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Genotyping of Patients with Adverse Drug Reaction or Therapy Failure: Database Analysis of a Pharmacogenetics Case Series Study. 药物不良反应或治疗失败患者的基因分型:药物遗传学病例系列研究的数据库分析。
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S415259
Anna Bollinger, Céline K Stäuble, Chiara Jeiziner, Florine M Wiss, Kurt E Hersberger, Markus L Lampert, Henriette E Meyer Zu Schwabedissen, Samuel S Allemann

Purpose: Pharmacogenetics (PGx) is an emerging aspect of personalized medicine with the potential to increase efficacy and safety of pharmacotherapy. However, PGx testing is still not routinely integrated into clinical practice. We conducted an observational case series study where PGx information from a commercially available panel test covering 30 genes was integrated into medication reviews. The aim of the study was to identify the drugs that are most frequently object of drug-gene-interactions (DGI) in the study population.

Patients and methods: In out-patient and in-patient settings, we recruited 142 patients experiencing adverse drug reaction (ADR) and/or therapy failure (TF). Collected anonymized data from the individual patient was harmonized and transferred to a structured database.

Results: The majority of the patients had a main diagnosis of a mental or behavioral disorder (ICD-10: F, 61%), of musculoskeletal system and connective tissue diseases (ICD-10: M, 21%), and of the circulatory system (ICD-10: I, 11%). The number of prescribed medicines reached a median of 7 per person, resulting in a majority of patients with polypharmacy (≥5 prescribed medicines, 65%). In total, 559 suspected DGI were identified in 142 patients. After genetic testing, an association with at least one genetic variation was confirmed for 324 suspected DGI (58%) caused by 64 different drugs and 21 different genes in 141 patients. After 6 months, PGx-based medication adjustments were recorded for 62% of the study population, whereby differences were identified in subgroups.

Conclusion: The data analysis from this study provides valuable insights for the main focus of further research in the context of PGx. The results indicate that most of the selected patients in our sample represent suitable target groups for PGx panel testing in clinical practice, notably those taking drugs for mental or behavioral disorder, circulatory diseases, immunological diseases, pain-related diseases, and patients experiencing polypharmacy.

目的:药物遗传学(PGx)是个性化医疗的一个新兴方面,具有提高药物治疗有效性和安全性的潜力。然而,PGx检测仍未常规纳入临床实践。我们进行了一项观察性病例系列研究,将来自涵盖30个基因的市售面板测试的PGx信息整合到药物评价中。该研究的目的是确定在研究人群中最常成为药物-基因相互作用(DGI)对象的药物。患者和方法:在门诊和住院环境中,我们招募了142名出现药物不良反应(ADR)和/或治疗失败(TF)的患者。从个别患者收集的匿名数据被协调并转移到结构化数据库。结果:大多数患者的主要诊断为精神或行为障碍(ICD-10: F, 61%)、肌肉骨骼系统和结缔组织疾病(ICD-10: M, 21%)和循环系统疾病(ICD-10: I, 11%)。处方药物数量中位数达到每人7种,导致大多数患者使用多种药物(处方药物≥5种,65%)。142例患者中共发现559例疑似DGI。基因检测后,141例患者中64种不同药物和21种不同基因引起的324例疑似DGI(58%)与至少一种遗传变异相关。6个月后,62%的研究人群记录了基于pgx的药物调整,从而在亚组中确定了差异。结论:本研究的数据分析为PGx背景下的进一步研究重点提供了有价值的见解。结果表明,我们样本中的大多数患者代表了临床实践中PGx面板检测的合适目标群体,特别是那些服用精神或行为障碍、循环系统疾病、免疫疾病、疼痛相关疾病的患者,以及服用多种药物的患者。
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引用次数: 0
A Review of the Pharmacokinetic Characteristics of Immune Checkpoint Inhibitors and Their Clinical Impact Factors. 免疫检查点抑制剂的药代动力学特性及其临床影响因素综述。
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S391756
Jun-Chen Liu, Hong-Jing Yu

Immune checkpoint inhibitors (ICIs) have been shown to be significant in improving the overall survival rate in certain malignancies with poor prognoses. However, only 20-40% of patients achieve long-term benefits, highlighting the relevance of the factors that influence the treatment, which can help clinicians improve their results and guide the development of new immune checkpoint therapies. In this study, the current pharmacokinetic aspects associated with the ICIs and the factors influencing clinical efficacy were characterised, including in terms of drug metabolism, drug clearance, hormonal effects and immunosuppressive effects.

