药物基因组学与个性化药物设计研究进展

药物基因组学是采用基因组学的信息和研究方法，通过分析DNA的遗传变异和监测基因表达谱，以阐明药物反应差异的遗传学本质。这不仅有利于根据药物代谢和药物反应的遗传学特点指导合理用药，而且有利于开发和设计新的药物。综述药物基因组学研究进展，论述与药物开发和临床用药相关的药物代谢的基因组学原理，给出CYP450、药物转运蛋白等实例，概述药物基因组学的一些潜在的用途，预测药物基因组学的发展和临床应用前景。     

部分抗肿瘤药物基因组学研究进展

近年来,由于个体差异引起抗肿瘤药物疗效和毒副作用的不同受到越来越多的重视。药物基因组学的研究结果表明基因多态性与抗肿瘤药物个体间作用多样性及毒副作用之间的关系密切。本文就部分抗肿瘤药物基因组学的研究进展加以综述。     

心脑血管药物基因组学与个体化治疗研究进展

心脑血管疾病是威胁人类健康的主要疾病,而药物基因组学与个体化治疗的研究和发展为这类疾病的治疗提供了新的思路。药物基因组通过研究药物效应与基因多态性之间的关系,为实现个体化治疗提供理论依据。本文从临床上最常用的抗凝药、抗高血压药、血小板聚集抑制剂和调节血脂药等药物出发,概述了心脑血管药物基因组学研究进展。     

药物基因组学的研究进展

药物反应的遗传多态性对药物疗效、毒副作用等有决定作用。药物基因组学应用分子遗传新技术研究基因组,加速发展对药物反应的标记（如药物作用目标、药物代谢、疾病通路等）、寻找药物反应的遗传分布,其发展促进了药物遗传学的进步,为疾病治疗和新药设计开辟了广阔的前景。     

瑞格列奈药物基因组学的研究进展

目的:了解瑞格列奈药物基因组学的研究进展,为瑞格列奈的临床个体化给药提供参考。方法:查阅近年来国内外相关文献,就瑞格列奈的药物基因组学的研究进行归纳和总结。结果:瑞格列奈相关的药物基因组学研究主要集中于药物代谢和转运相关基因、药物作用靶点和受体的编码基因、2型糖尿病(T2DM)易感基因等方面,其中KCNQ1、Neuro D1/BETA2、PAX4、NOS1AP、SLC30A8、IGF2BP2、UCP2、NAMPT为代表的T2DM易感基因对瑞格列奈药效学的影响是目前研究的重点。T2DM易感基因可能通过影响胰岛B细胞的增殖、腺苷三磷酸敏感性钾通道(KATP)和电压门控Ca~(2+)通道的表达和活性以及胰岛素分泌,从而增加T2DM的易感性并影响药物治疗反应性。CYP2C8、CYP3A4、SLCO1B1和MDR1等与药物代谢和转运有关的基因多态性可能影响瑞格列奈的药-时曲线下面积、峰浓度、半衰期和清除率等,间接影响药物疗效和安全性。在开展药物基因组学研究时,还应根据不同种族的等位基因频率来选择基因多态性位点,以期获得更大的临床应用价值。结论:基因多态性是瑞格列奈治疗反应性个体差异的部分原因,有望通过基因导向的个体化治疗提高疗效、减少不良反应。     

降血脂药物的药物基因组学研究进展

药物基因组学其研究基础是确定与药物作用和疾病病理生理机制相关的候选基因多态性,通过候选基因的多态性预测药物疗效,评价药物疗效. 大量的实验表明降脂药可以纠正血脂蛋白的异常,从而大大降低心脏事件的风险性. 而人体对这些降脂药的反应受众多因素的影响. 了解基因多态性对降脂药的影响, 以提高疗效, 减少其不良反应的发生.     

糖尿病治疗药物基因组学研究进展

通过对治疗糖尿病药物的介绍,来对糖尿病治疗药物基因组学的研究做一简要综述.药物基因组学其研究基础是确定与药物作用和疾病病理生理机制相关的候选基因多态性,通过候选基因的多态性预测药物疗效,评价药物疗效.本文通过了解磺脲类、双胍类等药物基因组方面的研究进展来诠释糖尿病药物基因组学研究的现状.     

风湿性疾病药物基因组学的研究进展

风湿性疾病泛指影响骨、关节及周围软组织,如肌腱、滑囊、筋膜等一组疾病,而药物是治疗风湿性疾病的重要手段,风湿性疾病常用的治疗药物包括镇痛药、非甾体抗炎药、皮质类固醇类药、缓解病情风湿药及生物制剂,但部分患者在治疗开始或期间就对药物不敏感,除了疾病自身的特点外,个体遗传因素也是一个重要的影响因素。风湿性疾病药物基因组学的研究进展可预测药物治疗的效果和不良反应,并可为临床治疗提供合理的指导和建议。本文以风湿性疾病常用的治疗药物为主线,归纳了近年来影响药物疗效中有关药物代谢酶、药物转运体和药物作用靶点的基因组学研究进展。     

