparison. EGFR mutation frequency of peripheral blood mononuclear cell for reference range determination was 0.002 ± 0.016% (95% CI: 0.000-0.036) (L858R) and 0.292 ± 0.289% (95% CI: 0.000-0.871) (T790M). The average TAT was 4.5 working days and the failure rate was less than 0.1%. In conclusion, this study provides a comprehensive report of lung cancer EGFR mutation detection from platform establishment, method validation to clinical routine practice. It may be a reference model for molecular diagnostics in cancer pharmacogenomics.

PMID: 27480787 [PubMed - in process]

Is there a role for pharmacogenetics in the treatment of anorexia nervosa?

Pharmacogenomics. 2016 Aug 1;

Authors: Smith S, Woodside B

PMID: 27479520 [PubMed - as supplied by publisher]

Warfarin Dosing Algorithms and the Need for Human Intervention.

Am J Med. 2016 Apr;129(4):431-7

Authors: Kasner SE, Wang L, French B, Messé SR, Ellenberg J, Kimmel SE, COAG Trial Steering Committee

Abstract
BACKGROUND: Dosing algorithms for warfarin incorporate clinical and genetic factors, but human intervention to overrule algorithm-based dosing may occasionally be required. The frequency and reasons for varying from algorithmic warfarin management have not been well studied.
METHODS: We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics trial who were randomized to either pharmacogenetic- or clinically-guided warfarin dosing algorithms. Clinicians and participants were blinded to dose but not international normalized ratio (INR) during the first 28 days. If an issue arose that raised concern for clinicians but might not be adequately accounted for by the protocol, then clinicians contacted the unblinded medical monitor who could approve exceptions if clinically justified. All granted exceptions were logged and categorized. We analyzed the relationships between dosing exceptions and both baseline characteristics and the outcome of percentage of time in the therapeutic INR range during the first 4 weeks.
RESULTS: Sixteen percent of participants required at least one exception to the protocol-defined warfarin dose (15% in the genotype arm and 17% in the clinical arm). Ninety percent of dose exceptions occurred after the first 5 days of dosing. The only baseline characteristic associated with dose exceptions was congestive heart failure (odds ratio 2.12, 95% confidence interval, 1.49-3.02, P <.001). Neither study arm nor genotype was associated with dose exceptions.
CONCLUSION: Despite rigorous algorithms, human intervention is frequently employed in the early management of warfarin dosing. Congestive heart failure at baseline appears to predict early exceptions to standardized protocol management.

PMID: 26642907 [PubMed - indexed for MEDLINE]

Chronic liver injury induced by drugs: a systematic review.

Liver Int. 2015 Nov;35(11):2343-53

Authors: Stine JG, Chalasani N

Abstract
To examine the available literature and summarize what is known about chronic drug-induced liver injury. We reviewed PubMed/MEDLINE through March 2015. We developed a MEDLINE search strategy using PubMed medical subject heading terms chronic liver injury, hepatotoxicity, drug-induced liver injury, cirrhosis and chronic liver disease. We reviewed the reference list of included articles to identify articles missed in the database search. Chronic liver injury from drugs is more common than once thought with prevalence as high as 18% based on large national registries. Patients with cholestatic injury, age ≤65 years, and a long latency period (>365 days) are at increased risk. Of the most common drugs associated with drug-induced liver injury, antibiotics (amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, azithromycin) are most likely to cause chronic injury. The presence of autoantibodies is common with chronic DILI, however, it is not diagnostic nor is it specific to autoimmune-like drug-induced liver injury. Immunosuppressive therapy may be necessary for individual cases of autoimmune-like drug-induced liver injury where cessation of the drug alone does not result in resolution of injury, however, the lowest dose should be used for the shortest duration with careful attention to the development of side effects. The effectiveness of treament of cholestatic liver injury with corticosteroids or ursodiol remains unclear. Cases of drug-induced fatty liver, nodular regenerative hyperplasia and peliosis hepatitis are less common subtypes of chronic drug-induced liver injury that deserve special consideration. A high degree of clinical suspicion is required for the diagnosis of chronic drug-induced liver injury and should be suspected in any patient with liver associated enzyme abnormalities that persist out past 6 months of initial presentation. Treatment with drug removal and/or immunosuppressive therapy appears to be effective for the majority of cases. More study into pharmacogenomics and personalized medicine may aid in predicting which patients will go on to develop chronic drug-induced liver injury.

