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Correction to: PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors 更正为血管内皮生长因子通路抑制剂诱发高血压的 PIK3R5 遗传预测因素
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-12-21 DOI: 10.1038/s41397-021-00264-2
Julia C. F. Quintanilha, Alessandro Racioppi, Jin Wang, Amy S. Etheridge, Stefanie Denning, Carol E. Peña, Andrew D. Skol, Daniel J. Crona, Danyu Lin, Federico Innocenti
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引用次数: 0
Pharmacogenomic analysis of a genetically distinct Indigenous population 对基因独特的土著人群进行药物基因组学分析
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-11-25 DOI: 10.1038/s41397-021-00262-4
Arvind Jaya Shankar, Sudhir Jadhao, Wendy Hoy, Simon J. Foote, Hardip R. Patel, Vinod Scaria, Brendan J. McMorran, Shivashankar H. Nagaraj
Indigenous Australians face a disproportionately severe burden of chronic disease relative to other Australians, with elevated rates of morbidity and mortality. While genomics technologies are slowly gaining momentum in personalised treatments for many, a lack of pharmacogenomic research in Indigenous peoples could delay adoption. Appropriately implementing pharmacogenomics in clinical care necessitates an understanding of the frequencies of pharmacologically relevant genetic variants within Indigenous populations. We analysed whole-genome sequence data from 187 individuals from the Tiwi Islands and characterised the pharmacogenomic landscape of this population. Specifically, we compared variant profiles and allelic distributions of previously described pharmacologically significant genes and variants with other population groups. We identified 22 translationally relevant pharmacogenomic variants and 18 clinically actionable guidelines with implications for drug dosing and treatment of conditions including heart disease, diabetes and cancer. We specifically observed increased poor and intermediate metabolizer phenotypes in the CYP2C9 (PM:19%, IM:44%) and CYP2C19 (PM:18%, IM:44%) genes.
与其他澳大利亚人相比,澳大利亚原住民面临着不成比例的严重慢性疾病负担,发病率和死亡率都很高。虽然基因组学技术在为许多人提供个性化治疗方面的发展势头缓慢,但缺乏针对土著居民的药物基因组学研究可能会延误该技术的应用。要在临床治疗中适当实施药物基因组学,就必须了解土著居民中与药物相关的基因变异的频率。我们分析了来自蒂维群岛(Tiwi Islands)187 人的全基因组序列数据,并描述了这一人群的药物基因组学特征。具体来说,我们将以前描述过的具有药理学意义的基因和变体的变异情况和等位基因分布与其他人群进行了比较。我们发现了 22 个具有转化意义的药物基因组变异和 18 个具有临床可操作性的指南,这些指南对药物剂量以及心脏病、糖尿病和癌症等疾病的治疗具有重要意义。我们特别观察到 CYP2C9(PM:19%,IM:44%)和 CYP2C19(PM:18%,IM:44%)基因中不良和中间代谢表型的增加。
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引用次数: 4
PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors 血管内皮生长因子通路抑制剂诱发高血压的 PIK3R5 遗传预测因子
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-11-13 DOI: 10.1038/s41397-021-00261-5
Julia C. F. Quintanilha, Alessandro Racioppi, Jin Wang, Amy S. Etheridge, Stefanie Denning, Carol E. Peña, Andrew D. Skol, Daniel J. Crona, Danyu Lin, Federico Innocenti
No biomarkers are available to predict patients at risk of developing hypertension induced by VEGF-pathway inhibitors. This study aimed to identify predictive biomarkers of hypertension induced by these drugs using a discovery-replication approach. The discovery set included 140 sorafenib-treated patients (TARGET study) genotyped for 973 SNPs in 56 genes. The most statistically significant SNPs associated with grade ≥2 hypertension were tested for association with grade ≥2 hypertension in the replication set of a GWAS of 1039 bevacizumab-treated patients from four clinical trials (CALGB/Alliance). In the discovery set, rs444904 (G > A) in PIK3R5 was associated with an increased risk of sorafenib-induced hypertension (p = 0.006, OR = 3.88 95% CI 1.54–9.81). In the replication set, rs427554 (G > A) in PIK3R5 (in complete linkage disequilibrium with rs444904) was associated with an increased risk of bevacizumab-induced hypertension (p = 0.008, OR = 1.39, 95% CI 1.09–1.78). This study identified a predictive marker of drug-induced hypertension that should be evaluated for other VEGF-pathway inhibitors. ClinicalTrials.gov Identifier:NCT00073307 (TARGET).