免疫检查点抑制剂(ICIs)已被证明在改善某些预后不良的恶性肿瘤的总生存率方面具有重要意义。然而,只有20-40%的患者获得长期受益,这突出了影响治疗的因素的相关性,这可以帮助临床医生改善他们的结果并指导新的免疫检查点疗法的发展。本研究从药物代谢、药物清除率、激素作用和免疫抑制作用等方面对目前与ICIs相关的药代动力学方面和影响临床疗效的因素进行了描述。
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引用次数: 0
Rs11479 in Thymidine Phosphorylase Associated with Prognosis of Patients with Colorectal Cancer Who Received Capecitabine-Based Adjuvant Chemotherapy. 胸苷磷酸化酶Rs11479与结直肠癌患者卡培他滨辅助化疗预后的关系
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S397382
Xiongjie Jia, Tao Zhang, Junjie Sun, Hengxue Lin, Tianliang Bai, Yating Qiao, Yaxin Li, Gang Li, Guicun Li, Xinyu Peng, Aimin Zhang

Objective: Thymidine Phosphorylase (TYMP) gene was of potential significance in the process of colorectal cancer (CRC) development and played an important role in capecitabine metabolism. This study was to identify the association between TYMP polymorphism and prognosis of postoperative patients with CRC who received capecitabine-based adjuvant chemotherapy.

Methods: A total of 218 patients with CRC who were treated with surgical resection and capecitabine-based adjuvant chemotherapy were included in this study retrospectively. Peripheral blood and peripheral blood mononuclear cell (PBMC) specimen of the patients were collected for the genotyping of TYMP polymorphism and TYMP mRNA expression, respectively. Univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, Cox regression analysis was adopted in multivariate analysis. The mRNA expression of TYMP according to genotype status was analyzed using non-parameter test.

Results: Prevalence of rs11479 in TYMP among the 218 patients exhibited that minor allele frequency of rs11479 was 0.20 (GG 141 cases, GA 68 cases and AA 9 cases), which was in accordance with Hardy-Weinberg equilibrium (P=0.825). Association analysis suggested that the median disease-free survival (DFS) of patients with GG genotype and GA/AA genotype was 3.1 and 6.1 years, respectively (P=0.004). Furthermore, the median overall survival of patients with GG genotype and GA/AA genotype was 5.0 and 7.0 years, respectively (P=0.033). Multivariate Cox regression analysis exhibited that rs11479 polymorphism was an independent factor for DFS (HR = 1.64, P=0.009). Additionally, of the 65 PBMC specimens, mRNA expression results indicated that patients with GA/AA genotypes conferred significantly higher mRNA expression of TYMP than that of patients with GG genotype (P<0.001).

Conclusion: Polymorphism rs11479 in TYMP gene might predict the prognosis of patients with CRC who received capecitabine-based adjuvant chemotherapy through mediation of the mRNA expression of TYMP. The conclusion of this study should be validated in prospective clinical trials subsequently.

目的:胸苷磷酸化酶(TYMP)基因在结直肠癌(CRC)发生发展过程中具有潜在意义,在卡培他滨代谢中发挥重要作用。本研究旨在确定TYMP多态性与术后接受卡培他滨辅助化疗的结直肠癌患者预后的关系。方法:回顾性分析218例行手术切除加卡培他滨辅助化疗的结直肠癌患者。采集患者外周血和外周血单个核细胞(PBMC)标本,分别对TYMP多态性和TYMP mRNA表达进行基因分型。单因素分析基因型与预后采用Kaplan-Meier生存分析,多因素分析采用Cox回归分析。采用非参数检验分析不同基因型的TYMP mRNA表达情况。结果:218例TYMP患者中rs11479的患病率显示,rs11479的次要等位基因频率为0.20 (GG 141例,GA 68例,AA 9例),符合Hardy-Weinberg平衡(P=0.825)。相关性分析显示,GG基因型和GA/AA基因型患者的中位无病生存期(DFS)分别为3.1年和6.1年(P=0.004)。GG基因型和GA/AA基因型患者的中位总生存期分别为5.0年和7.0年(P=0.033)。多因素Cox回归分析显示,rs11479多态性是影响DFS的独立因素(HR = 1.64, P=0.009)。此外,在65例PBMC标本中,mRNA表达结果显示GA/AA基因型患者的TYMP mRNA表达量显著高于GG基因型患者(p结论:TYMP基因rs11479多态性可能通过介导TYMP mRNA表达来预测卡培他滨辅助化疗的结直肠癌患者的预后。本研究结论应在后续的前瞻性临床试验中得到验证。
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引用次数: 1
Acute Myeloid Leukemia Secondary to Chronic Lymphocytic Leukemia After Prolonged Chlorambucil Therapy: A Case Report. 长期氯霉素治疗后继发于慢性淋巴细胞白血病的急性髓性白血病一例报告。
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S407940
Yan Wu, Shan Liu, Dongmei Wang, Xinjie Yao

Background: This study aimed to improve the understanding of acute myeloid leukemia (AML) secondary to chronic lymphocytic leukemia (CLL), and to explore the sequence of occurrence and clonal origin of the two diseases.

Case report: We reported a case of a 71-year-old man with a history of CLL. The patient was administrated with chlorambucil for 19 years and was admitted to our hospital due to fever. Then he was subjected with routine blood tests, bone marrow smear examination, flow cytometric immunophenotyping and cytogenetic analysis. A final diagnosis of AML-M2 secondary to CLL with -Y,del(4q),del(5q),-7,add(12p),der(17),der(18),-22,+mar was made. After rejecting the therapy with Azacitidine combined with B-cell lymphoma-2 (Bcl-2) inhibitor, the patient died of pulmonary infection.