PMID: 26346512 [PubMed - indexed for MEDLINE]

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Rational selection of predictive pharmacogenomics test for the Fluoropyrimidine/Oxaliplatin based therapy.

Eur Rev Med Pharmacol Sci. 2015 Nov;19(22):4443-54

Authors: Di Francia R, De Lucia L, Di Paolo M, Di Martino S, Del Pup L, De Monaco A, Lleshi A, Berretta M

Abstract
OBJECTIVE: Both Fluoropyrimidine and Oxaliplatin (FluOx) are the most common anticancer drugs used to treat colorectal, ovarian, and gastrointestinal cancers. Nevertheless, the efficacy of FluOx-based therapy is often compromised by the severe risk of neurotoxicity, cardiotoxicity, and gastrointestinal toxicity. Stratification of patients for their individual response to drugs is a promising approach for cancer treatment and cost-effectiveness. Here we evaluate the most recent findings on the most appropriate gene variants related to the toxicity in patients receiving FluOx chemotherapy.
MATERIALS AND METHODS: A systematic literature search of the MEDLINE, EMBASE, and Cochrane databases was conducted to identify all clinical studies of any association between DPYD and 5-FU correlated to allelic status of 6 validated polymorphisms in five genes Dihydropyrimidine Dehydrogenase (DPYD), Thymidylate Synthase (TYMS), Glutathione S-Transferase (GSTP1), and DNA-repair genes (ERCC2 and XRCC1).
RESULTS: The stratification of the patients into three genotype profiles group, who are most likely responders to FluOx treatments, provide informations about toxicity and/or resistance before starting therapy. Also, early evaluation cost of panel testing proposed is averaged about €100,00 per sample. The evaluation costs of genotyping before starting treatment could be a good cost-effectiveness strategy.
CONCLUSIONS: Based on the individual genomic profile, the oncologists will have new possibilities, based on the individual genetic profile, to make treatment decisions for their patients and to redefine scheduling and dosage of FluOx-based therapy.

PMID: 26636535 [PubMed - indexed for MEDLINE]

Pharmacogenomics of platinum-based chemotherapy sensitivity in NSCLC: toward precision medicine.

Pharmacogenomics. 2016 Jul 27;

Authors: Yin JY, Li X, Zhou HH, Liu ZQ

Abstract
Lung cancer is one of the leading causes of cancer-related death in the world. Platinum-based chemotherapy is the first-line treatment for non-small-cell lung cancer (NSCLC), however, the therapeutic efficiency varies remarkably among individuals. A large number of pharmacogenomics studies aimed to identify genetic variations which can be used to predict platinum response. Those studies are leading NSCLC treatment to the new era of precision medicine. In the current review, we provided a comprehensive update on the main recent findings of genetic variations which can be used to predict platinum sensitivity in the NSCLC patients.

PMID: 27462924 [PubMed - as supplied by publisher]

Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome.

Pharmacogenomics J. 2016 Jul 26;

Authors: Hall KT, Kossowsky J, Oberlander TF, Kaptchuk TJ, Saul JP, Wyller VB, Fagermoen E, Sulheim D, Gjerstad J, Winger A, Mukamal KJ

Abstract
Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04). There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions.The Pharmacogenomics Journal advance online publication, 26 July 2016; doi:10.1038/tpj.2016.53.