目前还没有生物标志物来预测血管内皮生长因子途径抑制剂诱发高血压的风险。本研究采用发现-复制的方法,旨在确定这些药物诱发高血压的预测性生物标志物。发现集包括 140 例索拉非尼治疗患者(TARGET 研究),对 56 个基因中的 973 个 SNP 进行了基因分型。在对来自四项临床试验(CALGB/Alliance)的 1039 名贝伐珠单抗治疗患者进行的 GWAS 复制集中,检测了与≥2 级高血压相关的最具统计学意义的 SNPs。在发现集中,PIK3R5中的rs444904(G >A)与索拉非尼诱发的高血压风险增加有关(p = 0.006,OR = 3.88 95% CI 1.54-9.81)。在复制集中,PIK3R5中的rs427554(G >A)(与rs444904完全连锁不平衡)与贝伐珠单抗诱发高血压的风险增加有关(p = 0.008,OR = 1.39,95% CI 1.09-1.78)。这项研究发现了药物诱发高血压的预测标志物,应该对其他血管内皮生长因子途径抑制剂进行评估。ClinicalTrials.gov Identifier:NCT00073307 (TARGET)。
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引用次数: 2
Application of long-read sequencing to elucidate complex pharmacogenomic regions: a proof of principle 应用长序列测序阐明复杂的药物基因组区域:原理验证
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-11-05 DOI: 10.1038/s41397-021-00259-z
Maaike van der Lee, William J. Rowell, Roberta Menafra, Henk-Jan Guchelaar, Jesse J. Swen, Seyed Yahya Anvar
The use of pharmacogenomics in clinical practice is becoming standard of care. However, due to the complex genetic makeup of pharmacogenes, not all genetic variation is currently accounted for. Here, we show the utility of long-read sequencing to resolve complex pharmacogenes by analyzing a well-characterised sample. This data consists of long reads that were processed to resolve phased haploblocks. 73% of pharmacogenes were fully covered in one phased haploblock, including 9/15 genes that are 100% complex. Variant calling accuracy in the pharmacogenes was high, with 99.8% recall and 100% precision for SNVs and 98.7% precision and 98.0% recall for Indels. For the majority of gene-drug interactions in the DPWG and CPIC guidelines, the associated genes could be fully resolved (62% and 63% respectively). Together, these findings suggest that long-read sequencing data offers promising opportunities in elucidating complex pharmacogenes and haplotype phasing while maintaining accurate variant calling.
药物基因组学在临床实践中的应用正逐渐成为护理标准。然而,由于药物基因的遗传结构复杂,目前并没有考虑到所有的遗传变异。在这里,我们通过分析一个特征良好的样本,展示了长读数测序在解析复杂药物基因方面的效用。该数据由长读数组成,经过处理后可解析相位单倍群。73%的药物基因被完全覆盖在一个阶段性单倍区块中,包括9/15个100%复杂的基因。药物基因的变异调用准确率很高,SNV 的召回率为 99.8%,准确率为 100%;Indels 的准确率为 98.7%,召回率为 98.0%。对于 DPWG 和 CPIC 指南中的大多数基因-药物相互作用,相关基因可以完全解析(分别为 62% 和 63%)。这些发现共同表明,长读程测序数据为阐明复杂的药物基因和单体型分期提供了大有可为的机会,同时还能保持变异调用的准确性。
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引用次数: 9
Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation 候选 DNA 修复基因变异与接受异体造血干细胞移植的儿科患者急性移植物抗宿主疾病的关联研究
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-10-28 DOI: 10.1038/s41397-021-00251-7
C. R. S. Uppugunduri, P. Huezo-Diaz Curtis, T. Nava, M. A. Rezgui, V. Mlakar, S. Jurkovic Mlakar, N. Waespe, Y. Théoret, F. Gumy-Pause, F. Bernard, Y. Chalandon, J. J. Boelens, R. G. M. Bredius, J. H. Dalle, C. Nath, S. Corbacioglu, C. Peters, P. Bader, P. Shaw, H. Bittencourt, M. Krajinovic, M. Ansari
Acute Graft versus Host Disease (aGvHD) grades 2–4 occurs in 15–60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2–4 in 60 pediatric patients. The cumulative incidence of aGvHD 2–4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2–4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3–191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2–4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06–3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.
