Abstract:
OBJECTIVE:To assess the impact of CYP2C9 variation on phenytoin patient response and clinician prescribing practice where genotype was unknown during treatment. METHODS:A retrospective analysis of Resource on Genetic Epidemiology Research on Adult Health and Aging cohort participants who filled a phenytoin prescription between 1996 and 2017. We used laboratory test results, medication dispensing records, and medical notes to identify associations of CYP2C9 genotype with phenytoin blood concentration, neurologic side effects, and medication dispensing patterns reflecting clinician prescribing practice and patient response. RESULTS:Among 993 participants, we identified 69% extensive, 20% high-intermediate, 10% low-intermediate, and 2% poor metabolizers based on CYP2C9 genotypes. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype was associated with increased dose-adjusted phenytoin blood concentration [21.3 pg/mL, 95% confidence interval (CI): 13.6-29.0 pg/mL; P < 0.01] and increased risk of neurologic side effects (hazard ratio: 2.40, 95% CI: 1.24-4.64; P < 0.01). Decreased function CYP2C9 genotypes were associated with medication dispensing patterns indicating dose decrease, use of alternative anticonvulsants, and worse adherence, although these associations varied by treatment indication for phenytoin. CONCLUSION:CYP2C9 variation was associated with clinically meaningful differences in clinician prescribing practice and patient response, with potential implications for healthcare utilization and treatment efficacy.
journal_name
Pharmacogenet Genomicsjournal_title
Pharmacogenetics and genomicsauthors
Fohner AE,Ranatunga DK,Thai KK,Lawson BL,Risch N,Oni-Orisan A,Jelalian AT,Rettie AE,Liu VX,Schaefer CAdoi
10.1097/FPC.0000000000000383subject
Has Abstractpub_date
2019-10-01 00:00:00pages
192-199issue
8eissn
1744-6872issn
1744-6880pii
01213011-201910000-00002journal_volume
29pub_type
杂志文章abstract:OBJECTIVE:Nicotine, the main addictive ingredient in tobacco, is metabolically inactivated to cotinine primarily by the hepatic enzyme CYP2A6. Considerable genetic variation in the CYP2A6 gene results in large variation in the rates of nicotine metabolism, which in turn alters smoking behaviours (e.g. amount of cigaret...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000026
更新日期:2014-02-01 00:00:00
abstract::Endocrine disrupters, such as persistent organohalogen pollutants (POPs) may cause hypospadias, which is a common congenital anomaly in males, affecting 0.2-0.7%. We hypothesized that hypospadias incidence would be high among Greenlanders, who are one of the most POP exposed populations on earth through consumption of...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01.fpc.0000199497.01101.93
更新日期:2006-05-01 00:00:00
abstract:OBJECTIVES:We tested the effect of kidney-specific multidrug resistance-related protein (MRP2, ABCC2) deficiency on renal organic solute disposition as well as on renal protein and gene expression. Furthermore, we investigated whether a particular kidney donor ABCC2 genotype is associated with delayed graft function in...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e328328d4e9
更新日期:2009-04-01 00:00:00
abstract:OBJECTIVE:To examine the hypothesis that genetic variation in enzymes and transporters associated with synthesis, storage, release, and metabolism of catecholamines contributes to the interindividual variability in plasma catecholamine concentrations at rest and after exercise. METHODS:We measured plasma norepinephrin...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e328350a274
更新日期:2012-04-01 00:00:00
abstract::Aberrations in ubiquitin pathway have been implicated in many diseases and drug response. In a previous study on rheumatoid arthritis (RA) in Japanese population, significant association of Cullin1 gene (CUL1), an ubiquitin E3 ligase, was observed. CUL1 also mediates degradation of IκBα and p27, levels of which has be...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e3283492af7
更新日期:2011-09-01 00:00:00
abstract:OBJECTIVE:Clinical response to topiramate can vary greatly in obese patients. Identifying genetic variants associated with treatment response could help gain insight into the mechanism of action of topiramate. Little is known about the relationship between genetic variability and topiramate treatment response. We perfo...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000185
更新日期:2016-02-01 00:00:00