Conclusion: This case highlights the rare occurrence of AML secondary to CLL after prolonged chlorambucil therapy and the poor prognosis of such cases, underscoring the importance of enhanced assessment of these patients.

背景:本研究旨在提高对继发于慢性淋巴细胞白血病(CLL)的急性髓系白血病(AML)的认识,探讨两种疾病的发生序列和克隆起源。病例报告:我们报告了一例71岁男性CLL病史。患者用药氯苯19年,因发热入院。然后进行血常规、骨髓涂片检查、流式细胞术免疫表型和细胞遗传学分析。最终诊断继发于CLL的AML-M2为-Y、del(4q)、del(5q)、-7、add(12p)、der(17)、der(18)、-22、+mar。在拒绝阿扎胞苷联合b细胞淋巴瘤-2 (Bcl-2)抑制剂治疗后,患者死于肺部感染。结论:本病例突出了氯霉素长期治疗后继发于CLL的AML发生率较低,且预后较差,强调了加强对这类患者评估的重要性。
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引用次数: 0
Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects. 两家系复发性胎儿先天性心脏缺陷的新致病变异检测。
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S394120
Rongqin Cai, Ya Tan, Mingming Wang, Huijun Yu, Jing Wang, Zhuo Ren, Zhe Dong, Yiwen He, Zhi Li, Li Lin, Ying Gu

Background: Congenital heart disease (CHD) is the most common birth defect with strong genetic heterogeneity. To date, about 400 genes have been linked to CHD, including cell signaling molecules, transcription factors, and structural proteins that are important for heart development. Genetic analysis of CHD cases is crucial for clinical management and etiological analysis.

Methods: Whole-exome sequencing (WES) was performed to identify the genetic variants in two independent CHD cases with DNA samples from fetuses and their parents, followed by the exclusion of aneuploidy and large copy number variations (CNVs). The WES results were verified by Sanger sequencing.

Results: In family A, a compound heterozygous variation in PLD1 gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus. The two variants were inherited from the father (c.1132dupA) and the mother (c.1171C>T), respectively. In family B, a hemizygous variant ZIC3: c.861delG (p.G289Afs*119) was identified in the fetus, which was inherited from the heterozygous mother. We further confirmed that these variants PLD1: c.1132dupA and ZIC3: c.861delG were novel.

Conclusion: The findings in our study identified novel variants to the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options to the affected families. Our study also demonstrates that WES has considerable prospects of clinical application in prenatal diagnosis.