在接受异基因造血干细胞移植(allo-HSCT)的儿童患者中,15%-60%会出现2-4级急性移植物抗宿主疾病(acute Graft versus Host Disease,aGvHD)。异体造血干细胞移植前的调理方案对正常组织造成的附带损伤是诱发GvHD的最初诱因。DNA 修复机制可能在减轻这种初始损伤中发挥重要作用,因此相应的 DNA 修复蛋白编码基因中的变异会影响其数量和/或功能。我们研究了 60 名儿科患者中 17 个 DNA 修复基因中的 51 个变异与 2-4 级 aGvHD 的关系。在探索性队列中,aGvHD 2-4 级的累积发病率为 12%(n = 7)。MGMT rs10764881(G>A)和EXO rs9350(c.2270C>T)变异与aGvHD 2-4级相关[比值比分别为14.8(rs10764881 GG组40例中0例)和11.5(95% CI:2.3-191.8),多重检验校正后p≤0.001]。在一个扩展队列(n = 182)中,aGvHD 2-4 的发生率为 22%(n = 40),在存在其他临床风险因素的情况下,只有 MGMT rs10764881 (G>A) 仍具有显著性(调整 HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03)。在rs10764881的GG携带者中,MGMT表达较高,这与布舒芬在淋巴母细胞中的IC50较高有关。MGMT rs10764881携带者状态可预测接受allo-HSCT的儿科患者发生GvHD的风险。
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引用次数: 1
Nine-gene pharmacogenomics profile service: The Mayo Clinic experience 九基因药物基因组学档案服务:梅奥诊所的经验
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-10-20 DOI: 10.1038/s41397-021-00258-0
Eric T. Matey, Ashley Kate Ragan, Lance J. Oyen, Carolyn R. Vitek, Stacy L. Aoudia, Ahmed K. Ragab, Kelliann C. Fee-Schroeder, John L. Black, Ann M. Moyer, Wayne T. Nicholson, Sofia Shrestha, Tammy M. McAllister, Jason P. Sinnwell, Stephanie S. Faubion, Konstantinos N. Lazaridis
The Pharmacogenomics (PGx) Profile Service was a proof-of-concept project to implement PGx in patient care at Mayo Clinic. Eighty-two healthy individuals aged 18 and older underwent genotyping of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, HLA-B*58:01, and VKORC1. A PGx pharmacist was involved in ordering, meeting with patients, interpreting, reviewing, and documenting results. Ninety three percent were CYP1A2 rapid metabolizers, 92% CYP3A4 normal metabolizers, and 88% CYP3A5 poor metabolizers; phenotype frequencies for CYP2C19 and CYP2D6 varied. Seventy-three percent had normal functioning SLCO1B1 transporter, 4% carried the HLA-B*58:01 risk variant, and 35% carried VKORC1 and CYP2C9 variants that increased warfarin sensitivity. Pre-emptive PGx testing offered medication improvement opportunity in 56% of participants for commonly used medications. A collaborative approach involving a PGx pharmacist integrated within a clinical practice with regards to utility of PGx results allowed for implementation of the PGx Profile Service.
