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miR-139-5p and miR-451a as a Diagnostic Biomarker in LUSC. miR-139-5p和miR-451a作为LUSC的诊断性生物标志物。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S402750
Bo Gao, Rui Li, Xiaojia Song, Shan Hu, Fengmei Yang

Background: Lung squamous cell carcinoma (LUSC) is a type of lung cancer that originates from segmental or subsegmental bronchial mucosa. There is evidence that miRNA plays an important role in the occurrence and progression of tumors.

Methods: In this study, plasma samples of patients with early LUSC and healthy volunteers were subjected to miRNA sequencing, and the levels of differentially expressed miRNAs (DEMs) in LUSC tissues were analyzed using R language. Cox regression and Kaplan-Meier (K-M) survival curve analyses were performed to determine the relationship between DEMs and prognosis in LUSC, and PCR method was verified for the plasma expression level of DEMs in patients with LUSC. The levels of CYFRA21-1 and SCC-Ag in plasma were measured, and area under curve (AUC) was used to evaluate the diagnostic value of the DEMs.

Results: A total of 21 DEMs were screened out by sequencing. The expression levels of DEMs in tissue samples in the TCGA database were analyzed, and four DEMs with consistent expression levels were further screened from plasma and tissue samples. Regression analysis and K-M curve were performed to select two DEMs (miR-139-5p, miR-451a) that were correlated with the prognosis. PCR verification results showed that the levels of miR-451a and miR-139-5p were low in patients, and the level of miR-139-5p in late stages III & IV with the patients of LUSC was higher than that in stages I & II. The AUC values of the four indicators (SCC-Ag, CYFRA21-1, miR-451a and miR-139-5p) in the diagnosis of LUSC, early and late cases were 0.884, 0.935 and 0.778, respectively.

Conclusion: The detection of miR-139-5p and miR-451a levels in plasma has a certain potential in the non-invasive diagnosis, especially in patients with early stages of LUSC.

背景:肺鳞状细胞癌(Lung squamous cell carcinoma, LUSC)是一种起源于支气管节段性或亚节段性粘膜的肺癌。有证据表明,miRNA在肿瘤的发生和发展中起着重要作用。方法:本研究对早期LUSC患者和健康志愿者的血浆样本进行miRNA测序,并使用R语言分析LUSC组织中差异表达的miRNA (DEMs)水平。采用Cox回归和Kaplan-Meier (K-M)生存曲线分析确定LUSC患者dem与预后的关系,并验证PCR法检测LUSC患者血浆中dem的表达水平。测定血浆CYFRA21-1和SCC-Ag水平,用曲线下面积(AUC)评价dem的诊断价值。结果:测序共筛选到21个dem。分析TCGA数据库组织样本中dem的表达水平,并进一步从血浆和组织样本中筛选出表达水平一致的4个dem。通过回归分析和K-M曲线选择与预后相关的两个dem (miR-139-5p、miR-451a)。PCR验证结果显示,miR-451a和miR-139-5p在患者中水平较低,且在LUSC患者的III、IV期晚期miR-139-5p水平高于I、II期。SCC-Ag、CYFRA21-1、miR-451a、miR-139-5p四项指标诊断LUSC、早期、晚期的AUC值分别为0.884、0.935、0.778。结论:检测血浆中miR-139-5p和miR-451a水平在无创诊断中具有一定的潜力,特别是在早期LUSC患者中。
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引用次数: 1
Role of CYP19A1 Loci (rs28757157 and rs3751591) with Ischemic Stroke Risk in the Chinese Han Population. CYP19A1位点(rs28757157和rs3751591)在中国汉族缺血性卒中风险中的作用
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S404160
Kang Huang, Tianyi Ma, Qiang Li, Zanrui Zhong, Ting Qin, Yilei Zhou, Wei Zhang, Shilin Tang, Jianghua Zhong, Shijuan Lu

Introduction: Ischemic stroke (IS) is a multifactorial and polygenic disease, which is affected by genetic factors. In this study, we explored the role of CYP19A1 single nucleotide polymorphisms (SNPs) in IS in the Chinese population.

Methods: 1302 subjects (651 controls and 651 cases) were recruited in this case-control study. Four candidate SNPs (rs28757157 C/T, rs3751592 C/T, rs3751591 G/A, rs59429575 C/T) of CYP19A1 were selected by the 1000 genomes project database. The association between CYP19A1 SNPs and IS risk was assessed using logistic regression analysis with odds ratio (OR) and 95% confidence intervals (CIs). False-positive report probability (FPRP) analysis further verified the positive results. The interaction of SNP-SNP was analyzed by multi-factor dimensionality reduction (MDR) to predict is risk.