背景:先天性心脏病(CHD)是最常见的先天缺陷,具有很强的遗传异质性。迄今为止,大约有400个基因与冠心病有关,包括细胞信号分子、转录因子和对心脏发育很重要的结构蛋白。冠心病病例的遗传分析对临床管理和病因分析至关重要。方法:采用全外显子组测序(WES)鉴定两例独立冠心病患者的遗传变异,并排除非整倍体和大拷贝数变异(CNVs)。通过Sanger测序对WES结果进行验证。结果:A家族在胎儿中发现了由c.1132dupA (p.I378fs)和c.1171C>T (p.R391C)组成的PLD1基因复合杂合变异。这两个变异分别遗传自父亲(c.1132dupA)和母亲(c.1171C>T)。在B家族中,胎儿中发现了一个半合子变异ZIC3: c.861delG (p.G289Afs*119),该变异遗传自杂合母亲。我们进一步证实这些变异PLD1: c.1132dupA和ZIC3: c.861delG是新的。结论:我们的研究结果确定了冠心病突变谱的新变异,为患病家庭的复发风险和生殖保健选择提供了可靠的证据。我们的研究也表明WES在产前诊断中具有相当的临床应用前景。
{"title":"Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects.","authors":"Rongqin Cai,&nbsp;Ya Tan,&nbsp;Mingming Wang,&nbsp;Huijun Yu,&nbsp;Jing Wang,&nbsp;Zhuo Ren,&nbsp;Zhe Dong,&nbsp;Yiwen He,&nbsp;Zhi Li,&nbsp;Li Lin,&nbsp;Ying Gu","doi":"10.2147/PGPM.S394120","DOIUrl":"https://doi.org/10.2147/PGPM.S394120","url":null,"abstract":"<p><strong>Background: </strong>Congenital heart disease (CHD) is the most common birth defect with strong genetic heterogeneity. To date, about 400 genes have been linked to CHD, including cell signaling molecules, transcription factors, and structural proteins that are important for heart development. Genetic analysis of CHD cases is crucial for clinical management and etiological analysis.</p><p><strong>Methods: </strong>Whole-exome sequencing (WES) was performed to identify the genetic variants in two independent CHD cases with DNA samples from fetuses and their parents, followed by the exclusion of aneuploidy and large copy number variations (CNVs). The WES results were verified by Sanger sequencing.</p><p><strong>Results: </strong>In family A, a compound heterozygous variation in <i>PLD1</i> gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus. The two variants were inherited from the father (c.1132dupA) and the mother (c.1171C>T), respectively. In family B, a hemizygous variant <i>ZIC3</i>: c.861delG (p.G289Afs*119) was identified in the fetus, which was inherited from the heterozygous mother. We further confirmed that these variants <i>PLD1</i>: c.1132dupA and <i>ZIC3</i>: c.861delG were novel.</p><p><strong>Conclusion: </strong>The findings in our study identified novel variants to the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options to the affected families. Our study also demonstrates that WES has considerable prospects of clinical application in prenatal diagnosis.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":"16 ","pages":"173-181"},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/33/42/pgpm-16-173.PMC10008912.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9475734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Serum Osteopontin, KL-6, and Syndecan-4 as Potential Biomarkers in the Diagnosis of Coal Workers' Pneumoconiosis: A Case-Control Study. 血清骨桥蛋白、KL-6和Syndecan-4作为煤工尘肺诊断的潜在生物标志物:一项病例对照研究
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S409644
Zhifei Hou, Xinran Zhang, Yong Gao, Jing Geng, Yu Jiang, Huaping Dai, Chen Wang
Background Coal worker’s pneumoconiosis (CWP) is a chronic occupational disease mainly caused by coal dust inhalation in miners. This study aimed to investigate the clinical value of Osteopontin (OPN), KL-6, Syndecan-4 and Gremlin-1 as serum biomarkers in CWP. Patients and Methods We integrated reported lung tissues transcriptome data in pneumoconiosis patients with silica-exposed alveolar macrophage microarray data to identify four CWP-associated serum biomarkers. The serum concentrations of Osteopontin, Krebs von den Lungen-6 (KL-6), Syndecan-4 and Gremlin-1 were measured in 100 healthy controls (HCs), 100 dust-exposed workers (DEWs) and 200 patients of CWP. Receiver operating characteristic (ROC) curve analysis was used to determine the sensitivity, specificity, cut-off value and area under the curve (AUC) value of biomarkers. Results The pulmonary function parameters decreased sequentially, and the serum OPN, KL-6, Syndecan-4 and Gremlin-1 concentrations were increased sequentially among the HC, DEW and CWP groups. Among all participants, multivariable analysis revealed that these four biomarkers were negatively correlated with the pulmonary function parameters (all p<0.05). Compared with HCs, patients with higher OPN, KL-6, Syndecan-4 and Gremlin-1 had higher risk for CWP. The combination of OPN, KL-6, and Syndecan-4 can improve the diagnostic sensitivity and specificity of CWP patients differentiated from HCs or DEWs. Conclusion OPN, KL-6 and Syndecan-4 are novel biomarkers that can be used for CWP auxiliary diagnosis. The combination of three biomarkers can improve the diagnostic values of CWP.
背景:煤矿工人尘肺病是一种主要由煤矿工人吸入煤尘引起的慢性职业病。本研究旨在探讨骨桥蛋白(Osteopontin, OPN)、KL-6、Syndecan-4和Gremlin-1作为CWP血清生物标志物的临床价值。患者和方法:我们将尘肺患者的肺组织转录组数据与二氧化硅暴露的肺泡巨噬细胞微阵列数据相结合,以确定四种与cwp相关的血清生物标志物。测定了100例健康对照(hc)、100例粉尘暴露工人(DEWs)和200例CWP患者血清骨桥蛋白(Osteopontin)、Krebs von den Lungen-6 (KL-6)、Syndecan-4和Gremlin-1的浓度。采用受试者工作特征(ROC)曲线分析确定生物标志物的敏感性、特异性、截止值和曲线下面积(AUC)值。结果:HC组、DEW组和CWP组肺功能指标依次下降,血清OPN、KL-6、Syndecan-4、Gremlin-1浓度依次升高。在所有参与者中,多变量分析显示这四种生物标志物与肺功能参数呈负相关(均为pp结论:OPN、KL-6和Syndecan-4是可用于CWP辅助诊断的新型生物标志物。三种生物标志物联合应用可提高CWP的诊断价值。
{"title":"Serum Osteopontin, KL-6, and Syndecan-4 as Potential Biomarkers in the Diagnosis of Coal Workers' Pneumoconiosis: A Case-Control Study.","authors":"Zhifei Hou,&nbsp;Xinran Zhang,&nbsp;Yong Gao,&nbsp;Jing Geng,&nbsp;Yu Jiang,&nbsp;Huaping Dai,&nbsp;Chen Wang","doi":"10.2147/PGPM.S409644","DOIUrl":"https://doi.org/10.2147/PGPM.S409644","url":null,"abstract":"Background Coal worker’s pneumoconiosis (CWP) is a chronic occupational disease mainly caused by coal dust inhalation in miners. This study aimed to investigate the clinical value of Osteopontin (OPN), KL-6, Syndecan-4 and Gremlin-1 as serum biomarkers in CWP. Patients and Methods We integrated reported lung tissues transcriptome data in pneumoconiosis patients with silica-exposed alveolar macrophage microarray data to identify four CWP-associated serum biomarkers. The serum concentrations of Osteopontin, Krebs von den Lungen-6 (KL-6), Syndecan-4 and Gremlin-1 were measured in 100 healthy controls (HCs), 100 dust-exposed workers (DEWs) and 200 patients of CWP. Receiver operating characteristic (ROC) curve analysis was used to determine the sensitivity, specificity, cut-off value and area under the curve (AUC) value of biomarkers. Results The pulmonary function parameters decreased sequentially, and the serum OPN, KL-6, Syndecan-4 and Gremlin-1 concentrations were increased sequentially among the HC, DEW and CWP groups. Among all participants, multivariable analysis revealed that these four biomarkers were negatively correlated with the pulmonary function parameters (all p<0.05). Compared with HCs, patients with higher OPN, KL-6, Syndecan-4 and Gremlin-1 had higher risk for CWP. The combination of OPN, KL-6, and Syndecan-4 can improve the diagnostic sensitivity and specificity of CWP patients differentiated from HCs or DEWs. Conclusion OPN, KL-6 and Syndecan-4 are novel biomarkers that can be used for CWP auxiliary diagnosis. The combination of three biomarkers can improve the diagnostic values of CWP.","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":"16 ","pages":"537-549"},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9a/5c/pgpm-16-537.PMC10241210.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9645600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Association of Methylation Level in the CYP39A1 Gene with High Altitude Pulmonary Edema in the Chinese Population. CYP39A1基因甲基化水平与中国人群高原肺水肿的关系
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S397862
Pingyi Wang, Hongyan Lu, Hao Rong, Yuhe Wang, Li Wang, Xue He, Dongya Yuan, Yongjun He, Tianbo Jin