PMID: 27457818 [PubMed - as supplied by publisher]

Promoter region variation in NFE2L2 influences susceptibility to ototoxicity in patients exposed to high cumulative doses of cisplatin.

Pharmacogenomics J. 2016 Jul 26;

Authors: Spracklen TF, Vorster AA, Ramma L, Dalvie S, Ramesar RS

Abstract
Ototoxicity is a disabling reaction to cisplatin chemotherapy. Much of the inter-individual variability in the development of hearing impairment among cisplatin-receiving patients has not been fully accounted for. In particular, little is known about the pharmacogenomics of cisplatin-induced ototoxicity. This study sought to investigate the role of variation in five candidate genes in a cohort of South African cancer patients. Five variants within the candidate genes were genotyped in 214 patients, of which SLC22A2 rs316019 and NFE2L2 rs6721961 associated with reduced rates of ototoxicity. In the patients who were exposed to cumulative cisplatin doses ⩾200 mg m(-)(2) (n=113), the variant rs6721961 associated with ototoxicity according to three different grading scales of hearing loss (ASHA, P=0.005; Chang, P=0.028; CTCAE, P=0.004). The NFE2L2 promotor variant rs6721961 may therefore be protective against hearing loss in cisplatin-receiving cancer patients.The Pharmacogenomics Journal advance online publication, 26 July 2016; doi:10.1038/tpj.2016.52.

PMID: 27457817 [PubMed - as supplied by publisher]

Ayurgenomics for stratified medicine: TRISUTRA consortium initiative across ethnically and geographically diverse Indian populations.

J Ethnopharmacol. 2016 Jul 22;

Authors: Prasher B, Varma B, Kumar A, Khuntia BK, Pandey R, Narang A, Tiwari P, Kutum R, Guin D, Kukreti R, Dash D, TRISUTRA Ayurgenomics Consortium, Mukerji M

Abstract
BACKGROUND: Genetic differences in the target proteins, metabolizing enzymes and transporters that contribute to inter-individual differences in drug response are not integrated in contemporary drug development programs. Ayurveda, that has propelled many drug discovery programs albeit for the search of new chemical entities incorporates inter-individual variability "Prakriti" in development and administration of drug in an individualized manner. Prakriti of an individual largely determines responsiveness to external environment including drugs as well as susceptibility to diseases. Prakriti has also been shown to have molecular and genomic correlates. We highlight how integration of Prakriti concepts can augment the efficiency of drug discovery and development programs through a unique initiative of Ayurgenomics TRISUTRA consortium.
METHODS: Five aspects that have been carried out are (1) analysis of variability in FDA approved pharmacogenomics genes/SNPs in exomes of 72 healthy individuals including predominant Prakriti types and matched controls from a North Indian Indo-European cohort (2) establishment of a consortium network and development of five genetically homogeneous cohorts from diverse ethnic and geo-climatic background (3) identification of parameters and development of uniform standard protocols for objective assessment of Prakriti types (4) development of protocols for Prakriti evaluation and its application in more than 7500 individuals in the five cohorts (5) Development of data and sample repository and integrative omics pipelines for identification of genomic correlates.
RESULTS: Highlight of the study are (1) Exome sequencing revealed significant differences between Prakriti types in 28 SNPs of 11 FDA approved genes of pharmacogenomics relevance viz CYP2C19 CYP2B6, ESR1, F2, PGR, HLA-B, HLA-DQA1, HLA-DRB1, LDLR, CFTR, CPS1. These variations are polymorphic in diverse Indian and world populations included in 1000 genomes project. (2) Based on the phenotypic attributes of Prakriti we identified anthropometry for anatomical features, biophysical parameters for skin types, HRV for autonomic function tests, spirometry for vital capacity and gustometry for taste thresholds as objective parameters. (3) Comparison of Prakriti phenotypes across different ethnic, age and gender groups led to identification of invariant features as well as some that require weighted considerations across the cohorts.
CONCLUSION: Considering the molecular and genomics differences underlying Prakriti and relevance in disease pharmacogenomics studies, this novel integrative platform would help in identification of differently susceptible and drug responsive population. Additionally, integrated analysis of phenomic and genomic variations would not only allow identification of clinical and genomic markers of Prakriti for application in personalized medicine but also its integration in drug discovery and development programs.

