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Association between functional FCGR3A F158V and FCGR2A R131H polymorphisms and responsiveness to rituximab in patients with autoimmune diseases: a meta-analysis 自身免疫性疾病患者功能性FCGR3A F158V和FCGR2A R131H多态性与利妥昔单抗应答性的关联:一项荟萃分析
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-05-06 DOI: 10.1038/s41397-023-00308-9
Young Ho Lee, Gwan Gyu Song
To investigate the association between the functional Fc gamma receptor 3 A (FCGR3A) V158F and FCGR2A R131H polymorphisms and rituximab therapy in patients with autoimmune diseases. We searched the Medline, Embase, and Cochrane databases for relevant articles. We conducted a meta-analysis of the association between FCGR3A V158F and FCGR2A R131H polymorphisms and responsiveness to rituximab in patients with autoimmune diseases. Eleven studies, consisting of 661 responders and 267 non-responders for FCGR3A V158F polymorphism and 156 responders and 89 non-responders for FCGR2A R131H polymorphism, were included. The meta-analysis revealed a significant association between the FCGR3A V allele and responsiveness to rituximab (odds ratio [OR] = 1.600, 95% confidence interval [CI] = 1.268–2.018, P < 0.001). Furthermore, associations were found using the dominant and homozygous contrast models. Subgroup analysis showed an association between the FCGR3A V allele and responsiveness to rituximab in European, RA, ITP, small (<50) and large (≥50) groups, and short- (≤6 months) and long-term follow-up periods (≥6 months). These associations were also found in recessive, dominant or homozygous contrast models. Meta-analysis revealed no association between the FCGR2A R allele and responsiveness to rituximab (OR = 1.243, 95% CI = 0.825–1.873, P = 0.229). We demonstrated that the FCGR3A F158V polymorphism is associated with better responsiveness to rituximab therapy in patients with autoimmune diseases, indicating that individuals carrying the FCGR3A V allele will likely respond better to rituximab. However, FCGR2A R131H polymorphism was not associated with better response to rituximab.
目的:探讨功能性Fc γ受体3a (FCGR3A) V158F和FCGR2A R131H多态性与自身免疫性疾病患者利妥昔单抗治疗的关系。方法:检索Medline、Embase和Cochrane数据库中的相关文章。我们对自身免疫性疾病患者中FCGR3A V158F和FCGR2A R131H多态性与利妥昔单抗应答性之间的关系进行了荟萃分析。结果:共纳入11项研究,其中FCGR3A V158F多态性有应答者661人,无应答者267人,FCGR2A R131H多态性有应答者156人,无应答者89人。荟萃分析显示,FCGR3A V等位基因与利妥昔单抗应答性之间存在显著相关性(优势比[OR] = 1.600, 95%可信区间[CI] = 1.238 -2.018, P)。结论:我们证明了FCGR3A F158V多态性与自身免疫性疾病患者对利妥昔单抗治疗的更好应答相关,表明携带FCGR3A V等位基因的个体可能对利妥昔单抗有更好的应答。然而,FCGR2A R131H多态性与利妥昔单抗的更好应答无关。
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引用次数: 0
Knowledge and attitudes of medical and pharmacy students about pharmacogenomics: a systematic review and meta-analysis 医学和药学学生对药物基因组学的知识和态度:系统综述和荟萃分析。
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-05-04 DOI: 10.1038/s41397-023-00306-x
Chen Li, Xiaona Su, Qidi Sun, Yi Huang
Pharmacogenomics (PGx) is rapidly growing branch of molecular genetics with high potentials to influence therapeutics. This review evaluates knowledge and attitudes of medical and pharmacy students about PGx. A literature search was conducted in electronic databases and studies were selected by following precise eligibility criteria. After quality assessment, studies were reviewed systematically, and meta-analyses of proportions were performed to estimate response rates of students. Fifteen studies (5509 students; 69% [95% confidence interval (CI): 60%, 77%] females) were included. Among students, 28% [95%CI: 12, 46] had adequate PGx knowledge; 65% [95%CI: 55, 75] were willing to have PGx test for their own risk assessment; 78% [95%CI: 71, 84] had intention to incorporate PGx in future practice; and 32% [95%CI: 21, 43] were satisfied with current PGx component of curriculum. Age, advanced year of educational program, and more time spent in PGx education were positively associated with PGx knowledge and positive attitudes.
