Pharmacogenomic Variants

药物基因组变异
  • 文章类型: Journal Article
    目的:研究CYP2C9(*2和*3等位基因)和VKORC1(rs9923231)基因的个体差异是否与非甾体抗炎药(NSAIDs)或低剂量阿司匹林(LDA)使用者的上消化道出血(UGIB)风险增加有关。方法:在巴西一家综合医院进行了一项全面的病例对照研究,包括200例诊断为UGIB的患者和706例对照。进行NSAIDs剂量效应分析,NSAIDs的规定日剂量(DDD)是在数据指数之前的7天病因窗中计算的.三类DDD,考虑到遗传变异的基因型,建立:非甾体抗炎药的非使用者(DDD=0),DDD≤0.5,且DDD>0.5。遗传变异体和LDA或NSAIDs使用的协同作用通过协同作用指数(SI)和由于相互作用的相对过量风险(RERI)来估计。结果:对于高于0.50的NSAIDs,在*3等位基因携带者(OR:15,650,95%CI:1.41-174.10)和rs9923231变体纯合基因型(TT)携带者(OR:38,850,95%CI:2.70-556.00)中确定了UGIB的风险。在LDA用户中,在CYP2C9和VKORC1基因的野生型纯合基因型携带者和变异等位基因携带者之间,观察到UGIB的风险相似.没有发现协同作用。结论:我们的研究结果表明,rs9923231变异等位基因携带者和与NSAIDs剂量大于0.5相关的*3等位基因携带者中UGIB的风险增加。因此,对这些变异体的评估可能会降低NSAIDs相关UGIB的发生率,并有助于NSAIDs使用者的安全性.
    Purpose: To investigate whether interindividual variability in the CYP2C9 (*2 and *3 alleles) and VKORC1 (rs9923231) genes is associated with increased risk of upper gastrointestinal bleeding (UGIB) in users of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA). Methods: A full case-control study including 200 cases of patients diagnosed with UGIB and 706 controls was conducted in a Brazilian hospital complex. To perform an analysis of NSAIDs dose-effect, the defined daily dose (DDD) for NSAIDs was calculated in the 7-day etiologic window preceding the data index. Three categories of DDD, considering the genotypes of the genetic variants, were established: non-users of NSAIDs (DDD = 0), DDD ≤0.5, and DDD >0.5. Genetic variants and LDA or NSAIDs use synergism was estimated through Synergism Index (SI) and Relative Excess Risk Due To Interaction (RERI). Results: For DDDs of NSAIDs upward of 0.50, a risk of UGIB was identified in carriers of the *3 allele (OR: 15,650, 95% CI: 1.41-174.10) and in carriers of the variant homozygous genotype (TT) of rs9923231 (OR: 38,850, 95% CI: 2.70-556.00). In LDA users, the risk of UGIB was observed to be similar between carriers of the wild type homozygous genotype and carriers of the variant alleles for the CYP2C9 and VKORC1 genes. No synergism was identified. Conclusion: Our findings suggest an increased risk of UGIB in carriers of the variant allele of rs9923231 and in carriers of the *3 allele associated with doses of NSAIDs greater than 0.5. Hence, the assessment of these variants might reduce the incidence of NSAIDs-related UGIB and contribute to the safety of the NSAIDs user.
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  • 文章类型: Journal Article
    背景:GST非功能性基因型可导致有毒中间体的积累,导致肝损伤和增加对ATDH的易感性。
    目的:为了研究GSTMu(GSTM1)的影响,GSTTheta(GSTT1)无效基因型,和GSTPi(GSTP1;腺苷(A)>鸟嘌呤(G),rs1695)变异等位基因对接受抗结核治疗的突尼斯患者ATDH发展的影响。
    方法:这是一项病例对照研究,包括接受抗结核治疗的患者。病例(n=23)是在抗结核药物治疗两个月期间出现ATDH的结核病患者。对照组(n=30)是接受结核病治疗的患者,但没有提交ATDH。使用聚合酶链反应-限制性片段长度多态性进行基因分型。
    结果:在GSTM1和GSTT1纯合无效基因型之间没有观察到统计学上显著的关联,以及ATDH的风险。GSTM1和GSTT1双无效基因型之间有统计学意义的关联,在病例和对照组之间发现ATDH的风险(p=0.033)。对于GSTP1,与野生和过渡A到G(AAAG)基因型相比,GG纯合突变基因型的分布与ATDH显着相关。
    结论:突尼斯人群中GSTM1和GSTT1的双重缺失可能易患ATDH。此外,GSTP1rs1695(A>G)基因分型可以预测ATDH的易感性。
    BACKGROUND: GST non-functional genotypes can lead to the accumulation of toxic intermediates, resulting in liver damage and increasing susceptibility to ATDH.