Results: In the research, CYP19A1 loci (rs28757157 and rs3751591) were associated with the occurrence of IS. The two variants conferred an increased susceptibility to IS in the subjects aged over 60 years old, smokers and drinkers. Rs28757157 was related to the risk of IS in females, non-smokers and subjects with BMI less than 24, while rs59429575 was related to the risk of IS in males and subjects with BMI greater than 24.

Conclusion: The study revealed that there is a significant association between CYP19A1 loci (rs28757157 and rs3751591) and IS risk in the Chinese Han population, providing a theoretical basis for further exploring its specific role in the pathogenesis of IS.

简介:缺血性脑卒中是一种受遗传因素影响的多因素、多基因疾病。在这项研究中,我们探讨了CYP19A1单核苷酸多态性(snp)在中国人群IS中的作用。方法:本研究共纳入1302例受试者,其中对照组651例,病例651例。通过千人基因组计划数据库筛选CYP19A1的4个候选snp (rs28757157 C/T、rs3751592 C/T、rs3751591 G/A、rss59429575 C/T)。CYP19A1 snp与IS风险之间的关系采用logistic回归分析,比值比(OR)和95%置信区间(CIs)。假阳性报告概率(FPRP)分析进一步验证了阳性结果。采用多因素降维法(MDR)分析SNP-SNP的相互作用,预测其风险。结果:在本研究中,CYP19A1位点(rs28757157和rs3751591)与IS的发生有关。这两种变异使得60岁以上、吸烟者和饮酒者对IS的易感性增加。Rs28757157与女性、非吸烟者和BMI小于24的受试者发生IS的风险相关,rss59429575与男性和BMI大于24的受试者发生IS的风险相关。结论:本研究发现CYP19A1位点(rs28757157和rs3751591)与中国汉族人群is发病风险存在显著相关性,为进一步探索其在is发病机制中的具体作用提供了理论依据。
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引用次数: 0
Personalized Dietary Regimens for Inflammatory Bowel Disease: Current Knowledge and Future Perspectives. 炎症性肠病的个性化饮食方案:目前的知识和未来的展望。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S359365
Judith Wellens, Eva Vissers, Christophe Matthys, Séverine Vermeire, João Sabino

Inflammatory bowel diseases (IBD) are chronic and incurable conditions of the gastro-intestinal tract with an increasing incidence and prevalence worldwide. Common symptoms are abdominal pain, diarrhea, and weight loss. Despite recent advances in medical management, many patients fail to achieve clinical remission and healing of the mucosa of the bowel. The cause is thought to involve an inappropriate reaction of the immune system, the microbiome and the environment in genetically susceptible individuals, leading to chronic bowel inflammation. Evidence is emerging that diet is a key environmental factor that might influence disease onset and course, and therefore may become a therapeutic strategy to mitigate inflammation and symptoms. Since IBD is a heterogeneous disease on a clinical and a molecular level, personalizing dietary advice could be the crucial factor to achieve long-lasting changes in dietary behaviors that could not only improve nutritional status but also tackle gut inflammation and abdominal symptoms on an individual level. In this review, we first discuss different aspects of personalized nutrition, namely the level, focus, and scope of personalized dietary regimens. Then, we provide a framework for the different goals of nutritional therapy in IBD and current evidence for personalized dietary approaches. Lastly, we discuss the need for adequate trial designs, access to the right data types and the bioinformatic tools that are necessary to develop algorithms that will allow us to move from general "healthy eating" advice to truly personalized nutritional plans for the individual IBD patient.