药物基因组学(PGx)是分子遗传学的一个快速发展的分支,具有很高的影响治疗学的潜力。这篇综述评估了医学和药学学生对PGx的知识和态度。在电子数据库中进行文献检索,并根据准确的资格标准选择研究。在质量评估后,对研究进行了系统回顾,并对比例进行了荟萃分析,以估计学生的反应率。纳入了15项研究(5509名学生;69%[95%置信区间(CI):60%,77%]女性)。在学生中,28%[95%CI:12,46]具有足够的PGx知识;65%[95%CI:55,75]的人愿意进行PGx测试以进行自己的风险评估;78%[95%CI:71,84]有在未来实践中纳入PGx的意向;32%[95%CI:21,43]对当前课程的PGx组成部分感到满意。年龄、教育项目的高年级以及在PGx教育中花费的更多时间与PGx知识和积极态度呈正相关。
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引用次数: 0
DNA polymerase gamma variants and hepatotoxicity during maintenance therapy of childhood acute lymphoblastic leukemia: is there a causal relationship? DNA聚合酶γ变体与儿童急性淋巴细胞白血病维持治疗期间的肝毒性:是否存在因果关系?
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-05-03 DOI: 10.1038/s41397-023-00303-0
Tekla Harju, Anri Hurme-Niiranen, Maria Suo-Palosaari, Stine Nygaard Nielsen, Reetta Hinttala, Kjeld Schmiegelow, Johanna Uusimaa, Arja Harila, Riitta Niinimäki
Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.
肝毒性是用6-巯基嘌呤和甲氨蝶呤维持治疗急性淋巴细胞白血病(ALL)的常见并发症。甲基化6-巯基嘌呤代谢产物(MeMP)水平升高与肝毒性有关。然而,并非所有导致all患者肝功能衰竭的机制都是已知的。POLG基因编码线粒体DNA聚合酶γ(POLG1)的催化亚基,其变体与药物诱导的肝毒性有关,例如丙戊酸钠。研究了34例儿童ALL患者在维持治疗期间常见POLG变异与肝毒性的关系。在筛选的POLG变体中,在12名患者中检测到4种不同的变体。一名患者在MeMP水平未升高的情况下出现严重肝毒性,并携带杂合子POLG p.G517V变体,而在其他患者中未发现该变体。
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引用次数: 0
Polygenic risk scores analyses of psychiatric and metabolic traits with antipsychotic-induced weight gain in schizophrenia: an exploratory study 精神分裂症患者抗精神病药物引起的体重增加的精神和代谢特征的多因素风险评分分析:一项探索性研究。
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-04-27 DOI: 10.1038/s41397-023-00305-y
Kazunari Yoshida, Victoria S. Marshe, Samar S. M. Elsheikh, Malgorzata Maciukiewicz, Arun K. Tiwari, Eva J. Brandl, Jeffrey A. Lieberman, Herbert Y. Meltzer, James L. Kennedy, Daniel J. Müller
Given the polygenic nature of antipsychotic-induced weight gain (AIWG), we investigated whether polygenic risk scores (PRS) for various psychiatric and metabolic traits were associated with AIWG. We included individuals with schizophrenia (SCZ) of European ancestry from two cohorts (N = 151, age = 40.3 ± 11.8 and N = 138, age = 36.5 ± 10.8). We investigated associations of AIWG defined as binary and continuous variables with PRS calculated from genome-wide association studies of body mass index (BMI), coronary artery disease (CAD), fasting glucose, fasting insulin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, type 1 and 2 diabetes mellitus, and SCZ, using regression models. We observed nominal associations (uncorrected p < 0.05) between PRSs for BMI, CAD, and LDL-C, type 1 diabetes, and SCZ with AIWG. While results became non-significant after correction for multiple testing, these preliminary results suggest that PRS analyses might contribute to identifying risk factors of AIWG and might help to elucidate mechanisms at play in AIWG.