    OBJECTIVE: To investigate the impact of GST Mu (GSTM1), GST Theta (GSTT1) null genotypes, and GST Pi (GSTP1; adenosine (A) > guanine (G), rs1695) variant allele on the development of ATDH in Tunisian patients treated with anti-tuberculosis therapy.
    METHODS: This was a case-control study including patients receiving anti-tuberculosis regimen. Cases (n = 23) were tuberculosis patients presenting ATDH during two months of anti-tuberculosis drug therapy. Controls (n = 30) were patients treated for tuberculosis, but presenting no ATDH. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism.
    RESULTS: No statistically significant association was observed between GSTM1 and GSTT1 homozygous null genotypes, and the risk of ATDH. A statistically significant association between GSTM1 and GSTT1 double null genotypes, and the risk of ATDH was found (p = 0.033) between cases and controls. For GSTP1, the distribution of GG homozygous mutant genotype was significantly associated with ATDH compared with the wild and the transition A to G (AA + AG) genotypes.
    CONCLUSIONS: Double deletion of GSTM1 and GSTT1 may predispose to ATDH in a Tunisian population. Moreover, GSTP1 rs1695 (A > G) genotyping can predict susceptibility to developing ATDH.
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  • 文章类型: Case Reports
    We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient\'s pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine.
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  • 文章类型: Case Reports
    背景:具有BCR/ABL突变(Ph+B-LBL)的B淋巴母细胞淋巴瘤(B-LBL)是儿童和成人罕见的癌症类型。其临床表现与其他类型淋巴瘤相似。然而,靶向治疗可以显著改善Ph+B-LBL的预后。
    方法:一名19岁的O型血男性,Rh+于2018年8月14日入院,因反复发烧和低细胞血症6个月。
    方法:血常规检查显示全血细胞减少。骨髓样本流式细胞术(FCM)检查显示异常细胞占有核细胞的2.27%,并被分类为异常的早期B系淋巴母细胞。FISH检测显示BCR/ABL阳性细胞率为13.6%。核型分析显示46,XY,t(9;22)(q34;q11)。ABL激酶上BCR/ABL突变的分子分析显示BCR/ABLT315I突变。患者被诊断为具有BCR/ABL突变的B-LBL(Ph+B-LBL)。
    方法:患者给予VDPI方案化疗(长春瑞滨,柔红霉素,泼尼松,伊马替尼)。
    结果:患者在治疗2个疗程后达到完全缓解,随后是一个疗程的克拉霉素方案和另外两个疗程的VDPI方案。截至2021年3月10日,患者仍处于完全缓解状态。
    结论:在B-LBL中,其中一些患者可能发生BCR/ABL突变。指导病理学家进行适当的基因突变检测,除了常规的免疫组织化学检查,以确保准确诊断并使用靶向药物进行治疗。根据文献和我们的研究结果,似乎强化化疗加TKI方案对诱导完全缓解有效,和全SCT应用作长期策略。
    BACKGROUND: B-lymphoblastic lymphoma (B-LBL) with BCR/ABL mutation (Ph+ B-LBL) is a rare type of cancer in both childhood and adults. Its clinical manifestations are similar to those of other types lymphoma. However, the targeted therapy can substantially improve the outcome of Ph+ B-LBL.
    METHODS: A 19-year-old male with blood type O, Rh+ was admitted into our hospital on August 14, 2018, due to a recurrent fever and hypocytosis for 6 months.
