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Mouse nerve growth factor suppresses neuronal apoptosis in valproic acid-induced autism spectrum disorder rats by regulating the phosphoinositide-3-kinase/serine/threonine kinase signaling pathway. 小鼠神经生长因子通过调节磷酸肌醇-3-激酶/丝氨酸/苏氨酸激酶信号通路抑制丙戊酸诱导的自闭症谱系障碍大鼠神经元凋亡
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-07-01 DOI: 10.1097/FPC.0000000000000498
Jie Jian, Li-Guo Li, Peng-Ju Zhao, Rui-Juan Zheng, Xian-Wen Dong, Yong-Hong Zhao, Bao-Qi Yin, Sheng Li, Hui Cheng, Hong-Lei Li, En-Yao Li

Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by deficits in social communication and restrictive behaviors. Mouse nerve growth factor (mNGF), a neurotrophic factor, is critical for neuronal growth and survival, and the mNGF treatment is considered a promising therapy for neurodegeneration. In light of this, we aimed to evaluate the effect of mNGF on neurological function in ASD.

Methods: An ASD rat model was established by intraperitoneal injection of valproic acid (VPA). Social behavior, learning, and memory of the rats were measured. TdT-mediated dUTP Nick-end labeling and Nissl assays were performed to detect neuronal apoptosis and survival in the hippocampus and prefrontal cortex. Apoptosis-related proteins and oxidative stress markers were detected.

Results: mNGF improved locomotor activity, exploratory behavior, social interaction, and spatial learning and memory in VPA-induced ASD rats. In the hippocampus and prefrontal cortex, mNGF suppressed neuronal apoptosis, increased the number of neurons, superoxide dismutase, and glutathione levels, and decreased reactive oxygen species, nitric oxide, TNF-α, and IL-1β levels compared with the VPA group. In addition, mNGF increased the levels of Bcl-2, p-phosphoinositide-3-kinase (PI3K), and p-serine/threonine kinase (Akt), and decreased the levels of Bax and cleaved caspase-3, while the PI3K inhibitor LY294002 reversed these effects.

Conclusion: These data suggest that mNGF suppressed neuronal apoptosis and ameliorated the abnormal behaviors in VPA-induced ASD rats, in part, by activating the PI3K/Akt signaling pathway.

背景:自闭症谱系障碍(Autism spectrum disorder, ASD)是一组以社会沟通缺陷和限制性行为为特征的神经发育障碍。小鼠神经生长因子(mNGF)是一种神经营养因子,对神经元的生长和存活至关重要,mNGF治疗被认为是一种很有前途的治疗神经退行性疾病的方法。鉴于此,我们旨在评估mNGF对ASD神经功能的影响。方法:采用丙戊酸(VPA)腹腔注射建立ASD大鼠模型。测量大鼠的社会行为、学习和记忆能力。采用tdt介导的dUTP镍端标记法和Nissl法检测海马和前额叶皮层神经元凋亡和存活情况。检测细胞凋亡相关蛋白和氧化应激标志物。结果:mNGF改善了vpa诱导的ASD大鼠的运动活动、探索行为、社会互动和空间学习记忆。在海马和前额叶皮层,与VPA组相比,mNGF抑制神经元凋亡,增加神经元数量、超氧化物歧化酶和谷胱甘肽水平,降低活性氧、一氧化氮、TNF-α和IL-1β水平。此外,mNGF增加Bcl-2、对磷酸肌苷-3激酶(PI3K)和对丝氨酸/苏氨酸激酶(Akt)的水平,降低Bax和cleaved caspase-3的水平,而PI3K抑制剂LY294002逆转了这些作用。结论:mNGF通过激活PI3K/Akt信号通路,抑制vpa诱导的ASD大鼠神经元凋亡,改善其异常行为。
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引用次数: 0
'Effect of CYP2C19 genetic variants on bleeding and major adverse cardiovascular events in a cohort of Arab patients undergoing percutaneous coronary intervention and stent implantation' by Ali et al. - reassess the evidence, shall we? Ali等人的“CYP2C19基因变异对经皮冠状动脉介入治疗和支架植入的阿拉伯患者出血和主要不良心血管事件的影响”——重新评估证据,好吗?
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-06-01 DOI: 10.1097/FPC.0000000000000496
Miriam Saiz-Rodríguez, Pablo Zubiaur, Francisco Abad-Santos
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引用次数: 0
Associations between four polymorphisms of the SLCO1B1 and effectiveness of the statins: a meta-analysis. 四种SLCO1B1多态性与他汀类药物有效性之间的关联:一项荟萃分析。
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-06-01 DOI: 10.1097/FPC.0000000000000490
Hong Ha Nguyen, Cuc Thi Thu Nguyen, Tran Ngoc Phuong Mai, Phung Thanh Huong