Background: High altitude pulmonary edema (HAPE) is still the most common fatal disease at high altitudes. DNA methylation proceeds with an important role in HAPE progression. This study was designed to investigate the association between CYP39A1 methylation and HAPE.

Methods: Peripheral blood samples were enrolled from 106 participants (53 HAPE patients and 53 healthy subjects) to study the association of CYP39A1 methylation with HAPE. DNA methylation site in the promoter region of CYP39A1 was detected by Sequenom MassARRAY EpiTYPER platform.

Results: Probability analysis showed that the methylation probabilities of CYP39A1_1_CpG_5 and CYP39A1_3_CpG_21 are significant differences between the cases and controls (p< 0.05). The methylation level analysis indicated that CYP39A1_1_CpG_2.3.4, CYP39A1_5_CpG_6.7, and CYP39A1_5_CpG_9.10 were higher methylation in HAPE compared to the controls (p< 0.05). CYP39A1_3_CpG_21 and CYP39A1_4_CpG_3 exhibited a lower methylation level in HAPE than that in the controls (p< 0.05). The association analysis given that CYP39A1_1_CpG_2.3.4 (OR 2.56, p= 0.035), CYP39A1_5_CpG_6.7 (OR 3.99, p= 0.003), CYP39A1_5_CpG_9.10 (OR 3.99, p= 0.003), CYP39A1_5_CpG_16.17.18 (OR 2.53, p= 0.033), and CYP39A1_5_CpG_20 (OR 3.05, p= 0.031) are associated with an increased risk of HAPE. Whereas CYP39A1_1_CpG_5 (OR 0.33, p= 0.016) and CYP39A1_3_CpG_21 (OR 0.18, p= 0.005) have a protective role in HAPE. Besides, age-stratification analysis showed that CYP39A1_1_CpG_5 (OR 0.16, p= 0.014) and CYP39A1_3_CpG_21 (OR 0.08, p= 0.023) had a protective impact on HAPE in people aged ≤32 years. CYP39A1_5_CpG_6.7 (OR 6.70, p= 0.008) and CYP39A1_5_CpG_9.10 (OR 6.70, p= 0.008) were related to an increased susceptibility to HAPE aged >32 years. Moreover, the diagnostic value of CYP39A1_3_CpG_21 (AUC = 0.712, p< 0.001) was significantly better than other CpG sites.

Conclusion: The methylation level of CYP39A1 was associated with a risk of HAPE in the Chinese population, which provided new perspective for preventing and diagnosing of HAPE.