    METHODS: Routine blood exam showed pancytopenia. Bone marrow sample flow cytometry (FCM) exam showed abnormal cells were 2.27% of the nucleated cells, and was classified as the abnormal early B-lineage lymphoblastic cells. FISH testing showed the BCR/ABL positive cells were 13.6%. Karyotype analysis showed the 46, XY, t(9;22)(q34;q11). Molecular analysis of BCR/ABL mutation on ABL kinase showed that BCR/ABL T315I mutation. Patient was diagnosed with B-LBL with BCR/ABL mutation (Ph+ B-LBL).
    METHODS: The patient was given chemotherapy with VDPI regimen (Vinorelbine, daunorubicin, prednisone, imatinib).
    RESULTS: The patient achieved complete remission after 2 courses\' treatment, followed by one course of clarithromycin regimen and another two courses of VDPI regimen. Patient remains in complete remission as of March 10, 2021.
    CONCLUSIONS: In B-LBL, a BCR/ABL mutation can happen in some of these patients. It is important to guide the pathologist to perform appropriate gene mutation detection, in addition to routine Immunohistochemistry test, to ensure an accurate diagnosis and use the targeted agent for treatment. According to the literature and our results, it seems that intensive chemotherapy plus TKI regimen is effective in inducing complete remission, and allo-SCT should be used as a long-term strategy.
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  • 文章类型: Case Reports
    背景:据报道,具有单个上皮生长因子受体(EGFR)激活突变的非小细胞肺癌(NSCLC)患者在接受EGFR-TKIs治疗时具有较高的客观缓解率。然而,由于罕见的案件,EGFR双突变或多突变患者的反应尚不清楚.患者来源的类器官技术已成为癌症个性化医疗的有力工具。
    方法:一名60岁不吸烟的女性因胸部CT术后肺癌入院。
    方法:患者无明显临床症状。术后病理证实为I期NSCLC。在患者的癌症样本序列中检测到EGFR双突变19Del/L643V。
    方法:患者手术切除后情况良好,没有肺癌复发的迹象.患者尚未开始使用靶向药物。
    结果:从患者的癌组织中建立了肺癌类器官培养物,概括了癌组织的形态和分子特征。药物敏感性试验显示,保留原始突变的癌症类器官对抗癌药奥希替尼和吉非替尼敏感,而对埃罗替尼和埃克替尼耐药。
    结论:不常见的EGFR双突变对EGFR-TKIs的不同靶药物表现出独特的敏感性。我们的研究结果为EGFR-TKIs对具有不常见EGFR双突变的患者来源的癌症类器官的影响提供了更好的理解。
    BACKGROUND: It has been well reported that non-small-cell lung cancer (NSCLC) patients with single epithelial growth factor receptor (EGFR) activating mutation have high objective response rate when treated with EGFR-TKIs. However, due to rarity of cases, the response of patients with EGFR double or multiple mutations is not yet well understood. Patient-derived organoid technology has become to a powerful tool in cancer personalized medicine.
    METHODS: A 60-year-old nonsmoking female was admitted to hospital for lung cancer after Chest CT.
    METHODS: The patient had no obvious clinical symptoms. Postoperative pathology confirmed a stage I of NSCLC. An EGFR double mutation 19Del/L643V was detected in the sequence of patient\'s cancer specimen.
    METHODS: The patient was in good condition after surgical resection, with no sign of lung cancer recurrence. The patient has not yet started on targeted medicine.
    RESULTS: A lung cancer organoid culture was established from the cancer tissue of the patient, which recapitulated the morphological and molecular characteristics of cancer tissue. The drug sensitivity test showed that the cancer organoids that retained original mutations were sensitive to anticancer agents osimertinib and gefitinib, while resistant to erlotinib and icotinib.
    CONCLUSIONS: The uncommon EGFR double mutation exhibits distinctive sensitivities towards different target drugs of EGFR-TKIs. Our findings provide a better understanding of EGFR-TKIs\' effects on patient-derived cancer organoids harboring uncommon EGFR double mutation(s).