Objective: Statins are the first-choice therapy for dyslipidemia, but their effectiveness can be influenced by genetic polymorphisms. This study was conducted to assess the association of variants of the solute carrier anion transporter family 1B1 (SLCO1B1) gene, which encodes a transporter involving the hepatic clearance of the statins and their therapeutic efficacy.

Method: A systematic review was performed on four electronic databases to identify relevant studies. The pooled mean difference with 95% confidence interval (CI) in percentage change of concentration of LDL-C, total cholesterol (TC), HDL-C, and triglycerides was calculated. Heterogeneity between studies and publication bias, subgroup analyses, and sensitivity analyses were also carried out using R software.

Results: Twenty-one studies on 24 365 participants and four variants [rs4149056 (c.521T>C), rs2306283 (c.388A>G), rs11045819 (c.463C>A), rs4363657 (g.89595T>C)] were analyzed. A statistically significant association was found between the LDL-C-lowering effectiveness and the rs4149056 and rs11045819 in the heterozygote model; and the rs4149056, rs2306283, and rs11045819 in the homozygote model. In the subgroup analyses, non-Asian populations, simvastatin, and pravastatin showed significant associations between LDL-C-lowering efficacy and the rs4149056 or rs2306283. Significant associations between the rs2306283 and HDL-C-increasing effectiveness were found in the homozygote model. Regarding TC-reducing, significant associations were observed in the heterozygote and homozygote models of the rs11045819. There was no heterogeneity and publication bias among most studies.

Conclusion: SLCO1B1 variants can be used as signals to predict the statins' effectiveness.

目的:他汀类药物是治疗血脂异常的首选药物,但其疗效可能受到遗传多态性的影响。本研究旨在评估溶质阴离子转运蛋白家族1B1 (SLCO1B1)基因变异的相关性,该基因编码一种转运蛋白,参与他汀类药物的肝脏清除及其治疗效果。方法:对四个电子数据库进行系统回顾,找出相关研究。计算LDL-C、总胆固醇(TC)、HDL-C和甘油三酯浓度百分比变化的95%置信区间(CI)的合并平均差值。研究之间的异质性、发表偏倚、亚组分析和敏感性分析也使用R软件进行。结果:共分析了21项研究共24 365名参与者和4个变异[rs4149056 (C . 521t >C)、rs2306283 (C . 388a >G)、rs11045819 (C . 463c >A)、rs4363657 (G . 89595t >C)]。在杂合子模型中,rs4149056和rs11045819降低ldl - c的有效性与rs4149056和rs11045819存在显著的统计学相关性;纯合子模型中的rs4149056、rs2306283和rs11045819。在亚组分析中,非亚洲人群、辛伐他汀和普伐他汀显示降低ldl - c的疗效与rs4149056或rs2306283之间存在显著关联。在纯合子模型中发现rs2306283与hdl - c增加有效性之间存在显著关联。关于tc降低,在rs11045819的杂合子和纯合子模型中观察到显著的关联。大多数研究不存在异质性和发表偏倚。结论:SLCO1B1变异可作为预测他汀类药物疗效的信号。
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引用次数: 0
Pharmacogenetics of tenofovir clearance among Southern Africans living with HIV. 南部非洲艾滋病毒感染者替诺福韦清除率的药物遗传学。
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-06-01 Epub Date: 2023-03-06 DOI: 10.1097/FPC.0000000000000495
Zinhle Cindi, Aida N Kawuma, Gary Maartens, Yuki Bradford, Simiso Sokhela, Nomathemba Chandiwana, Willem D Francois Venter, Roeland E Wasmann, Paolo Denti, Lubbe Wiesner, Marylyn D Ritchie, David W Haas, Phumla Sinxadi

Background: Tenofovir is a component of preferred combination antiretroviral therapy (ART) regimens in Africa. Few pharmacogenetic studies have been conducted on tenofovir exposure in Africa, where genetic diversity is greatest.