药物基因组学(PGx)档案服务是梅奥诊所在患者护理中实施 PGx 的一个概念验证项目。82 名 18 岁及以上的健康人接受了 CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4、CYP3A5、SLCO1B1、HLA-B*58:01 和 VKORC1 的基因分型。一名 PGx 药剂师参与了下单、与患者会面、解释、审核和记录结果等工作。93%的患者为 CYP1A2 快速代谢者,92%为 CYP3A4 正常代谢者,88%为 CYP3A5 不良代谢者;CYP2C19 和 CYP2D6 的表型频率各不相同。73%的患者SLCO1B1转运体功能正常,4%携带HLA-B*58:01风险变体,35%携带可增加华法林敏感性的VKORC1和CYP2C9变体。56% 的参与者通过先期 PGx 检测获得了改善常用药物治疗的机会。PGx药剂师与临床实践中的PGx药剂师就PGx结果的效用进行了合作,从而使PGx简介服务得以实施。
{"title":"Nine-gene pharmacogenomics profile service: The Mayo Clinic experience","authors":"Eric T. Matey, Ashley Kate Ragan, Lance J. Oyen, Carolyn R. Vitek, Stacy L. Aoudia, Ahmed K. Ragab, Kelliann C. Fee-Schroeder, John L. Black, Ann M. Moyer, Wayne T. Nicholson, Sofia Shrestha, Tammy M. McAllister, Jason P. Sinnwell, Stephanie S. Faubion, Konstantinos N. Lazaridis","doi":"10.1038/s41397-021-00258-0","DOIUrl":"10.1038/s41397-021-00258-0","url":null,"abstract":"The Pharmacogenomics (PGx) Profile Service was a proof-of-concept project to implement PGx in patient care at Mayo Clinic. Eighty-two healthy individuals aged 18 and older underwent genotyping of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, HLA-B*58:01, and VKORC1. A PGx pharmacist was involved in ordering, meeting with patients, interpreting, reviewing, and documenting results. Ninety three percent were CYP1A2 rapid metabolizers, 92% CYP3A4 normal metabolizers, and 88% CYP3A5 poor metabolizers; phenotype frequencies for CYP2C19 and CYP2D6 varied. Seventy-three percent had normal functioning SLCO1B1 transporter, 4% carried the HLA-B*58:01 risk variant, and 35% carried VKORC1 and CYP2C9 variants that increased warfarin sensitivity. Pre-emptive PGx testing offered medication improvement opportunity in 56% of participants for commonly used medications. A collaborative approach involving a PGx pharmacist integrated within a clinical practice with regards to utility of PGx results allowed for implementation of the PGx Profile Service.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2021-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9216849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 9
Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking β-blockers ADRB2 和 ADRB1 的基因多态性与服用 β 受体阻滞剂的心力衰竭患者的不同存活率有关
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-10-12 DOI: 10.1038/s41397-021-00257-1
Leonardo A. Guerra, Christelle Lteif, Meghan J. Arwood, Caitrin W. McDonough, Leanne Dumeny, Ankit A. Desai, Larisa H. Cavallari, Julio D. Duarte
Single nucleotide polymorphisms (SNPs) have been associated with differential beta-blocker (BB) effects on heart rate, blood pressure, and left ventricular ejection fraction in various patient populations. This study aimed to determine if SNPs previously associated with BB response are also associated with differential survival in heart failure (HF) patients receiving BBs. HF patient data were derived from electronic health records and the Social Security Death Index. Associations and interactions between BB dose, SNP genotype, and the outcome of death were assessed using a Cox proportional-hazard model adjusting for covariates known to be associated with differential survival in HF patients. Two SNPs, ADRB1 Arg389Gly and ADRB2 Glu27Gln, displayed significant interactions (Pint = 0.043 and Pint = 0.017, respectively) with BB dose and their association with mortality. Our study suggests that ADRB2 27Glu and ADRB1 389Arg may confer a larger survival benefit with higher BB doses in patients with HF.
在不同的患者群体中,单核苷酸多态性(SNPs)与β-受体阻滞剂(BB)对心率、血压和左心室射血分数的不同影响有关。本研究旨在确定以前与β-受体阻滞剂反应相关的 SNPs 是否也与接受β-受体阻滞剂治疗的心力衰竭(HF)患者的不同存活率有关。心衰患者的数据来自电子健康记录和社会保障死亡指数。使用Cox比例危险模型评估了BB剂量、SNP基因型和死亡结果之间的关联和相互作用,并调整了已知与HF患者不同生存率相关的协变量。ADRB1的Arg389Gly和ADRB2的Glu27Gln这两个SNP与BB剂量及其与死亡率的关系有显著的相互作用(Pint = 0.043和Pint = 0.017)。我们的研究表明,ADRB2 27Glu 和 ADRB1 389Arg 可使高血压患者在较高的 BB 剂量下获得更大的生存获益。
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引用次数: 1
A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin NOS1AP 基因变异与地高辛 QT 间期缩短效应的矛盾性增加有关
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-10-06 DOI: 10.1038/s41397-021-00256-2
Negin Soroush, Albert-Jan Aarnoudse, Maryam Kavousi, Jan A. Kors, M. Arfan Ikram, Christopher Newton-Cheh, Fariba Ahmadizar, Bruno H. Stricker
Digoxin is characterized by a small therapeutic window and a QT-interval shortening effect. Moreover, it has been shown that the genetic variants of the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. We investigated whether the rs10494366 variant of the NOS1AP gene decreases the QT-interval shortening effect of digoxin in patients using this drug. We included 10,057 individuals from the prospective population-based cohort of the Rotterdam Study during a median of 12.2 (interquartile range (IQR) 6.7–18.1) years of follow-up. At study entry, the mean age was 64 years and almost 59% of participants were women. A total of 23,179 ECGs were longitudinally recorded, of which 334 ECGs were from 249 individuals on digoxin therapy. The linear mixed model analysis was used to estimate the effect of the rs10494366 variant on the association between digoxin use and QT-interval duration, adjusted for age, sex, RR interval, diabetes, heart failure, and history of myocardial infarction. In non-users of digoxin, the GG genotype was associated with a significant 6.5 ms [95% confidence interval (CI) 5.5; 7.5] longer QT-interval duration than the TT variant. In current digoxin users, however, the GG variant was associated with a significantly −23.9 [95%CI −29.5; −18.5] ms shorter mean QT-interval duration than in those with the TT variant with −15.9 [95%CI −18.7; −13.1]. This reduction was strongest in the high digoxin dose category [≥0.250 mg/day] with the GG genotype group, with −40.8 [95%CI −52.5; −29.2] ms changes compared to non-users. Our study suggests that the minor homozygous GG genotype group of the NOS1AP gene rs10494366 variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin in a population of European ancestry.