鉴于抗精神病药物诱导的体重增加(AIWG)的多基因性质,我们研究了各种精神和代谢特征的多基因风险评分(PRS)是否与AIWG相关。我们纳入了来自两个队列(N = 151,年龄 = 40.3 ± 11.8和N = 138岁 = 36.5 ± 10.8)。我们使用回归模型研究了定义为二元和连续变量的AIWG与PRS的相关性,PRS是根据体重指数(BMI)、冠状动脉疾病(CAD)、空腹血糖、空腹胰岛素、高密度脂蛋白胆固醇、低密度脂蛋白胆甾醇(LDL-C)、甘油三酯、1型和2型糖尿病以及SCZ的全基因组关联研究计算的。我们观察到名义关联(未校正的p
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引用次数: 0
One year of experience with combined pharmacokinetic/pharmacogenetic monitoring of anti-TNF alpha agents: a retrospective study 抗TNF-α药物药代动力学/药理学联合监测一年的经验:一项回顾性研究。
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-04-04 DOI: 10.1038/s41397-023-00304-z
Stefania Cheli, Diego Savino, Annalisa De Silvestri, Lorenzo Norsa, Naire Sansotta, Francesca Penagini, Dario Dilillo, Roberto Panceri, Dario Cattaneo, Emilio Clementi, Giovanna Zuin
Anti-tumor necrosis factor alpha (anti-TNFα) inhibitors are used extensively for the management of moderate to severe inflammatory bowel disease (IBD) in both adult and pediatric patients. Unfortunately, not all patients show an optimal response to induction therapy, while others lose their response over time for reasons yet poorly understood. We report on a pharmacokinetic/pharmacogenetic approach to monitor the therapy with anti-TNFα in a real-world cohort of seventy-nine pediatric patients affected by IBD that was analyzed retrospectively. We evaluated plasma concentrations of infliximab, adalimumab, and related anti-drug antibodies (ADAs), and single nucleotide polymorphisms (SNPs) in genes involved in immune processes and inflammation on the anti-TNFα response. We found a significant association between the SNP in TNFα promoter (−308G>A) and clinical remission without steroids in patients on infliximab therapy. Additionally, a potential connection between HLA-DQA1*05 genetic variant carriers and a higher risk of anti-TNFα immunogenicity emerged.
抗肿瘤坏死因子-α(Anti-TNFα)抑制剂广泛用于成人和儿童中重度炎症性肠病(IBD)的治疗。不幸的是,并非所有患者都对诱导治疗表现出最佳反应,而其他患者则因尚不清楚的原因而随着时间的推移而失去反应。我们报告了一种药代动力学/药物遗传学方法,在一个由79名IBD患儿组成的真实队列中监测抗TNFα的治疗,该队列进行了回顾性分析。我们评估了英夫利昔单抗、阿达木单抗和相关抗药物抗体(ADAs)的血浆浓度,以及参与免疫过程和炎症的基因对抗TNFα反应的单核苷酸多态性(SNPs)。我们发现,在接受英夫利昔单抗治疗的患者中,TNFα启动子中的SNP(-308G>a)与无类固醇的临床缓解之间存在显著关联。此外,HLA-DQA1*05基因变异携带者与抗TNFα免疫原性的更高风险之间存在潜在联系。
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引用次数: 0
Non-steroidal anti-inflammatory drug target gene associations with major depressive disorders: a Mendelian randomisation study integrating GWAS, eQTL and mQTL Data 非甾体抗炎药靶基因与重度抑郁障碍的关系:一项整合了 GWAS、eQTL 和 mQTL 数据的孟德尔随机化研究
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-03-25 DOI: 10.1038/s41397-023-00302-1
Qian He, Kevin Chun Hei Wu, Adam N. Bennett, Beifang Fan, Jundong Liu, Ruixuan Huang, Alice P. S. Kong, Xiaoyu Tian, Man Ki Maggie Kwok, Kei Hang Katie Chan
Previous observational studies reported associations between non-steroidal anti-inflammatory drugs (NSAIDs) and major depressive disorder (MDD), however, these associations are often inconsistent and underlying biological mechanisms are still poorly understood. We conducted a two-sample Mendelian randomisation (MR) study to examine relationships between genetic variants and NSAID target gene expression or DNA methylation (DNAm) using publicly available expression, methylation quantitative trait loci (eQTL or mQTL) data and genetic variant-disease associations from genome-wide association studies (GWAS of MDD). We also assessed drug exposure using gene expression and DNAm levels of NSAID targets as proxies. Genetic variants were robustly adjusted for multiple comparisons related to gene expression, DNAm was used as MR instrumental variables and GWAS statistics of MDD as the outcome. A 1-standard deviation (SD) lower expression of NEU1 in blood was related to lower C-reactive protein (CRP) levels of −0.215 mg/L (95% confidence interval (CI): 0.128–0.426) and a decreased risk of MDD (odds ratio [OR] = 0.806; 95% CI: 0.735–0.885; p = 5.36 × 10−6). A concordant direction of association was also observed for NEU1 DNAm levels in blood and a risk of MDD (OR = 0.886; 95% CI: 0.836–0.939; p = 4.71 × 10−5). Further, the genetic variants associated with MDD were mediated by NEU1 expression via DNAm (β = −0.519; 95% CI: −0.717 to −0.320256; p = 3.16 × 10−7). We did not observe causal relationships between inflammatory genetic marker estimations and MDD risk. Yet, we identified a concordant association of NEU1 messenger RNA and an adverse direction of association of higher NEU1 DNAm with MDD risk. These results warrant increased pharmacovigilance and further in vivo or in vitro studies to investigate NEU1 inhibitors or supplements for MDD.