背景:高原肺水肿(HAPE)仍然是高海拔地区最常见的致命性疾病。DNA甲基化在HAPE进展中起着重要作用。本研究旨在探讨CYP39A1甲基化与HAPE之间的关系。方法:收集106例HAPE患者(53例HAPE患者)外周血样本,研究CYP39A1甲基化与HAPE的关系。采用Sequenom MassARRAY EpiTYPER平台检测CYP39A1启动子区DNA甲基化位点。结果:概率分析显示,CYP39A1_1_CpG_5和CYP39A1_3_CpG_21的甲基化概率在病例与对照组之间差异有统计学意义(p< 0.05)。甲基化水平分析显示,CYP39A1_1_CpG_2.3.4、CYP39A1_5_CpG_6.7和CYP39A1_5_CpG_9.10在HAPE中甲基化水平高于对照组(p< 0.05)。CYP39A1_3_CpG_21和CYP39A1_4_CpG_3在HAPE中的甲基化水平低于对照组(p< 0.05)。关联分析显示,CYP39A1_1_CpG_2.3.4 (OR 2.56, p= 0.035)、CYP39A1_5_CpG_6.7 (OR 3.99, p= 0.003)、CYP39A1_5_CpG_9.10 (OR 3.99, p= 0.003)、CYP39A1_5_CpG_16.17.18 (OR 2.53, p= 0.033)、CYP39A1_5_CpG_20 (OR 3.05, p= 0.031)与HAPE风险增加相关。而CYP39A1_1_CpG_5 (OR 0.33, p= 0.016)和CYP39A1_3_CpG_21 (OR 0.18, p= 0.005)在HAPE中具有保护作用。此外,年龄分层分析显示CYP39A1_1_CpG_5 (OR 0.16, p= 0.014)和CYP39A1_3_CpG_21 (OR 0.08, p= 0.023)对≤32岁人群HAPE有保护作用。CYP39A1_5_CpG_6.7 (OR 6.70, p= 0.008)和CYP39A1_5_CpG_9.10 (OR 6.70, p= 0.008)与32岁以上HAPE易感性增加相关。CYP39A1_3_CpG_21的诊断价值(AUC = 0.712, p< 0.001)显著优于其他CpG位点。结论:CYP39A1甲基化水平与中国人群HAPE发生风险相关,为HAPE的预防和诊断提供了新的视角。
{"title":"The Association of Methylation Level in the <i>CYP39A1</i> Gene with High Altitude Pulmonary Edema in the Chinese Population.","authors":"Pingyi Wang,&nbsp;Hongyan Lu,&nbsp;Hao Rong,&nbsp;Yuhe Wang,&nbsp;Li Wang,&nbsp;Xue He,&nbsp;Dongya Yuan,&nbsp;Yongjun He,&nbsp;Tianbo Jin","doi":"10.2147/PGPM.S397862","DOIUrl":"https://doi.org/10.2147/PGPM.S397862","url":null,"abstract":"<p><strong>Background: </strong>High altitude pulmonary edema (HAPE) is still the most common fatal disease at high altitudes. DNA methylation proceeds with an important role in HAPE progression. This study was designed to investigate the association between <i>CYP39A1</i> methylation and HAPE.</p><p><strong>Methods: </strong>Peripheral blood samples were enrolled from 106 participants (53 HAPE patients and 53 healthy subjects) to study the association of <i>CYP39A1</i> methylation with HAPE. DNA methylation site in the promoter region of <i>CYP39A1</i> was detected by Sequenom MassARRAY EpiTYPER platform.</p><p><strong>Results: </strong>Probability analysis showed that the methylation probabilities of CYP39A1_1_CpG_5 and CYP39A1_3_CpG_21 are significant differences between the cases and controls (<i>p</i>< 0.05). The methylation level analysis indicated that CYP39A1_1_CpG_2.3.4, CYP39A1_5_CpG_6.7, and CYP39A1_5_CpG_9.10 were higher methylation in HAPE compared to the controls (<i>p</i>< 0.05). CYP39A1_3_CpG_21 and CYP39A1_4_CpG_3 exhibited a lower methylation level in HAPE than that in the controls (<i>p</i>< 0.05). The association analysis given that CYP39A1_1_CpG_2.3.4 (OR 2.56, <i>p</i>= 0.035), CYP39A1_5_CpG_6.7 (OR 3.99, <i>p</i>= 0.003), CYP39A1_5_CpG_9.10 (OR 3.99, <i>p</i>= 0.003), CYP39A1_5_CpG_16.17.18 (OR 2.53, <i>p</i>= 0.033), and CYP39A1_5_CpG_20 (OR 3.05, <i>p</i>= 0.031) are associated with an increased risk of HAPE. Whereas CYP39A1_1_CpG_5 (OR 0.33, <i>p</i>= 0.016) and CYP39A1_3_CpG_21 (OR 0.18, <i>p</i>= 0.005) have a protective role in HAPE. Besides, age-stratification analysis showed that CYP39A1_1_CpG_5 (OR 0.16, <i>p</i>= 0.014) and CYP39A1_3_CpG_21 (OR 0.08, <i>p</i>= 0.023) had a protective impact on HAPE in people aged ≤32 years. CYP39A1_5_CpG_6.7 (OR 6.70, <i>p</i>= 0.008) and CYP39A1_5_CpG_9.10 (OR 6.70, <i>p</i>= 0.008) were related to an increased susceptibility to HAPE aged >32 years. Moreover, the diagnostic value of CYP39A1_3_CpG_21 (AUC = 0.712, <i>p</i>< 0.001) was significantly better than other CpG sites.</p><p><strong>Conclusion: </strong>The methylation level of <i>CYP39A1</i> was associated with a risk of HAPE in the Chinese population, which provided new perspective for preventing and diagnosing of HAPE.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":"16 ","pages":"617-628"},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/16/33/pgpm-16-617.PMC10290841.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10095445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Pharmacogenetics-Based Approach to Managing Gastroesophageal Reflux Disease: Current Perspectives and Future Steps. 基于药物遗传学的治疗胃食管反流病的方法:目前的观点和未来的步骤。
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S371994
Eda Eken, David S Estores, Emily J Cicali, Kristin K Wiisanen, Julie A Johnson

Proton pump inhibitors (PPIs) are commonly used medications to treat acid-related conditions, including gastro-esophageal reflux disease (GERD). Gastroenterology guidelines mention the importance of CYP2C19 in PPI metabolism and the influence of CYP2C19 genetic variations on variable responses to PPIs, but do not currently recommend the genotyping of CYP2C19 prior to prescribing PPIs. There are strong data to support the influence of CYP2C19 genetic variations on the pharmacokinetics of PPIs and clinical outcomes. Existing pharmacogenetic guideline recommendations for dose increases focus on H. pylori and erosive esophagitis indications, but PPIs are also the main therapy for treating GERD. Recent data suggest GERD patients being treated with a PPI may also benefit from genotype-guided dosing. We summarize the literature supporting this contention and highlight future directions for improved management of patients with GERD through precision medicine approaches.