Objective: We characterized the pharmacogenetics of plasma tenofovir clearance in Southern Africans receiving tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF).

Methods: Adults randomized to TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262) were studied. Linear regression models stratified by study arm examined associations with unexplained variability in tenofovir clearance. We investigated genetic associations with polymorphisms selected a priori followed by genome-wide associations.

Results: A total of 268 participants (138 and 130 in the TAF and TDF arm, respectively) were evaluable for associations. Among polymorphisms previously associated with any drug-related phenotype, IFNL4 rs12979860 was associated with more rapid tenofovir clearance in both arms (TAF: P = 0.003; TDF: P = 0.003). Genome-wide, the lowest P values for tenofovir clearance in TAF and TDF arms were LINC01684 rs9305223 (P = 3.0 × 10-8) and intergenic rs142693425 (P = 1.4 × 10-8), respectively.

Conclusion: Among Southern Africans randomized to TAF or TDF in ADVANCE, unexplained variability in tenofovir clearance was associated with a polymorphism in IFNL4, an immune-response gene. It is unclear how this gene would affect tenofovir disposition.

背景替诺福韦是非洲首选的抗逆转录病毒联合疗法(ART)方案的组成部分。在遗传多样性最丰富的非洲,很少有关于替诺福韦暴露的药物遗传学研究:我们研究了接受富马酸替诺福韦二吡呋酯(TDF)或替诺福韦阿拉非那胺(TAF)治疗的南部非洲人血浆替诺福韦清除率的药物遗传学特征:研究对象为ADVANCE试验(NCT03122262)中随机接受TAF或TDF治疗的成人。按研究臂分层的线性回归模型检验了替诺福韦清除率与无法解释的变异性之间的关联。我们调查了与先验选择的多态性的遗传相关性,然后是全基因组相关性:共有 268 名参与者(TAF 和 TDF 治疗组分别有 138 人和 130 人)可进行相关性评估。在以前与任何药物相关表型有关的多态性中,IFNL4 rs12979860与两种治疗组中更快的替诺福韦清除率有关(TAF:P = 0.003;TDF:P = 0.003)。在全基因组范围内,TAF和TDF两组中替诺福韦清除率P值最低的分别是LINC01684 rs9305223(P = 3.0 × 10-8)和基因间rs142693425(P = 1.4 × 10-8):在ADVANCE中随机接受TAF或TDF治疗的南部非洲人中,替诺福韦清除率的不明变异与免疫反应基因IFNL4的多态性有关。目前还不清楚该基因会如何影响替诺福韦的处置。
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引用次数: 0
Association of the ACE and AGT gene polymorphisms with global disparities in COVID-19-related deaths. ACE和AGT基因多态性与covid -19相关死亡的全球差异的关系
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-04-01 DOI: 10.1097/FPC.0000000000000492
Yolande B Saab, Zahi S Nakad, Stephanie J Mehanna

Objective: The aim of the study was to investigate the gene polymorphisms of angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin type 1 receptor (AT1R) in association with coronavirus disease 2019 (COVID-19) mortality rates worldwide.

Methods: The prevalence of ACE I/D, AGT M235T, and AT1R A1166C alleles' frequencies in different populations was assessed. Data on COVID-19-related cases and deaths were acquired from the European Center for Disease Prevention and Control, which included weekly reports by country and continent. An Excel tool was developed to visualize the acquired data of mortality and incidence by classifying them by continent/country across specific periods of time. Spearman's nonparametric correlation was used to evaluate the association between country-based frequencies in RAS gene polymorphisms and COVID-19-related deaths.

Results: While China constituted the initial reservoir of COVID-19, incidence/mortality rates in Europe and America outnumbered the figures in the former. A clear association was identified between death rates and ACE D/I ( r  = 0.3659; P  = 0.033), as well as AGT A/G variants ( r  = 0.7576; P  = 0.015). Data on AT1R polymorphisms suggested no correlation with mortality rates.

Conclusion: Our results demonstrated a significant disparity in COVID-19-related susceptibility and mortality among different populations and corroborate the importance of gene polymorphisms in predicting and consequently improving patients' outcomes.