以往的观察性研究报告了非甾体抗炎药(NSAIDs)与重度抑郁症(MDD)之间的关联,然而,这些关联往往并不一致,而且人们对其背后的生物学机制仍然知之甚少。我们进行了一项双样本孟德尔随机化(MR)研究,利用可公开获得的表达、甲基化定量性状位点(eQTL 或 mQTL)数据以及全基因组关联研究(GWAS of MDD)中的遗传变异-疾病关联,研究遗传变异与非甾体抗炎药靶基因表达或 DNA 甲基化(DNAm)之间的关系。我们还使用非甾体抗炎药靶点的基因表达和DNAm水平作为替代物评估了药物暴露。基因变异经稳健调整后用于与基因表达相关的多重比较,DNAm被用作MR工具变量,MDD的GWAS统计数据被用作结果。血液中 NEU1 表达量减少 1 个标准差 (SD) 与 C 反应蛋白 (CRP) 水平降低 -0.215 mg/L(95% 置信区间 (CI):0.128-0.426)和 MDD 风险降低有关(比值比 [OR] = 0.806;95% CI:0.735-0.885;P = 5.36 × 10-6)。血液中 NEU1 DNAm 水平与 MDD 风险的关联方向也一致(OR = 0.886;95% CI:0.836-0.939;p = 4.71 × 10-5)。此外,与 MDD 相关的遗传变异是通过 DNAm 的 NEU1 表达介导的(β = -0.519;95% CI:-0.717 至 -0.320256;p = 3.16 × 10-7)。我们没有观察到炎症遗传标记估计值与 MDD 风险之间的因果关系。然而,我们发现 NEU1 信使 RNA 与 MDD 风险之间存在一致的关联,而较高的 NEU1 DNAm 与 MDD 风险之间存在不利的关联方向。这些结果表明,有必要加强药物警戒,并进一步开展体内或体外研究,以调查治疗 MDD 的 NEU1 抑制剂或补充剂。
{"title":"Non-steroidal anti-inflammatory drug target gene associations with major depressive disorders: a Mendelian randomisation study integrating GWAS, eQTL and mQTL Data","authors":"Qian He,&nbsp;Kevin Chun Hei Wu,&nbsp;Adam N. Bennett,&nbsp;Beifang Fan,&nbsp;Jundong Liu,&nbsp;Ruixuan Huang,&nbsp;Alice P. S. Kong,&nbsp;Xiaoyu Tian,&nbsp;Man Ki Maggie Kwok,&nbsp;Kei Hang Katie Chan","doi":"10.1038/s41397-023-00302-1","DOIUrl":"10.1038/s41397-023-00302-1","url":null,"abstract":"Previous observational studies reported associations between non-steroidal anti-inflammatory drugs (NSAIDs) and major depressive disorder (MDD), however, these associations are often inconsistent and underlying biological mechanisms are still poorly understood. We conducted a two-sample Mendelian randomisation (MR) study to examine relationships between genetic variants and NSAID target gene expression or DNA methylation (DNAm) using publicly available expression, methylation quantitative trait loci (eQTL or mQTL) data and genetic variant-disease associations from genome-wide association studies (GWAS of MDD). We also assessed drug exposure using gene expression and DNAm levels of NSAID targets as proxies. Genetic variants were robustly adjusted for multiple comparisons related to gene expression, DNAm was used as MR instrumental variables and GWAS statistics of MDD as the outcome. A 1-standard deviation (SD) lower expression of NEU1 in blood was related to lower C-reactive protein (CRP) levels of −0.215 mg/L (95% confidence interval (CI): 0.128–0.426) and a decreased risk of MDD (odds ratio [OR] = 0.806; 95% CI: 0.735–0.885; p = 5.36 × 10−6). A concordant direction of association was also observed for NEU1 DNAm levels in blood and a risk of MDD (OR = 0.886; 95% CI: 0.836–0.939; p = 4.71 × 10−5). Further, the genetic variants associated with MDD were mediated by NEU1 expression via DNAm (β = −0.519; 95% CI: −0.717 to −0.320256; p = 3.16 × 10−7). We did not observe causal relationships between inflammatory genetic marker estimations and MDD risk. Yet, we identified a concordant association of NEU1 messenger RNA and an adverse direction of association of higher NEU1 DNAm with MDD risk. These results warrant increased pharmacovigilance and further in vivo or in vitro studies to investigate NEU1 inhibitors or supplements for MDD.