炎症性肠病(IBD)是一种慢性且无法治愈的胃肠道疾病,在世界范围内的发病率和患病率不断上升。常见的症状是腹痛、腹泻和体重减轻。尽管最近在医疗管理方面取得了进展,但许多患者未能达到临床缓解和肠粘膜愈合。其原因被认为与免疫系统、微生物群和遗传易感个体的环境的不适当反应有关,从而导致慢性肠道炎症。越来越多的证据表明,饮食是可能影响疾病发病和病程的关键环境因素,因此可能成为减轻炎症和症状的治疗策略。由于IBD在临床和分子水平上是一种异质性疾病,个性化的饮食建议可能是实现饮食行为长期改变的关键因素,这不仅可以改善营养状况,还可以在个体水平上解决肠道炎症和腹部症状。在这篇综述中,我们首先讨论了个性化营养的不同方面,即个性化饮食方案的水平、重点和范围。然后,我们为IBD营养治疗的不同目标和个性化饮食方法的当前证据提供了一个框架。最后,我们讨论了适当的试验设计的必要性,获得正确的数据类型和开发算法所必需的生物信息学工具,这些算法将使我们能够从一般的“健康饮食”建议转向针对个体IBD患者的真正个性化的营养计划。
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引用次数: 2
Identification and Validation of Ferroptosis-Related Subtypes and a Predictive Signature in Hepatocellular Carcinoma. 肝细胞癌中铁中毒相关亚型的鉴定和验证及其预测特征。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S397892
Chunlan Zheng, Yanan Peng, Haizhou Wang, Youwei Wang, Lan Liu, Qiu Zhao

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world with an immunosuppressive Tumor microenvironment (TME). Ferroptosis plays an essential role in tumor proliferation, invasion, and metastasis. However, the relationship between ferroptosis and TME of HCC has remained elusive.

Methods: Differentially expressed ferroptosis-related genes (DE FRGs) between normal liver tissues and HCC tissues were obtained from The Cancer Genome Atlas (TCGA). On this basis, we identified the molecular subtypes mediated by DE FRGs and TME cell infiltration. Next, a predictive signature was established to quantity the ferroptosis-related characteristics by performing the least absolute shrinkage and selection operator Cox regression analyses. Univariate and multivariate COX analyses determined the independent prognostic factors. Finally, the expression stability of 3 ferroptosis-related signature genes was verified in cancer and paracancerous normal tissues of HCC.

Results: We identified three different molecular subtypes and found that the subtype with the better prognosis was associated with high enrichment of immune- and metabolic-related hallmark signaling pathways and high infiltration of immune cells in TME. The signature was considered to be an independent prognostic factor. We also found that the signature can reflect the infiltration characteristics of different immune cells in TME. Immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells, and type 17 T helper cells were significantly enriched in the high-risk group. The analysis data of immune checkpoints and tumor mutation load indicated that the signature had great potential in predicting Immunotherapy response and chemotherapeutic sensitivity. In addition, the overexpression of 3 ferroptosis-related signature genes was confirmed in HCC tissues and HCC cell lines. Ferroptosis inducer RSL3 inhibited the proliferation of HCC cells and was a potential cancer immunotherapy agent.

Conclusion: These findings enhanced our understanding of the regulatory mechanism of ferroptosis in HCC and provided new insights into evaluating prognosis and developing more effective Immunotherapy and chemotherapy strategies.

背景:肝细胞癌(HCC)是世界上最常见的恶性肿瘤之一,具有免疫抑制肿瘤微环境(TME)。铁下垂在肿瘤的增殖、侵袭和转移中起着重要的作用。然而,铁下垂与肝癌TME之间的关系尚不明确。方法:从癌症基因组图谱(TCGA)中获取正常肝组织与HCC组织间差异表达的铁中毒相关基因(DE FRGs)。在此基础上,我们确定了DE FRGs和TME细胞浸润介导的分子亚型。接下来,通过执行最小绝对收缩和选择算子Cox回归分析,建立了预测特征,以量化铁衰相关特征。单因素和多因素COX分析确定了独立的预后因素。最后,我们验证了3个铁中毒相关特征基因在HCC癌及癌旁正常组织中的表达稳定性。结果:我们鉴定出三种不同的分子亚型,发现预后较好的亚型与TME中免疫和代谢相关标志信号通路的高富集和免疫细胞的高浸润有关。该特征被认为是一个独立的预后因素。我们还发现该特征可以反映TME中不同免疫细胞的浸润特征。免疫抑制细胞,如髓源性抑制细胞(MDSCs)、调节性T细胞和17型T辅助细胞在高危组中显著富集。免疫检查点和肿瘤突变负荷的分析数据表明,该标记在预测免疫治疗反应和化疗敏感性方面具有很大的潜力。此外,在HCC组织和HCC细胞系中证实了3个铁中毒相关特征基因的过表达。铁下垂诱导剂RSL3可抑制肝癌细胞的增殖,是一种潜在的肿瘤免疫治疗药物。结论:这些发现增强了我们对肝癌铁下垂的调控机制的认识,为肝癌预后评估和制定更有效的免疫治疗和化疗策略提供了新的见解。
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引用次数: 2
Identification of Two Novel Variants of the DMD Gene in Chinese Families with Duchenne Muscular Dystrophy. 中国杜氏肌营养不良症家族DMD基因两个新变异的鉴定。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S416294
Jiangfen Wu, Lingyan Ren, Xinyi Huang, Li Hu, Liangliang Zhang, Dan Xie, Zhimin Li, Naijian Han, Shengwen Huang