PMID: 27457695 [PubMed - as supplied by publisher]

Personalized Therapy of Hypertension: the Past and the Future.

Curr Hypertens Rep. 2016 Mar;18(3):24

Authors: Manunta P, Ferrandi M, Cusi D, Ferrari P, Staessen J, Bianchi G

Abstract
During the past 20 years, the studies on genetics or pharmacogenomics of primary hypertension provided interesting results supporting the role of genetics, but no actionable finding ready to be translated into personalized medicine. Two types of approaches have been applied: a "hypothesis-driven" approach on the candidate genes, coding for proteins involved in the biochemical machinery underlying the regulation of BP, and an "unbiased hypothesis-free" approach with GWAS, based on the randomness principles of frequentist statistics. During the past 10-15 years, the application of the latter has overtaken the application of the former leading to an enlargement of the number of previously unknown candidate loci or genes but without any actionable result for the therapy of hypertension. In the present review, we summarize the results of our hypothesis-driven approach based on studies carried out in rats with genetic hypertension and in humans with essential hypertension at the pre-hypertensive and early hypertensive stages. These studies led to the identification of mutant adducin and endogenous ouabain as candidate genetic-molecular mechanisms in both species. Rostafuroxin has been developed for its ability to selectively correct Na(+) pump abnormalities sustained by the two abovementioned mechanisms and to selectively reduce BP in rats and in humans carrying the gene variants underlying the mutant adducin and endogenous ouabain (EO) effects. A clinical trial is ongoing to substantiate these findings. Future studies should apply both the candidate gene and GWAS approaches to fully exploit the potential of genetics in optimizing the personalized therapy.

PMID: 26915067 [PubMed - indexed for MEDLINE]

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial.

Diabetologia. 2015 Nov;58(11):2494-502

Authors: Christensen MM, Højlund K, Hother-Nielsen O, Stage TB, Damkier P, Beck-Nielsen H, Brøsen K

Abstract
AIMS/HYPOTHESIS: Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production. Recent data indicate that metformin antagonises glucagon-dependent glucose output, suggesting that compensatory mechanisms protect against hypoglycaemia. Here, we examined the effect of metformin on glucose metabolism in humans after a glycogen-depleting fast and the role of reduced-function alleles in OCT1 (also known as SLC22A1).
METHODS: In a randomised, crossover trial, healthy individuals with or without reduced-function alleles in OCT1 were fasted for 42 h twice, either with or without prior treatment with 1 g metformin twice daily. Participants were recruited from the Pharmacogenomics Biobank of the University of Southern Denmark. Treatment allocation was generated by the Good Clinical Practice Unit, Odense University Hospital, Denmark. Variables of whole-body glucose metabolism were assessed using [3-(3)H]glucose, indirect calorimetry and measurement of substrates and counter-regulatory hormones. The primary outcome was endogenous glucose production (EGP).
RESULTS: Thirty-seven individuals were randomised. Thirty-four completed the study (12 had none, 13 had one and nine had two reduced-function alleles in OCT1). Three were excluded from the analysis because of early dropout. Metformin significantly stimulated glucose disposal rates and non-oxidative glucose metabolism with no effect on glucose oxidation. This increase in glucose utilisation was explained by a concomitant increase in glycolytic flux and accompanied by increased EGP, most likely mediated by increased plasma lactate, glucagon and cortisol levels. There was no effect of reduced-function OCT1 alleles on any of these measures. All individuals completed the glycogen-depleting fast without hypoglycaemia.
CONCLUSIONS/INTERPRETATION: Metformin stimulates glycolytic glucose utilisation and lactate production in the glycogen-depleted state. This may trigger a rise in glucose counter-regulatory hormones and subsequently an increase in EGP, which protects against hypoglycaemia.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01400191 FUNDING: Danish Research Council for Health and Disease (0602-02695B) and Odense University Hospital Free Research Fund, 2012.