abstract:OBJECTIVE:Compared with genetic factors, drug interactions are largely unexplored in pharmacogenetic studies. This study sought to systematically investigate the effects of VKORC1, STX4A, CYP2C9, CYP4F2, CYP3A4, and GGCX gene polymorphisms and interacting drugs on warfarin maintenance dose. METHODS:A retrospective stu...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32834f45f9
更新日期:2012-03-01 00:00:00
abstract:OBJECTIVES:Controversy exists regarding the effects of polymorphisms in the endothelial nitric oxide synthase (eNOS) gene on nitrites/nitrates (NOx) plasma concentrations. In this study we compared the distribution of haplotypes involving three relevant eNOS polymorphisms (T-786C in the promoter region; b/a in intron 4...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01.fpc.0000167328.85163.44
更新日期:2005-08-01 00:00:00
abstract:OBJECTIVES:Nine different functional UGT1A enzymes are generated from a single UGT1A gene by alternative splicing, with each enzyme having a unique exon 1. SN-38, the active metabolite of the anticancer agent irinotecan, is metabolized by both UGT1A1 and UGT1A9. We aim to characterize the UGT1A9-UGT1A1 haplotypes in As...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01213011-200505000-00004
更新日期:2005-05-01 00:00:00
abstract:OBJECTIVES:It has been shown that acetaldehyde is an active metabolite of ethanol with central actions that modulate behavior. Catalase has been proposed as the main enzyme responsible for the synthesis of acetaldehyde from ethanol in the brain. Recent studies, however, suggest that cytochrome, in particular the isofor...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e328324e726
更新日期:2009-03-01 00:00:00
abstract:OBJECTIVE:The aim of this study was to investigate whether there is a genotype-by-treatment interaction in patients experiencing stroke and treated with one of three antihypertensive drugs, that is chlorthalidone, amlodipine, or lisinopril. PARTICIPANTS AND METHODS:A population of 436 African Americans and 539 whites ...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000088
更新日期:2014-11-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000020
更新日期:2014-01-01 00:00:00
abstract:OBJECTIVE:Exemestane is a third-generation aromatase inhibitor used in the treatment of breast cancer in postmenopausal women. Reduction to form 17-dihydroexemestane and subsequent glucuronidation to exemestane-17-O-glucuronide is a major pathway for exemestane metabolism. The goal of this study was to analyze 17-dihyd...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32833b04af
更新日期:2010-10-01 00:00:00
abstract:OBJECTIVE:To determine whether polymorphisms in the sulfonamide detoxification genes, CYB5A (encoding cytochrome b(5)), CYB5R3 (encoding cytochrome b(5) reductase), or NAT2 (encoding N-acetyltransferase 2) were over-represented in patients with delayed sulfonamide drug hypersensitivity, compared with control patients w...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e328357a735
更新日期:2012-10-01 00:00:00
abstract:BACKGROUND:The mammalian target of rapamycin (m-TOR) inhibitor sirolimus is an immunosuppressive drug used in kidney transplantation. m-TOR binds with Raptor and phosphorylates p70S6 kinase, a protein involved in numerous cell signalling pathways. We examined the association of candidate polymorphisms in m-TOR, Raptor ...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1097/FPC.0b013e328357359d
更新日期:2012-10-01 00:00:00
abstract::Vitamin D has potent anti-tumour properties. Calcitriol [1,25(OH)2D3], the hormonal derivative of vitamin D3, is an antiproliferative and prodifferentiation factor for several cell types, including human squamous cells of the head and neck. Several polymorphisms of the vitamin D receptor (VDR) gene have been described...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01213011-200503000-00004
更新日期:2005-03-01 00:00:00
abstract:OBJECTIVE:The immunosuppressive drug tacrolimus requires strict therapeutic monitoring due to its narrow therapeutic index and great inter-individual variability. Cytochrome P450 3A4 (Cyp3A4) and Cyp3A5 are the most important contributors to tacrolimus metabolism while the P-glycoprotein pump (MDR-1) modulates its bioa...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01.fpc.0000220571.20961.dd
更新日期:2006-09-01 00:00:00
abstract:OBJECTIVE:We investigated whether the UGT1A3 polymorphisms play an important role in interindividual variations in atorvastatin lactonization and lipid-lowering effect. METHODS:Twenty-three healthy volunteers were administered atorvastatin 20 mg once daily for 14 days. Serum levels of lipids were measured before and 7...