Background: Duchenne muscular dystrophy (DMD), an X-linked recessive neuromuscular disorder, is caused by pathogenic variants in the DMD gene encoding a large structural protein in muscle cells.

Methods: Two probands, a 6-year old boy and a 1-month old infant, respectively, were clinically diagnosed with DMD based on elevated levels of creatine kinase and creatine kinase isoenzyme. CNVplex and whole exome sequencing (WES) were performed for causal variants, and Sanger sequencing was used for verification.

Results: CNVplex found no large deletions or duplications in the DMD gene in both patients, but WES discovered a single-nucleotide deletion in exon 48 (NM_004006.2:c.6963del, p.Asp2322ThrfsTer16) in the proband of pedigree 1, and a nonsense mutation in exon 27 (NM_004006.2:c.3637A>T, p.K1213Ter) in the proband of pedigree 2.

Conclusion: The results of our study expand the mutation spectrum of DMD and enrich our understanding of the clinical characteristics of DMD. Genetic counseling was provided for the two families involved in this study.

背景:杜氏肌营养不良症(DMD)是一种x连锁的隐性神经肌肉疾病,是由编码肌肉细胞中一个大结构蛋白的DMD基因的致病性变异引起的。方法:根据肌酸激酶和肌酸激酶同工酶水平升高,对2例6岁男童和1月龄婴儿进行临床诊断。对因果变异进行CNVplex和全外显子组测序(WES),并使用Sanger测序进行验证。结果:CNVplex在两例患者中均未发现DMD基因的大缺失或重复,但WES在48外显子(NM_004006.2:c)上发现了单核苷酸缺失。在第1家系先显子(NM_004006.2:c)中存在无义突变(NM_004006.2:c)。3637A>T, p.K1213Ter)系2先证者。结论:本研究结果拓展了DMD的突变谱,丰富了我们对DMD临床特征的认识。为参与本研究的两个家庭提供了遗传咨询。
{"title":"Identification of Two Novel Variants of the <i>DMD</i> Gene in Chinese Families with Duchenne Muscular Dystrophy.","authors":"Jiangfen Wu,&nbsp;Lingyan Ren,&nbsp;Xinyi Huang,&nbsp;Li Hu,&nbsp;Liangliang Zhang,&nbsp;Dan Xie,&nbsp;Zhimin Li,&nbsp;Naijian Han,&nbsp;Shengwen Huang","doi":"10.2147/PGPM.S416294","DOIUrl":"https://doi.org/10.2147/PGPM.S416294","url":null,"abstract":"<p><strong>Background: </strong>Duchenne muscular dystrophy (DMD), an X-linked recessive neuromuscular disorder, is caused by pathogenic variants in the <i>DMD</i> gene encoding a large structural protein in muscle cells.</p><p><strong>Methods: </strong>Two probands, a 6-year old boy and a 1-month old infant, respectively, were clinically diagnosed with DMD based on elevated levels of creatine kinase and creatine kinase isoenzyme. CNVplex and whole exome sequencing (WES) were performed for causal variants, and Sanger sequencing was used for verification.</p><p><strong>Results: </strong>CNVplex found no large deletions or duplications in the <i>DMD</i> gene in both patients, but WES discovered a single-nucleotide deletion in exon 48 (NM_004006.2:c.6963del, p.Asp2322ThrfsTer16) in the proband of pedigree 1, and a nonsense mutation in exon 27 (NM_004006.2:c.3637A>T, p.K1213Ter) in the proband of pedigree 2.</p><p><strong>Conclusion: </strong>The results of our study expand the mutation spectrum of DMD and enrich our understanding of the clinical characteristics of DMD. Genetic counseling was provided for the two families involved in this study.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":null,"pages":null},"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/cc/c8/pgpm-16-759.PMC10441636.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10413897","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
Germline PRDM1 Variant rs2185379 in Long-Term Recurrence-Free Survivors of Advanced Ovarian Cancer. 生殖系PRDM1变异rs2185379在晚期卵巢癌长期无复发幸存者中的作用
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-11-29 eCollection Date: 2022-01-01 DOI: 10.2147/PGPM.S387120
Takashi Mitamura, Tianyue Zhai, Kanako C Hatanaka, Yutaka Hatanaka, Toraji Amano, Lei Wang, Shinya Tanaka, Hidemichi Watari