目的:研究血管紧张素转换酶(ACE)、血管紧张素原(AGT)和血管紧张素1型受体(AT1R)基因多态性与全球冠状病毒病2019 (COVID-19)死亡率的关系。方法:分析不同人群ACE I/D、AGT M235T、AT1R A1166C等位基因频率的流行情况。有关covid -19相关病例和死亡的数据来自欧洲疾病预防控制中心,其中包括按国家和大陆分列的每周报告。开发了一个Excel工具,通过按大陆/国家在特定时期对所获得的死亡率和发病率数据进行分类,使其可视化。使用Spearman非参数相关性来评估基于国家的RAS基因多态性频率与covid -19相关死亡之间的关系。结果:虽然中国是COVID-19的初始库,但欧洲和美国的发病率/死亡率超过了前者。死亡率与ACE D/I之间存在明显关联(r = 0.3659;P = 0.033),以及AGT A/G变异(r = 0.7576;P = 0.015)。AT1R多态性数据显示与死亡率无相关性。结论:不同人群在covid -19相关易感性和死亡率方面存在显著差异,证实了基因多态性在预测和改善患者预后方面的重要性。
{"title":"Association of the ACE and AGT gene polymorphisms with global disparities in COVID-19-related deaths.","authors":"Yolande B Saab,&nbsp;Zahi S Nakad,&nbsp;Stephanie J Mehanna","doi":"10.1097/FPC.0000000000000492","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000492","url":null,"abstract":"<p><strong>Objective: </strong>The aim of the study was to investigate the gene polymorphisms of angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin type 1 receptor (AT1R) in association with coronavirus disease 2019 (COVID-19) mortality rates worldwide.</p><p><strong>Methods: </strong>The prevalence of ACE I/D, AGT M235T, and AT1R A1166C alleles' frequencies in different populations was assessed. Data on COVID-19-related cases and deaths were acquired from the European Center for Disease Prevention and Control, which included weekly reports by country and continent. An Excel tool was developed to visualize the acquired data of mortality and incidence by classifying them by continent/country across specific periods of time. Spearman's nonparametric correlation was used to evaluate the association between country-based frequencies in RAS gene polymorphisms and COVID-19-related deaths.</p><p><strong>Results: </strong>While China constituted the initial reservoir of COVID-19, incidence/mortality rates in Europe and America outnumbered the figures in the former. A clear association was identified between death rates and ACE D/I ( r  = 0.3659; P  = 0.033), as well as AGT A/G variants ( r  = 0.7576; P  = 0.015). Data on AT1R polymorphisms suggested no correlation with mortality rates.</p><p><strong>Conclusion: </strong>Our results demonstrated a significant disparity in COVID-19-related susceptibility and mortality among different populations and corroborate the importance of gene polymorphisms in predicting and consequently improving patients' outcomes.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"33 3","pages":"41-50"},"PeriodicalIF":2.6,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10563140","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: 0
Pharmacogenetic impact of SLC22A1 gene variant rs628031 (G/A) in newly diagnosed Indian type 2 diabetes patients undergoing metformin monotherapy. SLC22A1基因变异rs628031 (G/A)对接受二甲双胍单药治疗的新诊断印度2型糖尿病患者的药理学影响
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-04-01 DOI: 10.1097/FPC.0000000000000493
Shalini Singh, Ashwin Kumar Shukla, Kauser Usman, Monisha Banerjee

Objectives: Type 2 diabetes (T2D) imposes an enormous burden all over the world in both developed and developing countries. Inter-individual differences are attributed to polymorphisms in candidate genes resulting in altered absorption, transportation, distribution, and metabolism of oral antidiabetic drugs (OADs). Hence, the present study was undertaken to evaluate the pharmacogenetic impact of SLC22A1 gene variant rs628031 (G/A) on metformin monotherapy in newly diagnosed untreated T2D patients.

Methods: Newly diagnosed T2D patients ( n  = 500) were enrolled according to inclusion/exclusion criteria. Initially, enrolled subjects were prescribed metformin monotherapy and followed up for at least 12 weeks. Response to metformin was evaluated in 478 patients who revisited for follow-up by measuring HbA1c.

Result: Out of 478 patients, 373 were responders to metformin monotherapy while 105 were non-responders. The pharmacogenetic impact was evaluated by genotype, haplotype, and pharmacogenetic analyses. 'GG' genotype and 'G' allele of SLC22A1 rs628031 G/A were observed in 48.8% and 67.7% of Met responders, respectively, while 20.9% and 49.1 % were in non-responders. Therefore, there was a 2.18-fold increase in the success rate of Met therapeutics.