药物基因组学与新药开发

目的：探讨药物基因组学对未来新药开发的影响。方法：以国内外有影响和有代表性的文献为依据，对药物基因组学的概念及其与新药的研制、新药的临床试验、新药的开发前景进行论述。结果：药物基因组学的研究，将极大地推动新药开发的进程。结论：药物基因组学将对2l世纪新药的开发产生深远的影响，前景广阔。     

维生素的药物基因组学研究进展

维生素(vitamin)是人和动物维持正常生理功能所必需的一种微量有机物质,在机体生长、代谢、发育过程中发挥着重要作用。研究发现,维生素是体内多种酶发挥其活性的重要影响因子,是多种酶的辅酶或者辅酶的重要组成部分,人体内维生素的缺乏可导致各种代谢缺乏症。药物基因组学研究人类基因变异与药物反应的关系,利用基因组学的信息解答不同个体对同一药物反应存在个体差异的原因。维生素在维持人体正常生理功能中起重要作用,也是药物基因组学研究的一个重要组成部分。     

Genome-Wide Pharmacogenomic Study of Neurocognition As an Indicator of Antipsychotic Treatment Response in Schizophrenia

Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8, and IL1A. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99 × 10⁻⁸, q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 10⁻⁷, q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 10⁻⁷, q-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download.     

Clinical application of pharmacogenetics in gastrointestinal diseases

As knowledge of the human genome grows, there will be a direct impact on the management of specific diseases. Within gastroenterology and hepatology, there has been a change in the understanding of how variations or mutations in genes involved in drug metabolism or disease pathophysiology affect response to therapy. This review discusses the application of clinical pharmacogenetics to the following diseases and disorders: inflammatory bowel disease, Helicobacter pylori infections, gastroesophageal reflux disease, irritable bowel syndrome, functional dyspepsia, liver transplantation and colon cancer. Although only a few genotyping tests are regularly used in clinical practice, it is anticipated that studies will propel the routine use of many of the tests described in this review, in the future.     

Pharmacogenomics in cardiovascular disease: the role of single nucleotide polymorphisms in improving drug therapy

Pharmacogenomics is the study of how an individual’s genetic inheritance affects the body’s response to drugs. Pharmacogenomics holds the promise that drugs might one day be tailor-made for individuals and adapted to an individual’s genetic makeup. Several studies have shown that both adverse and beneficial responses to cardiovascular drugs can be influenced by single nucleotide polymorphisms in genes coding for metabolising enzymes, drug transporters and drug targets. Despite the large amount of data about gene–drug interactions, the translation of pharmacogenomics in clinical practise is slow. To improve this, there is a need of new technology and large prospective trials allowing for simultaneous analysis of multiple genetic variants in molecular pathways that could affect drug disposition and action.     

Role of single nucleotide polymorphisms in pharmacogenomics and their association with human diseases

Global statistical data shed light on an alarming trend that every year thousands of people die due to adverse drug reactions as each individual responds in a different way to the same drug. Pharmacogenomics has come up as a promising field in drug development and clinical medication in the past few decades. It has emerged as a ray of hope in preventing patients from developing potentially fatal complications due to adverse drug reactions. Pharmacogenomics also minimizes the exposure to drugs that are less/non-effective and sometimes even found toxic for patients. It is well reported that drugs elicit different responses in different individuals due to variations in the nucleotide sequences of genes encoding for biologically important molecules (drug-metabolizing enzymes, drug targets and drug transporters). Single nucleotide polymorphisms (SNPs), the most common type of polymorphism found in the human genome is believed to be the main reason behind 90% of all types of genetic variations among the individuals. Therefore, pharmacogenomics may be helpful in answering the question as to how inherited differences in a single gene have a profound effect on the mobilization and biological action of a drug. In the present review, we have discussed clinically relevant examples of SNP in associated diseases that can be utilized as markers for “better management of complex diseases” and attempted to correlate the drug response with genetic variations. Attention is also given towards the therapeutic consequences of inherited differences at the chromosomal level and how associated drug disposition and/or drug targets differ in various diseases as well as among the individuals.     

Comparative pharmacogenetic analysis of risk polymorphisms in Caucasian and Vietnamese children with acute lymphoblastic leukemia: prediction of therapeutic outcome?