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"23 4","pages":"95-104"},"PeriodicalIF":2.8,"publicationDate":"2023-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10382318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10276193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 expression level of Neuronal Calcium Sensor 1 can predict the prognosis of cytogenetically normal AML 神经元钙传感器 1 的表达水平可预测细胞遗传正常的急性髓细胞性白血病的预后
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-03-14 DOI: 10.1038/s41397-023-00301-2
Weilong Zhang, Jing Wang, Wei Li, Xiaoni Liu, Yali Zhao, Ping Yang, Mingxia Zhu, Kai Hu, Shaoxiang Li, Gehong Dong, Changjian Yan, Xue He, Xiuru Zhang, Hongmei Jing
Acute myeloid leukemia (AML) is malignant clonal expansion of myeloid blasts with high heterogeneity and numerous molecular biomarkers have been found to judge the prognosis in some specific classifications of AML. Furthermore, as for patients with cytogenetically normal acute myeloid leukemia (CN-AML), we need to find more new biomarkers to predict the patients’ outcomes. Recently, the expression level of Neuronal Calcium Sensor 1 (NCS1) has been associated with the prognosis of breast cancer and hepatocellular carcinoma, but nothing related has been reported about hematological malignancies. Therefore, we make this study to explore the relationship between the NCS1 expression level and CN-AML. We analyzed the relation between survival and NCS1 RNA expression through 75 CN-AML patients from Cancer Genome Atlas (TCGA) database and 433 CN-AML patients (3 independent datasets) from Gene Expression Omnibus (GEO) database. Additionally, we compared the NCS1 RNA expression between 138 leukemia stem cells positive (LSCs+) samples and 89 leukemia stem cells negative (LSCs−) samples from 78 AML patients from GSE76004 dataset. In our study, CN-AML patients with high expression level of NCS1 have longer EFS or OS. In addition, the NCS1 expression level in leukemia stem cells was low (p = 0.00039). According to these findings, we concluded that the high expression of NCS1 can predict favorable prognosis in CN-AML patients. Furthermore, our work put forward that NCS1 expresses lower in LSCs+, which might be an important mechanism to explain the aggressiveness of AML.
急性髓性白血病(AML)是一种具有高度异质性的髓样小体恶性克隆扩增,目前已发现许多分子生物标志物可用于判断某些特定分类的急性髓性白血病的预后。此外,对于细胞遗传学正常的急性髓性白血病(CN-AML)患者,我们需要找到更多新的生物标志物来预测患者的预后。最近,神经元钙传感器 1(NCS1)的表达水平与乳腺癌和肝细胞癌的预后有关,但与血液恶性肿瘤相关的研究却鲜有报道。因此,我们进行了这项研究,探讨 NCS1 表达水平与 CN-AML 之间的关系。我们通过癌症基因组图谱(TCGA)数据库中的 75 例 CN-AML 患者和基因表达总库(GEO)数据库中的 433 例 CN-AML 患者(3 个独立数据集)分析了生存与 NCS1 RNA 表达之间的关系。此外,我们还比较了GSE76004数据集中78名AML患者的138份白血病干细胞阳性(LSCs+)样本和89份白血病干细胞阴性(LSCs-)样本的NCS1 RNA表达。在我们的研究中,NCS1表达水平高的CN-AML患者的EFS或OS更长。此外,NCS1在白血病干细胞中的表达水平较低(p = 0.00039)。根据这些发现,我们得出结论:NCS1的高表达可预测CN-AML患者的良好预后。此外,我们的研究还提出,NCS1在LSCs+中表达较低,这可能是解释急性髓细胞性白血病侵袭性的一个重要机制。