Conclusion: Individuals carrying the 'GG' genotype or 'G' allele for SLC22A1 gene variant rs628031 G/A are better responders for Metformin monotherapy.

目的:2型糖尿病(T2D)在全世界发达国家和发展中国家都是一个巨大的负担。个体间差异归因于候选基因的多态性,导致口服降糖药(oad)的吸收、运输、分布和代谢发生改变。因此,本研究旨在评估SLC22A1基因变异rs628031 (G/A)对新诊断未经治疗的T2D患者二甲双胍单药治疗的药理学影响。方法:根据纳入/排除标准纳入新诊断的T2D患者500例。最初,受试者接受二甲双胍单药治疗,随访至少12周。通过测量HbA1c来评估478名患者对二甲双胍的反应。结果:478例患者中,373例对二甲双胍单药治疗有反应,105例无反应。通过基因型、单倍型和药物遗传分析来评估药物遗传影响。SLC22A1 rs628031 G/A“GG”基因型和“G”等位基因在Met应答者中分别占48.8%和67.7%,而在无应答者中分别占20.9%和49.1%。因此,Met疗法的成功率增加了2.18倍。结论:携带SLC22A1基因变异rs628031 G/A“GG”基因型或“G”等位基因的个体对二甲双胍单药治疗的反应更好。
{"title":"Pharmacogenetic impact of SLC22A1 gene variant rs628031 (G/A) in newly diagnosed Indian type 2 diabetes patients undergoing metformin monotherapy.","authors":"Shalini Singh,&nbsp;Ashwin Kumar Shukla,&nbsp;Kauser Usman,&nbsp;Monisha Banerjee","doi":"10.1097/FPC.0000000000000493","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000493","url":null,"abstract":"<p><strong>Objectives: </strong>Type 2 diabetes (T2D) imposes an enormous burden all over the world in both developed and developing countries. Inter-individual differences are attributed to polymorphisms in candidate genes resulting in altered absorption, transportation, distribution, and metabolism of oral antidiabetic drugs (OADs). Hence, the present study was undertaken to evaluate the pharmacogenetic impact of SLC22A1 gene variant rs628031 (G/A) on metformin monotherapy in newly diagnosed untreated T2D patients.</p><p><strong>Methods: </strong>Newly diagnosed T2D patients ( n  = 500) were enrolled according to inclusion/exclusion criteria. Initially, enrolled subjects were prescribed metformin monotherapy and followed up for at least 12 weeks. Response to metformin was evaluated in 478 patients who revisited for follow-up by measuring HbA1c.</p><p><strong>Result: </strong>Out of 478 patients, 373 were responders to metformin monotherapy while 105 were non-responders. The pharmacogenetic impact was evaluated by genotype, haplotype, and pharmacogenetic analyses. 'GG' genotype and 'G' allele of SLC22A1 rs628031 G/A were observed in 48.8% and 67.7% of Met responders, respectively, while 20.9% and 49.1 % were in non-responders. Therefore, there was a 2.18-fold increase in the success rate of Met therapeutics.</p><p><strong>Conclusion: </strong>Individuals carrying the 'GG' genotype or 'G' allele for SLC22A1 gene variant rs628031 G/A are better responders for Metformin monotherapy.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"33 3","pages":"51-58"},"PeriodicalIF":2.6,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10544143","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: 1
Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation. CYP3A5基因型对肾移植患者从头至尾LCP他克莫司给药和监测的影响。
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-04-01 DOI: 10.1097/FPC.0000000000000494
Nikhil Rao, Taylor Carcella, Neha Patel, Felicia Bartlett, Maria Aurora Posadas, Michael Casey, Derek A Dubay, David J Taber

Objectives: LCP tac has a recommended starting dose of 0.14 mg/kg/day in kidney transplant. The goal of this study was to assess the influence of CYP3A5 on perioperative LCP tac dosing and monitoring.

Methods: This was a prospective observational cohort study of adult kidney recipients receiving de-novo LCP tac. CYP3A5 genotype was measured and 90-day pharmacokinetic and clinical were assessed. Patients were classified as CYP3A5 expressors (*1 homozygous or heterozygous) or nonexpressors (LOF *3/*6/*7 allele).