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  • 文章类型: Journal Article
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  • 文章类型: Case Reports
    Prader-Willi syndrome (PWS) is associated with co-morbid psychiatric symptoms (disruptive behavior, anxiety, mood disorders, and psychosis) often requiring psychotropic medications. In this clinical case series of 35 patients with PWS, pharmacogenetic testing was obtained to determine allele frequencies predicting variations in activity of cytochrome (CYP) P450 drug metabolizing enzymes 2D6, 2B6, 2C19, 2C9, 3A4, and 1A2. Results were deidentified, collated, and analyzed by PWS genetic subtype: 14 deletion (DEL), 16 maternal uniparental disomy (UPD) and 5 DNA-methylation positive unspecified molecular subtype (PWS Unspec). Literature review informed comparative population frequencies of CYP polymorphisms, phenotypes, and substrate specificity. Among the total PWS cohort, extensive metabolizer (EM) activity prevailed across all cytochromes except CYP1A2, which showed greater ultra-rapid metabolizer (UM) status (p < 0.05), especially among UPD. Among PWS genetic subtypes, there were statistically significant differences in metabolizing status for cytochromes 2D6, 2C19, 2C9, 3A4 and 1A2 acting on substrates such as fluoxetine, risperidone, sertraline, modafinil, aripiprazole, citalopram, and escitalopram. Gonadal steroid therapy may further impact metabolism of 2C19, 2C9, 3A4 and 1A2 substrates. The status of growth hormone treatment may affect CYP3A4 activity with gender specificity. Pharmacogenetic testing together with PWS genetic subtyping may inform psychotropic medication dosing parameters and risk for adverse events.
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  • 文章类型: Case Reports
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  • 文章类型: Journal Article
    选择合适的治疗和给药方案是癌症治疗中的重大挑战。尽管对于某些类型的癌症有推荐的标准化化疗方案,通常仅在大型临床试验证明改善后才会发生方案变化,并且由于毒性的出现,个体患者通常需要修改剂量(剂量或间隔)或延迟剂量给药。在其他医学领域,治疗药物监测通常成功地用于确保适当的药物暴露并限制剂量相关毒性。目前,通过使用体表面积来确定药物剂量,在临床上解决了细胞毒性化疗的广泛药代动力学变异性;然而,这是过时的,显然对此无效。这篇综述讨论了剂量细胞毒性化疗的挑战,细胞毒性的剂量确定策略,有针对性的,和基于抗体的生物抗癌药物,并提供了有关癌症治疗药物监测的最新文献的概述。
    The selection of an appropriate therapy and dosing regimen is a significant challenge in the treatment of cancer. Although there are recommended standardized chemotherapy protocols for some types of cancer, protocol changes that usually only occur after large clinical trials demonstrate improvements and individual patients often require dose modifications (amount or interval) or delays in dose administration as toxicities arise. In other areas of medicine, therapeutic drug monitoring is commonly and successfully used to ensure appropriate drug exposure and to limit dose-related toxicities. Currently, the wide pharmacokinetic variability of cytotoxic chemotherapies is addressed clinically by the use of body surface area to determine drug doses; however, this is outdated and demonstrably ineffective for this purpose. This review discusses the challenges of dosing cytotoxic chemotherapies, dose determination strategies for cytotoxic, targeted, and antibody-based biological anticancer drugs, and provides an overview of the recent literature regarding the use of therapeutic drug monitoring in cancer.
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  • 文章类型: Case Reports
    Anthracyclines are highly effective anticancer medication prescribed for the treatment of breast cancer. Nevertheless, the use of anthracyclines as chemotherapeutic agents involves a risk for development of cardiac toxicity which may cause restrictive and dilated cardiomyopathy. Currently, genetic predisposition is not considered as a risk factor for cardiotoxicity associated to the use of anthracyclines.
    We report the case of a 37-years old Panamanian female patient diagnosed with breast cancer who developed clinical signs of severe heart failure after treatment with doxorubicin. A diagnosis of anthracycline induced cardiomyopathy was made and treatment was initiated accordingly. A whole exome sequencing study performed to the patient showed the presence of a missense mutation in LMNA gene, which codifies for lamin A/C. Our results points to a correlation between the LMNA variant and the anthracycline cardiotoxicity developed by the woman. Improvement of the clinical symptoms and the left ventricle ejection fraction was observed after proper treatment.
    This case report suggests for the first time a potential genetic predisposition for anthracyclines induced cardiomyopathy in patients with mutations in LMNA gene. Perhaps chemotherapies accelerate or deliver the \"second-hit\" in the development of DCM in patients with genetic mutations. More data is needed to understand the contribution of LMNA variants that predispose to DCM in patients receiving cardiotoxic therapies.
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