{"title":"The expression level of Neuronal Calcium Sensor 1 can predict the prognosis of cytogenetically normal AML","authors":"Weilong Zhang,&nbsp;Jing Wang,&nbsp;Wei Li,&nbsp;Xiaoni Liu,&nbsp;Yali Zhao,&nbsp;Ping Yang,&nbsp;Mingxia Zhu,&nbsp;Kai Hu,&nbsp;Shaoxiang Li,&nbsp;Gehong Dong,&nbsp;Changjian Yan,&nbsp;Xue He,&nbsp;Xiuru Zhang,&nbsp;Hongmei Jing","doi":"10.1038/s41397-023-00301-2","DOIUrl":"10.1038/s41397-023-00301-2","url":null,"abstract":"Acute myeloid leukemia (AML) is malignant clonal expansion of myeloid blasts with high heterogeneity and numerous molecular biomarkers have been found to judge the prognosis in some specific classifications of AML. Furthermore, as for patients with cytogenetically normal acute myeloid leukemia (CN-AML), we need to find more new biomarkers to predict the patients’ outcomes. Recently, the expression level of Neuronal Calcium Sensor 1 (NCS1) has been associated with the prognosis of breast cancer and hepatocellular carcinoma, but nothing related has been reported about hematological malignancies. Therefore, we make this study to explore the relationship between the NCS1 expression level and CN-AML. We analyzed the relation between survival and NCS1 RNA expression through 75 CN-AML patients from Cancer Genome Atlas (TCGA) database and 433 CN-AML patients (3 independent datasets) from Gene Expression Omnibus (GEO) database. Additionally, we compared the NCS1 RNA expression between 138 leukemia stem cells positive (LSCs+) samples and 89 leukemia stem cells negative (LSCs−) samples from 78 AML patients from GSE76004 dataset. In our study, CN-AML patients with high expression level of NCS1 have longer EFS or OS. In addition, the NCS1 expression level in leukemia stem cells was low (p = 0.00039). According to these findings, we concluded that the high expression of NCS1 can predict favorable prognosis in CN-AML patients. Furthermore, our work put forward that NCS1 expresses lower in LSCs+, which might be an important mechanism to explain the aggressiveness of AML.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"23 4","pages":"89-94"},"PeriodicalIF":2.8,"publicationDate":"2023-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9900350","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
Targeted next-generation sequencing of genes involved in Warfarin Pharmacodynamics and pharmacokinetics pathways using the Saudi Warfarin Pharmacogenetic study (SWAP) 利用沙特华法林药物基因研究(SWAP)对涉及华法林药效学和药代动力学途径的基因进行有针对性的新一代测序
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-02-04 DOI: 10.1038/s41397-023-00300-3
Maha Al Ammari, Bader Almuzzaini, Khalid Al Sulaiman, Mohammed AlBalwi, Khizra Sultana, Ibrahim B. Alabdulkareem, Nada S. Almakhlafi, Anoud Al Humoud, Mohammed Waheeby, Munee Balla, Asma Al Shehri, Adel Alharf, Jahad Alghamdi
Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins’s narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients’ therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness. A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation. The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.