Results: In this study, 120 were screened, 90 were contacted and 52 provided consent; 50 had genotype results, and 22 patients expressed CYP3A5*1. African Americans (AA) comprised 37.5% of nonexpressors versus 81.8% of expressors (P = 0.001). Initial LCP tac dose was similar between CYP3A5 groups (0.145 vs. 0.137 mg/kg/day; P = 0.161), whereas steady state dose was higher in expressors (0.150 vs. 0.117 mg/kg/day; P = 0.026). CYP3A5*1 expressors had significantly more tac trough concentrations of less than 6 ng/ml and significantly fewer tac trough concentrations of more than 14 ng/ml. Providers were significantly more likely to under-adjust LCP tac by 10 and 20% in CYP3A5 expressors versus nonexpressors (P < 0.03). In sequential modeling, CYP3A5 genotype status explained the LCP tac dosing requirements significantly more than AA race.

Conclusion: CYP3A5*1 expressors require higher doses of LCP tac to achieve therapeutic concentrations and are at higher risk of subtherapeutic trough concentrations, persisting for 30-day posttransplant. LCP tac dose changes in CYP3A5 expressors are more likely to be under-adjusted by providers.

目的:LCP tac在肾移植中的推荐起始剂量为0.14 mg/kg/天。本研究的目的是评估CYP3A5对围手术期LCP tac给药和监测的影响。方法:这是一项前瞻性观察队列研究,研究对象是成年肾受体接受重新LCP治疗。测定CYP3A5基因型,评价90天药代动力学和临床疗效。将患者分为CYP3A5表达型(*1纯合或杂合)和非表达型(LOF *3/*6/*7等位基因)。结果:本次研究共筛选120人,联系90人,同意52人;50例有基因型结果,22例表达CYP3A5*1。非裔美国人(AA)占非表达者的37.5%,占表达者的81.8% (P = 0.001)。CYP3A5组间LCP tac初始剂量相似(0.145 vs 0.137 mg/kg/day;P = 0.161),而表达物的稳态剂量更高(0.150 vs. 0.117 mg/kg/day;P = 0.026)。CYP3A5*1表达者在低于6 ng/ml的tac谷浓度显著增加,在高于14 ng/ml的tac谷浓度显著减少。CYP3A5表达者与非表达者相比,提供者更有可能将LCP tac下调10%和20% (P < 0.03)。在序列建模中,CYP3A5基因型状态比AA种族更能解释LCP tac的剂量要求。结论:CYP3A5*1表达者需要更高剂量的LCP tac才能达到治疗浓度,并且亚治疗谷浓度的风险更高,持续30天。CYP3A5表达者的LCP剂量变化更可能被提供者低估。
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引用次数: 0
Pregnane X receptor gene variant rs7643645 and total mortality in subjects with nonalcoholic fatty liver disease. 妊娠X受体基因变异rs7643645与非酒精性脂肪肝患者的总死亡率
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-02-01 DOI: 10.1097/FPC.0000000000000489
Aki J Käräjämäki, Janne Hukkanen, Olavi Ukkola

Pregnane X receptor (PXR) gene variants rs7643645 and rs2461823 are reported to associate with clinically and histologically more severe liver injury in nonalcoholic fatty liver disease (NAFLD). It is known that the more progressive the NAFLD, the higher the hepatic and extra-hepatic mortality and morbidity. Thus, we investigated the total mortality in Finnish middle-aged ultrasonographically verified NAFLD patients with PXR rs7643645 AA/AG ( n  = 217) or GG ( n  = 27) variants and rs2461823 CC/CT ( n  = 215) or TT ( n  = 27) variants. In up to 30 years of follow-up, PXR rs7643645 GG subjects were at an increased risk of total mortality compared with AA/AG subjects, 1.676 (1.014-2.772), P  = 0.044. The statistically significant difference prevailed after multiple adjustments for potentially confounding factors, RR, 2.024 (1.191-3.440), P  = 0.009. In the subjects without NAFLD ( n  = 731), the mortality risk was not associated with rs7643645 variants, 1.051 (0.708-1.560; P  = 0.804). There was no difference in the total mortality between the PXR rs2461823 variant subgroups, 1.141 (0.663-1.962; P  = 0.634). As the rs7643645 G variant disrupts a putative hepatocyte nuclear factor 4α binding site located in the PXR gene promoter and is associated with lower hepatic expression of PXR and its target genes, our result suggests that genetic disruption of xenobiotic metabolism increases mortality in subjects with NAFLD. Further studies are needed to confirm the results of the present study.