journal_title:Pharmacogenetics and genomics
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doi:10.1097/FPC.0b013e3283544085
更新日期:2012-08-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000129
更新日期:2015-05-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000186
更新日期:2016-02-01 00:00:00
abstract:OBJECTIVE:Maldescended testes are the most common genital anomaly in newborns and are associated with testicular malignancy and infertility. As the inguinoscrotal phase of testis descent is androgen-dependent and requires integrity of the luteinizing hormone/chorionic gonadotropin receptor (LHCGR), we investigated whet...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e3282f4e98c
更新日期:2008-03-01 00:00:00
abstract:OBJECTIVE:The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single n...
journal_title:Pharmacogenetics and genomics
pub_type: 临床试验,杂志文章
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更新日期:2006-11-01 00:00:00
abstract:OBJECTIVE:Recently, the minor allele of the rs13064411A>G polymorphism in the WD repeat domain 52 (WDR52) gene was associated with increased statin-induced proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and with LDL cholesterol response to statins. PCSK9 promotes LDL receptor degradation, leading to incre...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000120
更新日期:2015-03-01 00:00:00
abstract:OBJECTIVE:To describe the usage patterns of antidepressants with published CYP2D6- and CYP2C19-based prescribing guidelines among depressed primary care patients and estimate the proportion of patients taking antidepressants not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer statu...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000406
更新日期:2020-09-01 00:00:00
abstract:INTRODUCTION:Elevated plasma homocysteine (Hcy) concentration is an independent risk factor for cardiovascular disease, and its involvement in endothelial cell dysfunction is well established. However, the role of Hcy and folate in the pathogenesis of Parkinson's disease (PD) remains controversial. OBJECTIVES:The stud...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32835693f7
更新日期:2012-10-01 00:00:00
abstract:OBJECTIVES:Body weight regulation is under complex control involving the central nervous system and peripheral pathways. The beta-adrenoceptor Galphas protein system plays an important role in heart rate regulation and lipid mobilization suggesting a key role for the stimulatory G protein Galphas in body weight regulat...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,随机对照试验
doi:10.1097/FPC.0b013e3282f49964
更新日期:2008-02-01 00:00:00
abstract::In humans, UDP-glucuronosyltransferase 1A9 is known to glucuronidate numerous lipophilic substances of pharmacological and toxicological importance. Although it has been established that individuals vary in their capacity to express this detoxification enzyme, little is known about the mechanisms that dictate the regu...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32801112b5
更新日期:2007-01-01 00:00:00
abstract::We recently showed an association between the FCGR3A V/F polymorphism and the biological response [assessed on the basis of a C-reactive protein (CRP) concentration decrease] to infliximab in Crohn's disease. The CRP and FCGR3A genes are located on the same 1q23 locus. The present study aimed: (i) to exclude a linkage...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/01.fpc.0000182776.57437.d8
更新日期:2006-01-01 00:00:00
abstract:OBJECTIVES:The development of targeted drugs would greatly benefit from the simultaneous identification of biomarkers to determine the aspects of bioactivity, drug safety and efficacy, particularly when affecting receptor-signaling pathways. However, the establishment of appropriate systems to monitor drug-induced even...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e328335731c
更新日期:2010-03-01 00:00:00
abstract:OBJECTIVES:Numerous functional polymorphisms in the CYP2C19 gene have been identified; some alleles (e.g. CYP2C19*2 and CYP2C19*3) are associated with poor metabolism of CYP2C19 substrate drugs. Studies have found that the proportion of poor metabolizers, explained by CYP2C19*2 and CYP2C19*3, varies from less than 50% ...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32801152c2
更新日期:2007-02-01 00:00:00