质子泵抑制剂(PPIs)是治疗酸相关疾病的常用药物,包括胃食管反流病(GERD)。胃肠病学指南提到了CYP2C19在PPI代谢中的重要性,以及CYP2C19基因变异对PPI可变反应的影响,但目前不建议在开PPI处方前进行CYP2C19基因分型。有强有力的数据支持CYP2C19基因变异对PPIs药代动力学和临床结果的影响。现有的药理学指南建议增加剂量的重点是幽门螺杆菌和糜烂性食管炎适应症,但PPIs也是治疗胃食管反流的主要治疗方法。最近的数据表明,接受PPI治疗的胃食管反流患者也可能受益于基因型引导给药。我们总结了支持这一论点的文献,并强调了通过精确医学方法改善胃食管反流患者管理的未来方向。
{"title":"A Pharmacogenetics-Based Approach to Managing Gastroesophageal Reflux Disease: Current Perspectives and Future Steps.","authors":"Eda Eken,&nbsp;David S Estores,&nbsp;Emily J Cicali,&nbsp;Kristin K Wiisanen,&nbsp;Julie A Johnson","doi":"10.2147/PGPM.S371994","DOIUrl":"https://doi.org/10.2147/PGPM.S371994","url":null,"abstract":"<p><p>Proton pump inhibitors (PPIs) are commonly used medications to treat acid-related conditions, including gastro-esophageal reflux disease (GERD). Gastroenterology guidelines mention the importance of CYP2C19 in PPI metabolism and the influence of <i>CYP2C19</i> genetic variations on variable responses to PPIs, but do not currently recommend the genotyping of <i>CYP2C19</i> prior to prescribing PPIs. There are strong data to support the influence of <i>CYP2C19</i> genetic variations on the pharmacokinetics of PPIs and clinical outcomes. Existing pharmacogenetic guideline recommendations for dose increases focus on <i>H. pylori</i> and erosive esophagitis indications, but PPIs are also the main therapy for treating GERD. Recent data suggest GERD patients being treated with a PPI may also benefit from genotype-guided dosing. We summarize the literature supporting this contention and highlight future directions for improved management of patients with GERD through precision medicine approaches.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":"16 ","pages":"645-664"},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5d/10/pgpm-16-645.PMC10296543.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10096414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
A Case-Control Study of the Relationship Between Genetic Polymorphism and Cretinism in Xinjiang. 新疆地区遗传多态性与克汀病关系的病例对照研究。
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S418722
Jia Huang, Haiyan Wu, Guiqiang Zhao, Yan Ma, Yunping An, Li Sun, Fuye Li, Shengling Wang

Background: Cretinism is a subtype of congenital hypothyroidism, an endocrine disorder resulting from inadequate thyroid hormone production or receptor deficiency. Genetic abnormalities play a major role in the development of thyroid dysfunction.

Methods: We recruited 183 participants with cretinism and 119 healthy participants from the Xinjiang Uyghur Autonomous Region and randomly selected 29 tag single nucleotide polymorphisms (tSNPs) in TSHB, PAX8, TPO, NKX2-5, and TSHR in all participants. We compared genotype and allele frequencies between cases and controls utilizing the chi-squared test, logistic regression analysis, and haplotype analysis.

Results: Using the chi-squared test, a single SNP was found to be associated with cretinism (recessive model: rs3754363, OR = 0.46, 95% CI = 0.27-0.80, P = 0.00519; genotype model: P = 0.01677). We stratified neurological, myxedematous, and mixed type and determined that another SNP was associated with a higher risk when comparing myxedematous type to the neurological type (rs2277923).

Conclusion: rs3754363 has a statistically significant protective effect on people with cretinism, while rs2277923 may play a greater role in promoting the development of neurocretinism.