Purpose: To identify the germline genetic characteristics of long-term recurrence-free survivors that can be applied to establishing a new strategy for curing advanced cancer, we investigated the whole-genome single nucleotide variants of ovarian cancer patients.

Patients and methods: DNA specimens were obtained from rare long-term recurrence-free survivors with FIGO stage III-IV ovarian cancer with no recurrence for 8-23 years after primary treatments for a whole-genome analysis of approximately 660,000 single nucleotide variants. We then established a mouse model with a notable gene alteration by CRISPR/Cas9 to confirm the biological role.

Results: The long-term recurrence-free survivors more frequently had germline heterozygous variant rs2185379 of the PRDM1 gene exon than patients with early recurrence (6.8-fold, P=0.013) and the general population. In the mouse model, primary intraperitoneal disseminated tumors of allograft ID8 were significantly smaller in the germline heterozygous rs2185379 group than in the wild-type group (57.4% decrease, P=0.008). Immunohistochemistry showed that the area of distribution of infiltrating T lymphocytes with positive CD8 staining was significantly increased in the germline heterozygous rs2185379 group in comparison to the wild-type group.

Conclusion: Germline heterozygous rs2185379 in PRDM1 is correlated with an excellent prognosis and can be used to establish a new strategy for treating advanced ovarian cancer.

目的:研究卵巢癌患者的全基因组单核苷酸变异,以确定长期无复发幸存者的种系遗传特征,为建立晚期癌症治疗的新策略奠定基础。患者和方法:从FIGO III-IV期卵巢癌的罕见长期无复发幸存者中获得DNA标本,这些患者在接受初步治疗后8-23年没有复发,用于对大约66万个单核苷酸变异进行全基因组分析。然后,我们通过CRISPR/Cas9建立了具有显著基因改变的小鼠模型,以确认其生物学作用。结果:长期无复发幸存者PRDM1基因外显子的种系杂合变异rs2185379的发生率高于早期复发患者(6.8倍,P=0.013)和一般人群。在小鼠模型中,种系杂合rs2185379组的ID8原发性腹腔播散性肿瘤明显小于野生型组(减少57.4%,P=0.008)。免疫组化结果显示,种系杂合rs2185379组CD8染色阳性浸润T淋巴细胞的分布面积较野生型组明显增加。结论:PRDM1的种系杂合rs2185379与预后良好相关,可为晚期卵巢癌的治疗建立新的策略。
{"title":"Germline <i>PRDM1</i> Variant rs2185379 in Long-Term Recurrence-Free Survivors of Advanced Ovarian Cancer.","authors":"Takashi Mitamura,&nbsp;Tianyue Zhai,&nbsp;Kanako C Hatanaka,&nbsp;Yutaka Hatanaka,&nbsp;Toraji Amano,&nbsp;Lei Wang,&nbsp;Shinya Tanaka,&nbsp;Hidemichi Watari","doi":"10.2147/PGPM.S387120","DOIUrl":"https://doi.org/10.2147/PGPM.S387120","url":null,"abstract":"<p><strong>Purpose: </strong>To identify the germline genetic characteristics of long-term recurrence-free survivors that can be applied to establishing a new strategy for curing advanced cancer, we investigated the whole-genome single nucleotide variants of ovarian cancer patients.</p><p><strong>Patients and methods: </strong>DNA specimens were obtained from rare long-term recurrence-free survivors with FIGO stage III-IV ovarian cancer with no recurrence for 8-23 years after primary treatments for a whole-genome analysis of approximately 660,000 single nucleotide variants. We then established a mouse model with a notable gene alteration by CRISPR/Cas9 to confirm the biological role.</p><p><strong>Results: </strong>The long-term recurrence-free survivors more frequently had germline heterozygous variant rs2185379 of the <i>PRDM1</i> gene exon than patients with early recurrence (6.8-fold, P=0.013) and the general population. In the mouse model, primary intraperitoneal disseminated tumors of allograft ID8 were significantly smaller in the germline heterozygous rs2185379 group than in the wild-type group (57.4% decrease, P=0.008). Immunohistochemistry showed that the area of distribution of infiltrating T lymphocytes with positive CD8 staining was significantly increased in the germline heterozygous rs2185379 group in comparison to the wild-type group.</p><p><strong>Conclusion: </strong>Germline heterozygous rs2185379 in <i>PRDM1</i> is correlated with an excellent prognosis and can be used to establish a new strategy for treating advanced ovarian cancer.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2022-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/92/0a/pgpm-15-977.PMC9719363.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35210812","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
Utilization of Drugs with Pharmacogenetic Dosing Recommendations in Switzerland: A Descriptive Study Using the Helsana Database. 瑞士药物遗传剂量推荐的使用:一项使用Helsana数据库的描述性研究。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-11-23 eCollection Date: 2022-01-01 DOI: 10.2147/PGPM.S382214
Nina L Wittwer, Christoph R Meier, Carola A Huber, Henriette E Meyer Zu Schwabedissen, Samuel Allemann, Cornelia Schneider