PMID: 26271344 [PubMed - indexed for MEDLINE]

Complete haplotype phasing of the MHC and KIR loci with targeted HaploSeq.

BMC Genomics. 2015;16:900

Authors: Selvaraj S, Schmitt AD, Dixon JR, Ren B

Abstract
BACKGROUND: The MHC and KIR loci are clinically relevant regions of the genome. Typing the sequence of these loci has a wide range of applications including organ transplantation, drug discovery, pharmacogenomics and furthering fundamental research in immune genetics. Rapid advances in biochemical and next-generation sequencing (NGS) technologies have enabled several strategies for precise genotyping and phasing of candidate HLA alleles. Nonetheless, as typing of candidate HLA alleles alone reveals limited aspects of the genetics of MHC region, it is insufficient for the comprehensive utility of the aforementioned applications. For this reason, we believe phasing the entire MHC and KIR locus onto a single locus-spanning haplotype can be a critical improvement for better understanding transplantation biology.
RESULTS: Generating long-range (>1 Mb) phase information is traditionally very challenging. As proximity-ligation based methods of DNA sequencing preserves chromosome-span phase information, we have utilized this principle to demonstrate its utility towards generating full-length phasing of MHC and KIR loci in human samples. We accurately (~99%) reconstruct the complete haplotypes for over 90% of sequence variants (coding and non-coding) within these two loci that collectively span 4-megabases.
CONCLUSIONS: By haplotyping a majority of coding and non-coding alleles at the MHC and KIR loci in a single assay, this method has the potential to assist transplantation matching and facilitate investigation of the genetic basis of human immunity and disease.

PMID: 26541200 [PubMed - indexed for MEDLINE]

Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia.

Int J Mol Sci. 2015;16(9):22811-29

Authors: Polillo M, Galimberti S, Baratè C, Petrini M, Danesi R, Di Paolo A

Abstract
Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics and pharmacodynamics of BCR-ABL1 tyrosine kinase activity inhibitors (TKIs). Transmembrane transporters seem to influence in a significant manner the disposition of TKIs, especially that of imatinib at both cellular and systemic levels. In particular, members of the ATP-binding cassette (ABC) family (namely ABCB1 and ABCG2) together with solute carrier (SLC) transporters (i.e., SLC22A1) are responsible for the differences in drug pharmacokinetics. In the case of the newer TKIs, such as nilotinib and dasatinib, the substrate affinity of these drugs for transporters is variable but lower than that measured for imatinib. In this scenario, the investigation of genetic variants as possible predictive markers has led to some discordant results. With the partial exception of imatinib, these discrepancies seem to limit the application of discovered biomarkers in the clinical settings. In order to overcome these issues, larger prospective confirmative trials are needed.

PMID: 26402671 [PubMed - indexed for MEDLINE]

[HORMONALLY-GENETICALLY DEPENDENT THERAPY, USING VITAMIN K IN PATIENTS, SUFFERING THE ULCER HEMORRHAGE].