地高辛的特点是治疗窗口小和具有 QT 间期缩短效应。此外,有研究表明,一氧化氮合酶-1 适应蛋白(NOS1AP)基因的遗传变异与 QT 间期延长有关。我们研究了 NOS1AP 基因的 rs10494366 变体是否会降低地高辛对使用该药物的患者的 QT 间期缩短效应。我们从鹿特丹研究的前瞻性人群队列中纳入了 10,057 人,随访时间中位数为 12.2 年(四分位数间距 (IQR) 6.7-18.1 年)。参加研究时的平均年龄为 64 岁,近 59% 的参与者为女性。共纵向记录了 23,179 张心电图,其中 334 张心电图来自 249 名接受地高辛治疗的患者。在对年龄、性别、RR 间期、糖尿病、心力衰竭和心肌梗死病史进行调整后,采用线性混合模型分析估计了 rs10494366 变异对地高辛使用和 QT 间期之间关系的影响。在不使用地高辛的人群中,GG 基因型比 TT 基因型的 QT 阈值显著长 6.5 毫秒[95% 置信区间(CI)为 5.5; 7.5]。然而,在目前使用地高辛的人群中,GG 基因变异型比 TT 基因变异型的平均 QT 间期明显缩短-23.9 [95%CI -29.5; -18.5]毫秒(-15.9 [95%CI -18.7; -13.1])。在地高辛高剂量组[≥0.250 毫克/天]中,GG 基因型组的平均 QT 间期缩短幅度最大,与未使用地高辛的人群相比,缩短了 -40.8 [95%CI -52.5; -29.2]毫秒。我们的研究表明,在欧洲血统的人群中,NOS1AP基因rs10494366变异的次要同源GG 基因型组与地高辛QT间期缩短效应的矛盾性增加有关。
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引用次数: 0
Polymorphisms at CYP enzymes, NR1I2 and NR1I3 in association with virologic response to antiretroviral therapy in Brazilian HIV-positive individuals 巴西艾滋病毒抗体阳性者体内 CYP 酶、NR1I2 和 NR1I3 的多态性与抗逆转录病毒疗法病毒学应答的关系
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-09-09 DOI: 10.1038/s41397-021-00254-4
Camila de Almeida Velozo, Tailah Bernardo de Almeida, Marcelo Costa Velho Mendes de Azevedo, Isabela Espasandin, Jorge Francisco da Cunha Pinto, Sheila López, Luciana Pizzatti, Amilcar Tanuri, Sabrina da Silva Santos, Marcelo Ribeiro-Alves, Cynthia Chester Cardoso
Virologic failure of antiretroviral therapy (ART) may be explained by single nucleotide polymorphisms (SNPs) in drug absorption and metabolism genes. Here, we characterized the associations between polymorphisms in cytochrome P450 enzymes’ genes CYP2B6 and CYP3A4/A5, nuclear receptor genes NR1I2/3, and initial ART efficacy among 203 HIV-positive individuals from Rio de Janeiro. Association between SNPs and virologic control was evaluated after 6 and 12 months of follow-up using Cox regression models. The SNP rs2307424 (NR1I3) was associated with increased virologic response after 12 months of treatment, while rs1523127 (NR1I2), rs3003596, and rs2502815 (NR1I3) were associated with decreased response. Increased virologic response after 12 months (adjHR = 1.54; p = 0.02) was also observed among carriers of the NR1I3 haplotype rs2502815G-rs3003596A-rs2307424A versus the reference haplotype G-A-G. Our results suggest that NR1I2 and NR1I3 variants are associated with virologic responses to ART among Brazilians.