Purpose: In Switzerland 167 drugs on the market contain information about pharmacogenetics in their drug label (PGx drug). Preemptive pharmacogenetic testing is reimbursed by health care insurance for only seven drugs (abacavir, carbamazepine, 6-mercaptopurine, azathioprine, 5-fluorouracil, capecitabine, and irinotecan) although, it is proposed to be a cost-effective approach to personalized medicine. The aim of this study was to describe the use of PGx drugs and their corresponding genes in Switzerland.

Methods: We identified 90 drugs with dosing recommendations from the Pharmacogenetic Knowledgebase involving 24 genes. We assessed the utilization of those drugs between 2016 and 2020, using claims data from a large Swiss insurance company (Helsana).

Results: Of 841 491 persons with drug claims during the whole study period, 78.7% were exposed to PGx drugs. Ibuprofen, pantoprazole, and tramadol had the highest number of users. Seven genes (CYP2C19, CYP2C9, CYP2D6, SLCO1B1, HLA-B, MT-RNR1, and VKORC1) were responsible for over 95% of all potential drug-gene interactions.

Conclusion: The prevalence of PGx drug prescriptions is high in the Swiss population. Therefore, intensified preemptive testing may be a useful option as a substantial amount of the Swiss population might benefit.

目的:在瑞士,市场上有167种药物在其药品标签中包含药物遗传学信息(PGx药物)。尽管预防性药物遗传学检测被认为是一种具有成本效益的个体化治疗方法,但医疗保险只报销七种药物(阿巴卡韦、卡马西平、6-巯基嘌呤、硫唑嘌呤、5-氟尿嘧啶、卡培他滨和伊立替康)。本研究的目的是描述PGx药物及其相应基因在瑞士的使用情况。方法:我们从药物遗传知识库中确定了涉及24个基因的90种推荐剂量药物。我们使用一家大型瑞士保险公司(Helsana)的索赔数据,评估了2016年至2020年期间这些药物的使用情况。结果:在整个研究期间有药品索赔的841 491人中,78.7%的人接触过PGx药物。布洛芬、泮托拉唑和曲马多的服用者最多。7个基因(CYP2C19、CYP2C9、CYP2D6、SLCO1B1、HLA-B、MT-RNR1和VKORC1)负责超过95%的潜在药物-基因相互作用。结论:在瑞士人群中,PGx药物处方的患病率较高。因此,加强先发制人的测试可能是一个有用的选择,因为大量的瑞士人口可能受益。
{"title":"Utilization of Drugs with Pharmacogenetic Dosing Recommendations in Switzerland: A Descriptive Study Using the Helsana Database.","authors":"Nina L Wittwer,&nbsp;Christoph R Meier,&nbsp;Carola A Huber,&nbsp;Henriette E Meyer Zu Schwabedissen,&nbsp;Samuel Allemann,&nbsp;Cornelia Schneider","doi":"10.2147/PGPM.S382214","DOIUrl":"https://doi.org/10.2147/PGPM.S382214","url":null,"abstract":"<p><strong>Purpose: </strong>In Switzerland 167 drugs on the market contain information about pharmacogenetics in their drug label (PGx drug). Preemptive pharmacogenetic testing is reimbursed by health care insurance for only seven drugs (abacavir, carbamazepine, 6-mercaptopurine, azathioprine, 5-fluorouracil, capecitabine, and irinotecan) although, it is proposed to be a cost-effective approach to personalized medicine. The aim of this study was to describe the use of PGx drugs and their corresponding genes in Switzerland.</p><p><strong>Methods: </strong>We identified 90 drugs with dosing recommendations from the Pharmacogenetic Knowledgebase involving 24 genes. We assessed the utilization of those drugs between 2016 and 2020, using claims data from a large Swiss insurance company (Helsana).</p><p><strong>Results: </strong>Of 841 491 persons with drug claims during the whole study period, 78.7% were exposed to PGx drugs. Ibuprofen, pantoprazole, and tramadol had the highest number of users. Seven genes (<i>CYP2C19, CYP2C9, CYP2D6, SLCO1B1, HLA-B, MT-RNR1</i>, and <i>VKORC1</i>) were responsible for over 95% of all potential drug-gene interactions.</p><p><strong>Conclusion: </strong>The prevalence of PGx drug prescriptions is high in the Swiss population. Therefore, intensified preemptive testing may be a useful option as a substantial amount of the Swiss population might benefit.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2022-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/39/dd/pgpm-15-967.PMC9701506.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40723062","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: 2
CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders. CES1和SLC6A2基因变异是自闭症谱系障碍患者对哌甲酯反应的预测因子。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-11-08 eCollection Date: 2022-01-01 DOI: 10.2147/PGPM.S377210
Marta H Hernandez, Valentin Bote, Alexandre Serra-LLovich, Marc Cendros, Juliana Salazar, Conxita Mestres, Silvina Guijarro, Aida Alvarez, Cristina Lamborena, Iria Mendez, Bernardo Sanchez, Amaia Hervas, Maria J Arranz