华法林是一种口服抗凝剂,常用于治疗和预防血栓栓塞事件。华法林的治疗指数窗狭窄是临床实践中的主要挑战之一,因此需要经常监测和调整剂量,以维持患者的治疗范围。华法林的剂量变化和反应可归因于个体间和个体内的多种因素,包括参与华法林药代动力学(PK)和药效学(PD)途径的酶的遗传变异。因此,我们旨在利用新一代测序(NGS)方法来鉴定可能与华法林反应性相关的罕见和常见基因变异。我们利用预先设计的 NGS 面板(包括华法林 PK/PD 通路中涉及的 16 个基因)对来自沙特华法林药物遗传队列(SWAP)的 786 名患者进行了测序。我们使用多种注释工具对鉴定出的变异进行了注释,以确定这些变异的致病性和等位基因频率。我们进行了变异与华法林剂量的关联测试。我们在测序基因中发现了 710 个变异,其中 19% 是新变异,绝大多数是稀缺变异。基因关联测试表明,VKORC1(rs9923231 和 rs61742245)、CYP2C9(rs98332238、rs9332172、rs1057910、rs9332230、rs1799853、rs1057911、和 rs9332119)、CYP2C19(rs28399511 和 rs3758581)和 CYP2C8(rs11572080 和 rs10509681)与华法林每周剂量显著相关。我们的模型包括遗传因素,非遗传因素解释了华法林剂量变化的 40.1%。这项研究发现了沙特人群中与华法林剂量相关的新型变异。这些变异更有可能是人群特异性变异,这表明在采用通用的华法林基因型指导剂量算法之前,应进行人群特异性研究。
{"title":"Targeted next-generation sequencing of genes involved in Warfarin Pharmacodynamics and pharmacokinetics pathways using the Saudi Warfarin Pharmacogenetic study (SWAP)","authors":"Maha Al Ammari,&nbsp;Bader Almuzzaini,&nbsp;Khalid Al Sulaiman,&nbsp;Mohammed AlBalwi,&nbsp;Khizra Sultana,&nbsp;Ibrahim B. Alabdulkareem,&nbsp;Nada S. Almakhlafi,&nbsp;Anoud Al Humoud,&nbsp;Mohammed Waheeby,&nbsp;Munee Balla,&nbsp;Asma Al Shehri,&nbsp;Adel Alharf,&nbsp;Jahad Alghamdi","doi":"10.1038/s41397-023-00300-3","DOIUrl":"10.1038/s41397-023-00300-3","url":null,"abstract":"Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins’s narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients’ therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness. A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation. The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.","PeriodicalId":54624,"journal":{"name":"Pharmacogenomics Journal","volume":"23 4","pages":"82-88"},"PeriodicalIF":2.8,"publicationDate":"2023-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9897148","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
Sequencing of genes of drug response in tumor DNA and implications for precision medicine in cancer patients 肿瘤 DNA 中的药物反应基因测序及其对癌症患者精准医疗的影响
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-01-28 DOI: 10.1038/s41397-023-00299-7
Nancy Gillis, Amy S. Etheridge, Sushant A. Patil, D. Neil Hayes, Michele C. Hayward, J. Todd Auman, Joel S. Parker, Federico Innocenti
Tumor DNA sequencing is becoming standard-of-care for patient treatment decisions. We evaluated genotype concordance between tumor DNA and genomic DNA from blood and catalogued functional effects of somatic mutations in 21 drug response genes in 752 solid tumor patients. Using a threshold of 10% difference between tumor and blood DNA variant allele fraction (VAF), concordance for heterogenous genotype calls was 78% and increased to 97.5% using a 30% VAF threshold. Somatic mutations were observed in all 21 drug response genes, and 44% of patients had at least one somatic mutation in these genes. In tumor DNA, eight patients had a frameshift mutation in CYP2C8, which metabolizes taxanes. Overall, somatic copy number losses were more frequent than gains, including for CYP2C19 and CYP2D6 which had the most frequent copy number losses. However, copy number gains in TPMT were more than four times as common as losses. Seven % of patients had copy number gains in ABCB1, a multidrug resistance transporter of anti-cancer agents. These results demonstrate tumor-only DNA sequencing might not be reliable to call germline genotypes of drug response variants.
肿瘤 DNA 测序正成为患者治疗决策的标准。我们评估了肿瘤DNA和血液基因组DNA之间的基因型一致性,并对752名实体瘤患者中21个药物反应基因的体细胞突变的功能影响进行了编目。以肿瘤和血液DNA变异等位基因比例(VAF)相差10%为阈值,异源基因型调用的一致性为78% ,以30% VAF 为阈值,一致性提高到97.5%。在所有 21 个药物反应基因中都观察到了体细胞突变,44% 的患者在这些基因中至少有一个体细胞突变。在肿瘤DNA中,有8名患者的CYP2C8发生了框架移位突变,而CYP2C8可代谢紫杉类药物。总体而言,体细胞拷贝数丢失比拷贝数增加更频繁,其中CYP2C19和CYP2D6的拷贝数丢失最为频繁。然而,TPMT的拷贝数增益是拷贝数丢失的四倍多。7%的患者存在抗癌药多药耐药性转运体ABCB1的拷贝数增加。这些结果表明,仅通过肿瘤DNA测序来确定药物反应变异的种系基因型可能并不可靠。
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引用次数: 0