Klin Khir. 2016 Apr;(4):9-11

Authors: Duzhyi ID, Kharchenko SV

Abstract
Pathophysiological mechanisms of the vitamin K impact, including those in the gut with ulcerative affection, are studied still insufficiently. Investigations of pharmacogenomics of the vitamin K gives a new approach to therapy in patients, suffering gastro-intestinal hemorrhage. Possibilities of titration of the vitamin K3 (menadione) doses, depending on level of estrogenemia and genetic constitution, concerning genes-candidates ESR1 (rs2234693) and VKORC1 (rs9923231), were studied. There were examined 36 patients, who were treated for the ulcer hemorrhage. The blood serum concentration of estradiol was investigated in accordance to method of solid phase enzyme immunoassay, the genotyping procedure was performed in accordance to indices of polymerase chain reaction with analysis of the restrictional fragments length. The initial daily dose of menadione have constituted 20 mg. After a genotype determination made (first-second day after admittance to hospital) in patients with normoestrogenemia in genotypes CC/GG, CC/GA, CT/GG, CT/GA a vitaminotherapy was prolonged in daily dose of 20 mg, and in a conditionally-pathological variant of genotype the dose of vitamin K was enhanced up to 30 mg. Determination of hormones and the patients' genetic constitution makes possible to apply a personified approach for the vitamin K3 application in the ulcerative hemorrhage.

PMID: 27434945 [PubMed - in process]

CYP2C19 Genotype-Dependent Pharmacokinetic Drug Interaction Between Voriconazole and Ritonavir-Boosted Atazanavir in Healthy Subjects.

J Clin Pharmacol. 2016 Jul 19;

Authors: Zhu L, Brüggemann RJ, Uy J, Colbers A, Hruska MW, Chung E, Sims K, Vakkalagadda B, Xu X, van Schaik RH, Burger DM, Bertz RJ

Abstract
Voriconazole, a broad-spectrum triazole antifungal agent, is metabolized by cytochrome P450 (CYP) 2C19 and to a lesser extent by CYP3A. Genetic polymorphism of CYP2C19 not only plays a prominent role in its disposition but may also influence potential drug interactions with CYP450 modulators such as ritonavir. This study assessed 2-way drug interactions of voriconazole added-on to ritonavir-boosted atazanavir in both CYP2C19 extensive metabolizer (EM) and poor metabolizer (PM) healthy subjects. Each subject received voriconazole alone on days 1-3 followed by a 7-day washout. Atazanavir/ritonavir 300/100 mg once daily was given on days 11-30 and voriconazole on days 21-30. Voriconazole doses were 200 mg (400 mg on days 1 and 21) twice daily and 50 mg (100 mg on days 1 and 21) twice daily for CYP2C19 EM and PM subjects, respectively. Upon coadministration, voriconazole AUC and Cmin decreased by 33% (90% CI = 22-42%) and 39% (90% CI = 28-49%), respectively, in CYP2C19 EMs, whereas voriconazole Cmax and AUC increased 4.4- (90% CI = 3.6-5.4) and 5.6-fold (90% CI = 4.5-7.0), respectively, in PMs. Adding voriconazole resulted in a 20-30% decrease in atazanavir Cmin in both EMs and PMs. Ritonavir exposures were generally unchanged in either population. The safety and tolerability profiles of the combination were comparable with atazanavir/ritonavir and voriconazole administered alone. The most frequent adverse events with voriconazole were visual disturbance and headache. Coadministration of voriconazole and atazanavir/ritonavir is not recommended unless the benefit/risk to the patient justifies the use of the combination. This article is protected by copyright. All rights reserved.

PMID: 27432796 [PubMed - as supplied by publisher]

Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs.

Pharmacogenomics J. 2016 Jul 19;

Authors: Daniels MA, Kan C, Willmes DM, Ismail K, Pistrosch F, Hopkins D, Mingrone G, Bornstein SR, Birkenfeld AL

Abstract
Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.The Pharmacogenomics Journal advance online publication, 19 July 2016; doi:10.1038/tpj.2016.54.

PMID: 27432533 [PubMed - as supplied by publisher]

Genomics era and complex disorders: Implications of GWAS with special reference to coronary artery disease, type 2 diabetes mellitus, and cancers.