Purpose: Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40-70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety.

Patients and methods: A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 (SLC6A2) and for its primary metabolic pathway (CES1) were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype.

Results: Single marker analyses considering gender, age, and dose as covariates showed association between CES1 variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05).

Conclusion: CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.

目的:自闭症谱系障碍(ASD)儿童和青少年通常存在合并症,其中40-70%的儿童和青少年伴有注意缺陷多动障碍(ADHD)。这些患者的首选药物治疗是哌甲酯(MPH)。ASD儿童比ADHD儿童表现出更多的副作用和更差的反应。我们的研究目的是确定自闭症儿童和青少年对MPH反应的遗传生物标志物,以提高其疗效和安全性。患者和方法:对140例接受MPH治疗的ASD儿童和青少年进行回顾性研究。对MPH靶基因NET1 (SLC6A2)及其主要代谢途径(CES1)的15个基因多态性进行了基因分型。对每种多态性和单倍型进行多变量分析,包括反应表型(疗效、副作用、嗜睡、易怒、情绪改变、攻击性、关闭、其他副作用)。结果:以性别、年龄和剂量为协变量的单标记分析显示,CES1等位基因与mph诱导的副作用(rs2244613-G (p=0.04)、rs2302722-C (p=0.02)、rs2307235-A (p=0.03)和rs8192950-T等位基因(p=0.03)存在关联,CES1 rs2302722-C等位基因与嗜睡存在(p=0.05)、SLC6A2 rs36029-G等位基因与关闭存在边际关联(p=0.05)。CES1单倍型组合与疗效和副作用相关(p分别=0.02和0.03)。SLC6A2单倍型组合与嗜睡相关(p=0.05)。结论:CES1基因变异可能影响儿童和青少年ASD合并ADHD患者MPH治疗的临床结果。
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引用次数: 0
Next-Generation Sequencing and Bioinformatics-Based Protocol for the Full-Length CYP2E1 Gene Polymorphism Analysis. 下一代测序和基于生物信息学的CYP2E1全长基因多态性分析方案。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-11-08 eCollection Date: 2022-01-01 DOI: 10.2147/PGPM.S371709
Viktorija Igumnova, Agnija Kivrane, Anda Viksna, Inga Norvaisa, Renate Ranka

Introduction: Pharmacogenetics studies provide clinically relevant information on the identified associations between genetic variants and individual variability in drug response, which, in turn, offers great promise for guiding personalized drug therapy and clinical trial design. However, there is a lack of information concerning the evidence-based clinical annotations of specific CYP2E1 genetic variants.