Investigating genetic variants for treatment response to selective serotonin reuptake inhibitors in syndromal factors and side effects among patients with depression in Taiwanese Han population 调查台湾汉族抑郁症患者对选择性血清素再摄取抑制剂的治疗反应在综合因素和副作用方面的遗传变异
IF 2.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2023-01-19 DOI: 10.1038/s41397-023-00298-8
Shiau-Shian Huang, Yi-Ting Chen, Mei-Hsin Su, Shih-Jen Tsai, Hsi-Han Chen, Albert C. Yang, Yu-Li Liu, Po-Hsiu Kuo
Major depressive disorder (MDD) is associated with high heterogeneity in clinical presentation. In addition, response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably among patients. Therefore, identifying genetic variants that may contribute to SSRI treatment responses in MDD is essential. In this study, we analyzed the syndromal factor structures of the Hamilton Depression Rating Scale in 479 patients with MDD by using exploratory factor analysis. All patients were followed up biweekly for 8 weeks. Treatment response was defined for all syndromal factors and total scores. In addition, a genome-wide association study was performed to investigate the treatment outcomes at week 4 and repeatedly assess all visits during follow-up by using mixed models adjusted for age, gender, and population substructure. Moreover, the role of genetic variants in suicidal and sexual side effects was explored, and five syndromal factors for depression were derived: core, insomnia, somatic anxiety, psychomotor-insight, and anorexia. Subsequently, several known genes were mapped to suggestive signals for treatment outcomes, including single-nucleotide polymorphisms (SNPs) in PRF1, UTP20, MGAM, and ENSG00000286536 for psychomotor-insight and in C4orf51 for anorexia. In total, 33 independent SNPs for treatment responses were tested in a mixed model, 12 of which demonstrated a p value <0.05. The most significant SNP was rs2182717 in the ENSR00000803469 gene located on chromosome 6 for the core syndromal factor (β = −0.638, p = 1.8 × 10−4) in terms of symptom improvement over time. Patients with a GG or GA genotype with the rs2182717 SNP also exhibited a treatment response (β = 0.089, p = 2.0 × 10−6) at week 4. Moreover, rs1836075352 was associated with sexual side effects (p = 3.2 × 10−8). Pathway and network analyses using the identified SNPs revealed potential biological functions involved in treatment response, such as neurodevelopment-related functions and immune processes. In conclusion, we identified loci that may affect the clinical response to treatment with antidepressants in the context of empirically defined depressive syndromal factors and side effects among the Taiwanese Han population, thus providing novel biological targets for further investigation.
重度抑郁障碍(MDD)的临床表现具有高度异质性。此外,不同患者对选择性血清素再摄取抑制剂(SSRIs)治疗的反应也有很大差异。因此,确定可能会影响 MDD 患者对 SSRI 治疗反应的遗传变异至关重要。在这项研究中,我们采用探索性因子分析方法分析了 479 名 MDD 患者的汉密尔顿抑郁量表(Hamilton Depression Rating Scale)的综合因子结构。所有患者均接受了为期 8 周的双周随访。所有综合因子和总分均定义为治疗反应。此外,还进行了一项全基因组关联研究,通过年龄、性别和人群亚结构调整后的混合模型,调查第 4 周的治疗结果,并在随访期间反复评估所有就诊情况。此外,还探讨了基因变异在自杀和性副作用中的作用,并得出了五个抑郁症综合因素:核心、失眠、躯体焦虑、精神运动-视力和厌食。随后,几个已知基因被映射到治疗结果的提示性信号上,包括PRF1、UTP20、MGAM和ENSG00000286536中的单核苷酸多态性(SNPs)(针对精神运动视力)和C4orf51中的单核苷酸多态性(SNPs)(针对厌食症)。在混合模型中,共有 33 个独立的 SNP 与治疗反应相关,其中 12 个 SNP 的 p 值为 0.05。最显著的 SNP 是位于 6 号染色体上的 ENSR00000803469 基因中的 rs2182717,该 SNP 与核心综合征因子有关(β = -0.638,p = 1.8 × 10-4)。在第 4 周时,rs2182717 SNP 基因型为 GG 或 GA 的患者也表现出治疗反应(β = 0.089,p = 2.0 × 10-6)。此外,rs1836075352 与性副作用相关(p = 3.2 × 10-8)。利用所鉴定的 SNPs 进行的通路和网络分析揭示了参与治疗反应的潜在生物功能,如神经发育相关功能和免疫过程。总之,我们在台湾汉族人群中根据经验定义的抑郁综合征因素和副作用发现了可能影响抗抑郁药物治疗临床反应的位点,从而为进一步研究提供了新的生物学靶点。
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引用次数: 1
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Pharmacogenomics Journal
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