抗逆转录病毒疗法(ART)的病毒学失败可能与药物吸收和代谢基因中的单核苷酸多态性(SNPs)有关。在此,我们研究了里约热内卢 203 名 HIV 阳性个体中细胞色素 P450 酶基因 CYP2B6 和 CYP3A4/A5、核受体基因 NR1I2/3 的多态性与最初抗逆转录病毒疗法疗效之间的关系。使用 Cox 回归模型评估了随访 6 个月和 12 个月后 SNP 与病毒学控制之间的关系。SNP rs2307424(NR1I3)与治疗 12 个月后病毒学应答的增加有关,而 rs1523127(NR1I2)、rs3003596 和 rs2502815(NR1I3)与应答的减少有关。与参考单倍型 G-A-G 相比,在 NR1I3 单倍型 rs2502815G-rs3003596A-rs2307424A 携带者中也观察到 12 个月后病毒学应答增加(adjHR = 1.54;p = 0.02)。我们的研究结果表明,NR1I2 和 NR1I3 变体与巴西人对抗病毒疗法的病毒学应答有关。
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引用次数: 3
Impact of genetic variation in CYP2C19, CYP2D6, and CYP3A4 on oxycodone and its metabolites in a large database of clinical urine drug tests 大型临床尿液药物检测数据库中 CYP2C19、CYP2D6 和 CYP3A4 基因变异对羟考酮及其代谢物的影响
IF 2.8 3区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2021-09-03 DOI: 10.1038/s41397-021-00253-5
Guang-dan Zhu, Penn Whitley, Leah LaRue, Brandon Adkins, Eric Dawson, Angela Huskey, Edmund V. Capparelli, Andria L. Del Tredici
Urine drug testing (UDT) is a tool for monitoring drug use, including oxycodone. While variation in cytochrome P450 (CYP) genes is known to alter oxycodone metabolism, its impact on UDT results of oxycodone and its metabolites has not been well-studied. Here, multivariate analysis was performed on retrospective UDT results of 90,379 specimens collected from 14,684 genotyped patients prescribed oxycodone. Genetic variation in CYP2D6 and CYP2C19 had a significant impact on oxymorphone/oxycodone ratios, with a 6.9-fold difference between CYP2D6 ultrarapid metabolizers (UMs) and poor metabolizers (PMs; p < 10−300) and a 1.6-fold difference between CYP2C19 UMs and PMs (p = 1.50 × 10−4). CYP2D6 variation also significantly impacted noroxycodone/oxycodone ratios (p = 6.95 × 10−38). Oxycodone-positive specimens from CYP2D6 PMs were ~5-fold more likely to be oxymorphone-negative compared to normal metabolizers. These findings indicate that multivariate analysis of UDT data may be used to reveal the real-world impact of genetic and non-genetic factors on drug metabolism.
尿液药物检测(UDT)是监测包括羟考酮在内的药物使用情况的一种工具。众所周知,细胞色素 P450(CYP)基因的变异会改变羟考酮的代谢,但其对羟考酮及其代谢物尿液检测结果的影响尚未得到充分研究。在此,我们对从 14,684 名开具羟考酮处方的基因分型患者处收集的 90,379 份标本的回顾性 UDT 结果进行了多变量分析。CYP2D6 和 CYP2C19 的基因变异对羟甲吗啡酮/羟考酮的比例有显著影响,CYP2D6 超快速代谢者(UMs)和不良代谢者(PMs;p <;10-300)之间相差 6.9 倍,CYP2C19 UMs 和 PMs 之间相差 1.6 倍(p = 1.50 × 10-4)。CYP2D6 变异也对去氧可酮/去氧可酮比率产生了显著影响(p = 6.95 × 10-38)。与正常代谢者相比,来自 CYP2D6 PMs 的羟考酮阳性标本出现羟吗啡酮阴性的可能性高出约 5 倍。这些发现表明,对 UDT 数据进行多变量分析可用于揭示遗传和非遗传因素对药物代谢的实际影响。
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引用次数: 0
期刊
Pharmacogenomics Journal
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