Aim: To design and evaluate the next-generation sequencing-based method for full-length CYP2E1 gene polymorphism analysis.

Materials and methods: Seven gene-specific oligonucleotide primer pairs targeting overlapping CYP2E1 gene fragments spanning all nine gene exons with interleaving introns, untranslated (UTR) and intergenic regions were designed. Human DNA samples (n = 3) were used as a training set to check the primer performance and to optimize the PCR conditions. The effectiveness of the developed target amplification and sequencing protocol was evaluated using the test set comprising human DNA samples (n = 3) obtained from tuberculosis patients. Sequencing data analysis was performed on the Galaxy online-based platform.

Results: The sequencing data quality was sufficient for the detection of genetic variants dispersed throughout the CYP2E1 gene with a high degree of confidence in fully covered regions achieving optimal reading depth of the targeted fragment with high base call accuracy.

Conclusion: Developed protocol can be applied in subpopulation-level association studies to determine whether single nucleotide variants (SNVs) or variant combinations from multiple regions of the CYP2E1 gene are of clinical significance.

前言:药物遗传学研究为基因变异与药物反应的个体差异之间的关联提供了临床相关信息,这反过来又为指导个性化药物治疗和临床试验设计提供了巨大的希望。然而,缺乏关于特定CYP2E1遗传变异的循证临床注释的信息。目的:设计并评价新一代CYP2E1基因全长多态性分析方法。材料和方法:设计了7对基因特异性的CYP2E1基因引物,这些引物针对的是跨越所有9个基因外显子的重叠CYP2E1基因片段,内含子、未翻译区(UTR)和基因间区。人类DNA样本(n = 3)作为训练集,检查引物性能并优化PCR条件。利用从结核病患者获得的人类DNA样本(n = 3)组成的测试集,评估开发的靶标扩增和测序方案的有效性。测序数据分析在Galaxy在线平台上进行。结果:测序数据质量足以检测分散在整个CYP2E1基因中的遗传变异,在完全覆盖的区域具有很高的置信度,达到了目标片段的最佳读取深度,碱基调用精度高。结论:制定的方案可应用于亚群体水平的关联研究,以确定CYP2E1基因多区域的单核苷酸变异(snv)或变异组合是否具有临床意义。
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引用次数: 0
Utilizing Pharmacogenomics Results to Determine Opioid Appropriateness and Improve Pain Management in a Patient with Osteoarthritis. 利用药物基因组学结果确定阿片类药物的适当性并改善骨关节炎患者的疼痛管理。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2022-11-07 eCollection Date: 2022-01-01 DOI: 10.2147/PGPM.S385272
Katie Pizzolato, David Thacker, Nicole Marie Del Toro-Pagán, Nishita S Amin, Abeer Hanna, Jacques Turgeon, Veronique Michaud

The opioid epidemic in the United States has exposed the need for providers to limit opioid dispensing and identify at-risk patients prior to prescribing opioids. With pharmacogenomic testing, clinicians can analyze hundreds of medications-including commonly prescribed opioids-against genetic results to understand and predict risk and response. Moreover, knowledge of genotypic variants and altered function can help decrease trial and error prescribing, identify patients at-risk for adverse drug events, and improve pain control. This patient case demonstrates how pharmacogenomic test results identified drug-gene interactions and provided insight about a patient's inadequate opioid therapy response. With pharmacogenomic information, the patient's healthcare team discontinued opioid therapy and selected a more appropriate regimen for osteoarthritis (ie, celecoxib), resulting in improved pain control and quality of life.

阿片类药物在美国的流行表明,提供者需要限制阿片类药物的配药,并在开阿片类药物处方之前识别有风险的患者。通过药物基因组学测试,临床医生可以根据基因结果分析数百种药物,包括常用的阿片类药物,以了解和预测风险和反应。此外,基因型变异和功能改变的知识可以帮助减少试验和错误处方,识别有药物不良事件风险的患者,并改善疼痛控制。该病例证明了药物基因组学测试结果如何识别药物-基因相互作用,并提供了有关患者阿片类药物治疗反应不足的见解。根据药物基因组学信息,患者的医疗团队停止了阿片类药物治疗,并选择了更适合骨关节炎的治疗方案(即塞来昔布),从而改善了疼痛控制和生活质量。
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引用次数: 0
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Pharmacogenomics & Personalized Medicine
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