AimsAcute lymphoblastic leukemia (ALL) is the most common of all paediatric cancers. Aside from predisposing to ALL, polymorphisms could also be associated with poor outcome. Indeed, genetic variations involved in drug metabolism could, at least partially, be responsible for heterogeneous responses to standardized leukemia treatments, hence requiring more personalized therapy. The aims of this study were to (a) to determine the prevalence of seven common genetic polymorphisms including those that affect the folate and/or thiopurine metabolic pathways, i.e. cyclin D1 (CCND1-G870A), γ-glutamyl hydrolase (GGH-C452T), methylenetetrahydrofolate reductase (MTHFR-C677T and MTHFR-A1298C), thymidylate synthase promoter (TYMS-TSER), thiopurine methyltransferase (TPMT*3A and TPMT*3C) and inosine triphosphate pyrophosphatase (ITPA-C94A), in Caucasian (n = 94, age < 20) and Vietnamese (n = 141, age < 16 years) childhood ALL and (b) to assess the impact of a multilocus genetic risk score (MGRS) on relapse-free survival (RFS) using a Cox proportional-hazards regression model.ResultsThe prevalence of MTHFR-677TT genotype was significantly higher in Caucasians (P = 0.008), in contrast to the prevalence of TYMS-TSER*3R/3R and ITPA-94AA/AC genotypes which were significantly higher in Vietnamese (P < 0.001 and P = 0.02, respectively). Compared with children with a low MGRS (≤3), those with a high MGRS (≥4) were 2.06 (95% CI = 1.01, 4.22; P = 0.04) times more likely to relapse. Adding MGRS into a multivariate Cox regression model with race/ethnicity and four clinical variables improved the predictive accuracy of the model (AUC from 0.682 to 0.709 at 24 months).ConclusionIncluding MGRS into a clinical model improved the predictive accuracy of short and medium term prognosis, hence confirming the association between well determined pharmacogenotypes and outcome of paediatric ALL. Whether variants on other genes associated with folate metabolism can substantially improve the predictive value of current MGRS is not known but deserves further evaluation.     

药物基因组学和个体化医学的转化研究进展

遗传药理学和药物基因组学作为新兴领域, 旨在促进个体化医学模式的早日实现。如何将遗传药理学和药物基因组学的实验研究成果转化为实际应用是目前最为重要和亟待解决的问题。本文将综述国际上遗传药理学和药物基因组学的研究成果在临床个体化治疗及新药开发领域的转化和应用的进展情况。     

北京军区总医院基因导向的个体化给药项目及其临床应用

本文介绍了北京军区总医院药理科应用焦磷酸测序基因分型技术开展的多种个体化给药基因检测项目,包括：β1肾上腺素受体基因和CYP2 D6基因;CYP2C19基因;维生素K环氧化物还原酶复合物1基因和CYP2C9基因;巯嘌呤甲基转移酶基因;表皮生长因子受体基因;IL28B基因;O6-甲基鸟嘌呤-DNA-甲基转移酶基因;SLCO1B1基因;HLA-B＊1502,HLA-B＊5801等位基因等。这些基因检测项目的实施为判断遗传因素对临床疗效及不良反应的影响提供了依据。     

DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines,oxaliplatin and irinotecan

Aims

Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations.

Methods

Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3–4 AEs.

Results

None of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3–4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c.496A > G and c.1896 T > C.

Conclusions

Concomitant assessment of DPYD variants and the UGT1A1*28 allele is a promising strategy needing further validation for dose personalization.     

Effects of Using Personal Genotype Data on Student Learning and Attitudes in a Pharmacogenomics Course

Objective. To evaluate the impact of personal genotyping and a novel educational approach on student attitudes, knowledge, and beliefs regarding pharmacogenomics and genomic medicine.Methods. Two online elective courses (pharmacogenomics and genomic medicine) were offered to student pharmacists at the University of Florida using a flipped-classroom, patient-centered teaching approach. In the pharmacogenomics course, students could be genotyped and apply results to patient cases.Results. Thirty-four and 19 student pharmacists completed the pharmacogenomics and genomic medicine courses, respectively, and 100% of eligible students (n=34) underwent genotyping. Student knowledge improved after the courses. Seventy-four percent (n=25) of students reported better understanding of pharmacogenomics based on having undergone genotyping.Conclusions. Completion of a novel pharmacogenomics elective course sequence that incorporated personal genotyping and genomic medicine was associated with increased student pharmacist knowledge and improved clinical confidence with pharmacogenomics.     

深圳市509例2型糖尿病患者常见口服降糖药物基因多态性分析

目的：探索深圳市糖尿病患者口服降糖药物相关单核苷酸多态性（single nucleotide polymorphism,SNPs）的分布特征,为糖尿病患者个体化用药指导提供参考。方法：采用外周血DNA抽提/焦磷酸测序检测509例糖尿病患者四大类降糖药物4个药物相关基因位点SNPs。采用SPSS 25.0软件统计相关基因位点的等位基因和基因型的频率分布差异。参照国内外不同人群的基因型频率数据,回顾性分析深圳市2020—2021年社区糖尿病患者的降糖药物相关SNPs的分布特征。结果：PPARG、SLCO1B1的SNPs与国外人群存在较大差异,与国内报道基本相符。CYP2C9*3的SNPs与欧洲人群存在差异,但与中国人群和美洲人群相关报道基本相符。然而有机阳离子转运体OCT2的SNPs与中国南方人群存在一定的差异,但与中国北京、欧洲、美洲相关报道的情况基本相符。结论：深圳市糖尿病患者降糖药物相关SNPs分布有自身特点,临床药师及医生应根据药物相关SNPs提供个体化用药指导建议。药物基因组学的个体化用药在参考PharmGKB等数据库的同时应结合国人的特点,不能完全参考国外人群数据库。