据报道,妊娠素X受体(PXR)基因变异rs7643645和rs2461823与非酒精性脂肪性肝病(NAFLD)的临床和组织学上更严重的肝损伤相关。众所周知,NAFLD越进展,肝脏和肝外死亡率和发病率越高。因此,我们研究了超声检查证实的芬兰中年NAFLD患者PXR rs7643645 AA/AG (n = 217)或GG (n = 27)变异和rs2461823 CC/CT (n = 215)或TT (n = 27)变异的总死亡率。在长达30年的随访中,与AA/AG受试者相比,PXR rs7643645 GG受试者的总死亡率风险增加,为1.676 (1.014-2.772),P = 0.044。对潜在混杂因素进行多重校正后,差异有统计学意义,RR为2.024 (1.191 ~ 3.440),P = 0.009。在没有NAFLD的受试者中(n = 731),死亡风险与rs7643645变异无关,为1.051 (0.708-1.560;P = 0.804)。PXR rs2461823变异亚组间的总死亡率无差异,分别为1.141 (0.663-1.962;P = 0.634)。由于rs7643645 G变异破坏了PXR基因启动子中一个假定的肝细胞核因子4α结合位点,并与PXR及其靶基因在肝脏中的低表达有关,我们的研究结果表明,外源代谢的遗传破坏增加了NAFLD患者的死亡率。需要进一步的研究来证实本研究的结果。
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引用次数: 1
Implementation of pharmacogenomics into inpatient general medicine. 药物基因组学在住院全科医学中的应用。
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-02-01 DOI: 10.1097/FPC.0000000000000487
Thomas Chen, Peter H O'Donnell, Merisa Middlestadt, Gregory W Ruhnke, Keith Danahey, Xander M R van Wijk, Anish Choksi, Randall Knoebel, Seth Hartman, Kiang-Teck Jerry Yeo, Paula N Friedman, Mark J Ratain, Edith A Nutescu, Kevin J O'Leary, Minoli A Perera, David O Meltzer

Pharmacogenomics is a crucial piece of personalized medicine. Preemptive pharmacogenomic testing is only used sparsely in the inpatient setting and there are few models to date for fostering the adoption of pharmacogenomic treatment in the inpatient setting. We created a multi-institutional project in Chicago to enable the translation of pharmacogenomics into inpatient practice. We are reporting our implementation process and barriers we encountered with solutions. This study, 'Implementation of Point-of-Care Pharmacogenomic Decision Support Accounting for Minority Disparities', sought to implement pharmacogenomics into inpatient practice at three sites: The University of Chicago, Northwestern Memorial Hospital, and the University of Illinois at Chicago. This study involved enrolling African American adult patients for preemptive genotyping across a panel of actionable germline variants predicting drug response or toxicity risk. We report our approach to implementation and the barriers we encountered engaging hospitalists and general medical providers in the inpatient pharmacogenomic intervention. Our strategies included: a streamlined delivery system for pharmacogenomic information, attendance at hospital medicine section meetings, use of physician and pharmacist champions, focus on hospitalists' care and optimizing system function to fit their workflow, hand-offs, and dealing with hospitalists turnover. Our work provides insights into strategies for the initial engagement of inpatient general medicine providers that we hope will benefit other institutions seeking to implement pharmacogenomics in the inpatient setting.