J Postgrad Med. 2016 Jul-Sep;62(3):188-98

Authors: Pranavchand R, Reddy MM

Abstract
The Human Genome Project (HGP) has identified millions of single nucleotide polymorphisms (SNPs) and their association with several diseases, apart from successfully characterizing the Mendelian/monogenic diseases. However, the dissection of precise etiology of complex genetic disorders still poses a challenge for human geneticists. This review outlines the landmark results of genome-wide association studies (GWAS) with respect to major complex diseases - Coronary artery disease (CAD), type 2 diabetes mellitus (T2DM), and predominant cancers. A brief account on the current Indian scenario is also given. All the relevant publications till mid-2015 were accessed through web databases such as PubMed and Google. Several databases providing genetic information related to these diseases were tabulated and in particular, the list of the most significant SNPs identified through GWAS was made, which may be useful for designing studies in functional validation. Post-GWAS implications and emerging concepts such as epigenomics and pharmacogenomics were also discussed.

PMID: 27424552 [PubMed - in process]

The Outlier in All of Us: Why Implementing Pharmacogenomics Could Matter for Everyone.

Clin Pharmacol Ther. 2016 Apr;99(4):401-4

Authors: O'Donnell PH, Danahey K, Ratain MJ

Abstract
The field of pharmacogenomics originally emerged in the 1950s from observations that a few rare individuals had unexpected, severe reactions to drugs. As recently as just 6 years ago, prominent views on the subject had largely remained unchanged, with authors from the US Food and Drug Administration (FDA) citing the purpose of pharmacogenetics as "tailoring treatment for the outliers." It should not be surprising if this is the prevailing view--the best-studied pharmacogenomic drug examples are indeed just that, genetic explanations of extreme responses or susceptibilities among usually a very small fraction of the human population. Thiopurine methyltransferase (TPMT) deficiency as a cause of severe myelosuppression upon treatment with azathioprine or mercaptopurine is found as a heterozygous trait in only ∼ 10% of patients, and homozygous (deficiency) carriers are even more rare--occurring in fewer than 1 in 300 patients. Malignant hyperthermia resulting from inhaled anesthetics and succinylcholine is believed to have a genetic incidence of only about 1 in 2000 people.

PMID: 26756170 [PubMed - indexed for MEDLINE]

Rapid and ultra-rapid metabolizers with CYP2C19*17 polymorphism do not respond to standard therapy with proton pump inhibitors.

Meta Gene. 2016 Sep;9:159-64

Authors: Deshpande N, V S, V V RK, H V V M, M S, Banerjee R, Tandan M, D NR

Abstract
INTRODUCTION AND OBJECTIVE: Polymorphisms in genes encoding drug metabolizing enzymes may lead to varied enzyme activity and inter-individual variability in drug efficacy and/or toxicity. Since CYP2C19 and CYP3A4 genes code for enzymes involved in metabolizing wide variety of drugs including proton pump inhibitors, we sought to identify polymorphisms in these genes in order to study their impact on drug metabolism in subjects.
METHODS: DNA was isolated from healthy individuals including tribals and genotyped for 11 single nucleotide polymorphisms in CYP2C19 and 6 polymorphisms in CYP3A4. Individuals were categorized into different phenotypes based on their drug metabolizing genotype. Volunteers from each group were administered proton pump inhibitors (Esomeprazole, Pantoprazole; 40 mg/day) for 5 days followed by pharmacokinetic studies and measurement of intra-gastric pH.
RESULTS: Of the 17 polymorphisms studied, only CYP2C19*2,*3,*17 and CYP3A4*1B polymorphisms were observed. In comparison to urban individuals, a significantly (p = 0.0003) higher number of poor metabolizers were noted in the tribal individuals. Pantoprazole was found to be most effective in poor metabolizers in terms of area under the curve and Tmax. No significant difference was observed in the intra-gastric pH at baseline and day 6 in rapid and ultra-rapid metabolizers.
CONCLUSION: Our study has demonstrated that 19.7% of our subjects are carriers of the CYP2C19*17 allele who did not respond to the standard dose of proton pump inhibitors. Genetic screening to identify subjects with variant alleles would thus be useful for personalization of therapy with proton pump inhibitors.

PMID: 27419077 [PubMed]