背景:克汀病是先天性甲状腺功能减退症的一种亚型,是一种由甲状腺激素分泌不足或受体缺乏引起的内分泌紊乱。遗传异常在甲状腺功能障碍的发展中起着重要作用。方法:从新疆维吾尔自治区招募克汀病患者183例和健康人群119例,随机选取TSHB、PAX8、TPO、NKX2-5和TSHR基因29个标签单核苷酸多态性(tsnp)。我们利用卡方检验、逻辑回归分析和单倍型分析比较了病例和对照组之间的基因型和等位基因频率。结果:卡方检验发现单个SNP与克汀病相关(隐性模型:rs3754363, OR = 0.46, 95% CI = 0.27-0.80, P = 0.00519;基因型模型:P = 0.01677)。我们将神经型、黏液性水肿型和混合型分层,并在比较黏液性水肿型和神经型时确定另一个SNP与更高的风险相关(rs2277923)。结论:rs3754363对克汀症患者有统计学意义上的保护作用,而rs2277923可能对神经克汀症的发展有更大的促进作用。
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引用次数: 0
Genetic Influence of Fracture Nonunion (FNU): A Systematic Review. 骨折不愈合(FNU)的遗传影响:系统综述。
IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S407308
Mir Sadat-Ali, Hussain K Al-Omar, Khalid W AlTabash, Ammar K AlOmran, Dakheel A AlDakheel, Hasan N AlSayed

Purpose: Nonunion of fractures occurs in about 15% of all fractures causing repeated surgical interference and prolonged morbidity. We performed this systematic review to assess genes and polymorphisms influencing fractures' nonunion (FNU).

Methods: We searched between 2000 and July 2022 in PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, Genome Wide Association Studies (GWAS) Catalog, and the Science Citation Index, with the keywords nonunion of fractures, genetic influence, and GWAS. The exclusion criteria were review articles and correspondence. The data were retrieved to determine the number of studies, genes, and polymorphisms and the total number of subjects screened.

Results: A total of 79 studies were reported on nonunion of fractures and genetic influence. After the inclusion and exclusion criteria, ten studies with 4402 patients' data were analyzed. Nine studies were case-controlled, and 1 GWAS. It was identified that patients with polymorphisms in the genes ANXA3, BMP2, CALY, CYR61, FGFR1, IL1β, NOG, NOS2, PDGF gene, and TACR1 are prone to develop a nonunion of fractures.

Conclusion: We believe that for patients who develop an early nonunion of fractures, a genetic study should be conducted for single nucleotide polymorphism (SNP) and genes so that alternative and more aggressive treatment can be performed to heal fractures without prolonged morbidity.

目的:骨折不愈合约占所有骨折的15%,导致反复手术干预和长期发病。我们进行了这项系统综述,以评估影响骨折不愈合(FNU)的基因和多态性。方法:检索2000年至2022年7月PubMed、EMBASE、Cochrane中央对照试验注册库和Cochrane系统评价数据库、全基因组关联研究(GWAS)目录和科学引文索引,检索关键词为骨折不愈合、遗传影响和GWAS。排除标准为综述文章和通信。检索数据以确定研究、基因和多态性的数量以及筛选的受试者总数。结果:共报道了79项关于骨折不愈合及其遗传影响的研究。根据纳入和排除标准,对10项研究4402例患者数据进行分析。9项研究为病例对照,1项为GWAS。研究发现,具有ANXA3、BMP2、CALY、CYR61、FGFR1、IL1β、NOG、NOS2、PDGF基因和TACR1基因多态性的患者易发生骨折不愈合。结论:我们认为,对于发生骨折早期不愈合的患者,应该进行单核苷酸多态性(SNP)和基因的遗传学研究,以便进行替代和更积极的治疗来治愈骨折,而不会延长发病率。
{"title":"Genetic Influence of Fracture Nonunion (FNU): A Systematic Review.","authors":"Mir Sadat-Ali,&nbsp;Hussain K Al-Omar,&nbsp;Khalid W AlTabash,&nbsp;Ammar K AlOmran,&nbsp;Dakheel A AlDakheel,&nbsp;Hasan N AlSayed","doi":"10.2147/PGPM.S407308","DOIUrl":"https://doi.org/10.2147/PGPM.S407308","url":null,"abstract":"<p><strong>Purpose: </strong>Nonunion of fractures occurs in about 15% of all fractures causing repeated surgical interference and prolonged morbidity. We performed this systematic review to assess genes and polymorphisms influencing fractures' nonunion (FNU).</p><p><strong>Methods: </strong>We searched between 2000 and July 2022 in PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, Genome Wide Association Studies (GWAS) Catalog, and the Science Citation Index, with the keywords nonunion of fractures, genetic influence, and GWAS. The exclusion criteria were review articles and correspondence. The data were retrieved to determine the number of studies, genes, and polymorphisms and the total number of subjects screened.</p><p><strong>Results: </strong>A total of 79 studies were reported on nonunion of fractures and genetic influence. After the inclusion and exclusion criteria, ten studies with 4402 patients' data were analyzed. Nine studies were case-controlled, and 1 GWAS. It was identified that patients with polymorphisms in the genes <i>ANXA3, BMP2, CALY, CYR61, FGFR1, IL1β, NOG, NOS2, PDGF gene, and TACR1</i> are prone to develop a nonunion of fractures.</p><p><strong>Conclusion: </strong>We believe that for patients who develop an early nonunion of fractures, a genetic study should be conducted for single nucleotide polymorphism (SNP) and genes so that alternative and more aggressive treatment can be performed to heal fractures without prolonged morbidity.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":"16 ","pages":"569-575"},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3a/03/pgpm-16-569.PMC10254683.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9621257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Pharmacogenomics & Personalized Medicine
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