药物基因组学是个性化医疗的重要组成部分。预防性药物基因组学检测仅在住院患者中很少使用,迄今为止,在住院患者中促进采用药物基因组学治疗的模式很少。我们在芝加哥创建了一个多机构项目,将药物基因组学转化为住院治疗。我们正在报告我们的实施过程和我们在解决方案中遇到的障碍。这项名为“为少数族裔差异实施即时护理药物基因组学决策支持”的研究,试图将药物基因组学应用到三个地点的住院实践中:芝加哥大学、西北纪念医院和芝加哥伊利诺伊大学。这项研究包括招募非裔美国成年患者,通过一组可操作的种系变异预测药物反应或毒性风险,进行先发制人的基因分型。我们报告了我们的实施方法和我们在住院患者药物基因组干预中遇到的障碍,包括医院医生和普通医疗提供者。我们的策略包括:一个简化的药物基因组学信息传递系统,参加医院医学部门会议,使用医生和药剂师冠军,关注医院医生的护理和优化系统功能以适应他们的工作流程,交接和处理医院医生的周转。我们的工作为住院普通医学提供者的初始参与策略提供了见解,我们希望这将有利于其他寻求在住院环境中实施药物基因组学的机构。
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引用次数: 2
A lifetime economic research of universal HLA-B*58:01 genotyping or febuxostat initiation therapy in Chinese gout patients with mild to moderate chronic kidney disease. 中国痛风合并轻中度慢性肾病患者HLA-B*58:01基因分型或非布司他起始治疗的终生经济研究
IF 2.6 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2023-02-01 DOI: 10.1097/FPC.0000000000000488
Yuan Hong, Xichuang Chen, Zhiping Li, Xiaoyan Zhang, Cong Zhou, Yan Wang, Guangfei Wang, Wei Wu, Danli Zhou, Hai Feng Li

Objective: To evaluate Chinese long-term economic impact of universal human leukocyte antigen B (HLA-B)*58:01 genotyping-guided urate-lowering therapy or febuxostat initiation therapy for gout patients with mild to moderate chronic kidney disease (CKD) from perspective of healthcare system.

Methods: A Markov model embedded in a decision tree was structured including four mutually exclusive health states (uncontrolled-on-therapy, controlled-on-therapy, uncontrolled-off-therapy, and death). Mainly based on Chinese real-world data, the incremental costs per quality-adjusted life years (QALYs) gained were evaluated from three groups (universal HLA-B*58:01 testing strategy, and no genotyping prior to allopurinol or febuxostat initiation therapy) at 25-year time horizon. All costs were adjusted to 2021 levels based on Chinese Consumer Price Index and were discounted by 5% annually. One-way and probability sensitivity analysis were performed.

Results: Among these three groups, universal HLA-B*58:01 genotyping was the most cost-effective strategy in base-case analysis according to Chinese average willingness-to-pay threshold of $37 654.50 per QALY. The based incremental cost-effectiveness ratio was $31784.55 per QALY, associated with 0.046 additional QALYs and $1463.81 increment costs per patient at a 25-year time horizon compared with no genotyping prior to allopurinol initiation strategy. Sensitivity analysis showed 64.3% robustness of these results.

Conclusion: From Chinese perspective of healthcare system, HLA-B*58:01 genotyping strategy was cost-effective for gout patients with mild to moderate CKD in mainland China, especially in the most developed area, such as Beijing and Shanghai. Therefore, we suggest China's health authorities choose the genotyping strategy and make different recommendations according to the differences of local conditions.

目的:从卫生保健系统角度评价通用人白细胞抗原B (HLA-B)*58:01基因分型引导的降尿酸治疗或非布司他起始治疗对痛风合并轻中度慢性肾病(CKD)患者的长期经济影响。方法:构建一个嵌入决策树的马尔可夫模型,包括四种互斥的健康状态(不受控制的治疗、不受控制的治疗、不受控制的治疗和死亡)。主要基于中国真实世界数据,从三组(通用HLA-B*58:01检测策略,在别嘌呤醇或非布司他起始治疗前未进行基因分型)中评估25年时间范围内获得的每个质量调整生命年(QALYs)的增量成本。所有成本均根据中国消费者价格指数调整至2021年水平,并按5%折现。进行单因素分析和概率敏感性分析。结果:根据中国人平均支付意愿阈值为37654.50美元/ QALY,在这三组中,通用HLA-B*58:01基因分型是基本病例分析中最具成本效益的策略。基于增量成本-效果比为每个QALY 31784.55美元,与在别嘌呤醇起始策略之前没有基因分型的患者相比,在25年的时间范围内,每位患者额外的QALY为0.046美元,增量成本为1463.81美元。敏感性分析结果稳健性为64.3%。结论:从中国医疗体系的角度来看,HLA-B*58:01基因分型策略在中国大陆地区,特别是在北京、上海等发达地区,对轻中度CKD痛风患者具有成本效益。因此,我们建议中国卫生部门选择基因分型策略,并根据当地情况的差异提出不同的建议。
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Pharmacogenetics and genomics
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