药物基因组学相关P450和ABCB1多态性及SNP检测技术

药物基因组学(phamacogenomics)是临床检测遗传差异引起药物应答个体性差异的学科,它涉及药物代谢和有害的药物反应的预测等方面的内容.个性化药物和个性化治疗发展的关键条件是能够快速简便的检测出病人的遗传多态性.文章综述了药物基因相关问题,细胞色素酶P450和ABCB1转运蛋白的遗传多态性以及检测遗传多态性的相...     

细胞色素P450基因遗传多态性的研究进展

细胞色素P450（cytochrome P450，CYP）在众多外源性物质和内源性物质的代谢中具有重要作用。家族1-3中编码P450的基因均存在多态性，特别是CYP2C9、CYP2C19、CYP2D6和CYP3A5。超过一半的临床药物是由多态性P450介导代谢，CYP基因的多态性是造成药物反应个体差异的主要原因。近几年，许多与P450酶活性和CYP基因表达相关的等位基因已被鉴定，因此通过分型CYP基因的功能性遗传变异或标签（Tag）遗传变异，就可以获得个体的代谢表型，有助于医生及时找到正确的用药方案，有效地提高药物疗效和降低毒副作用，特别是那些治疗指数窄的药物。显然，了解CYP基因的遗传变异对于临床药物治疗和药物开发是必不可少。基因芯片技术具有高多重水平和高通量的特点，使同时分型大量CYP基因遗传变异成为可能，是实现个性化医疗的重要技术保障。然而，DNA制备制约了预测性CYP基因分型芯片的发展，其在临床上的广泛应用尚需时日。     

北方满族人β1肾上腺素能受体基因Arg389Gly多态性分布

随着药物基因组学的发展,遗传因素在疾病发生、发展和药物反应个体差异中的作用也得到了越来越深入的阐明。受体基因的变异导致结构功能异常进而导致机体对疾病的易患性及药物的反应发生改变,所以了解不同人群中β1肾上腺素能受体基因多态性的分布,不仅为今后进一步研究不同人群中某些疾病的发生发展与β1肾上腺素能受体基因多态性间的关系提供实验依据,还可为实现以基因为导向的药物治疗和个体化用药提供可靠依据。本文对224例北方满族人β1肾上腺素能受体(adrenoreceptor,AR)基因Arg389G ly的多态性进行检测。1材料与方法1·1研究对象:2…     

置入心血管支架后冠状动脉粥样硬化性心脏病患者的C-反应蛋白变化

背景:心血管支架作为一种异体物质,置入后存在明显的炎症反应过程,主要表现在凝血系统的激活以及炎性标志物血清C-反应蛋白的显著升高。目的:总结探讨支架置入后冠状动脉粥样硬化性心脏病患者炎症反应及C-反应蛋白的变化。方法:应用计算机检索中文期刊全文数据库1990/2009相关文献,检索词为"心血管支架,C-反应蛋白,炎症反应",同时检索PubMed数据库1990/2009相关文献,检索词为"cardiovascular stent on plasma,c-reactive protein"。结果与结论:药物涂层支架以金属支架为载体携带药物到达血管损伤局部,使药物在较长的时间内充分释放到血管壁内,减少支架置入后再狭窄的发生。抗炎药物涂层支架主要药物为地塞米松、甲泼尼龙等。抗迁移、抗增生药物涂层支架主要药物为雷帕霉素、紫杉醇、放线菌素D等。支持内膜愈合的药物涂层支架主要药物为雌二醇等。经皮冠状动脉支架置入可诱导和加重局部炎症反应,这对血管内皮的增生与再狭窄有重要影响。反映急性炎症反应的敏感指标如血清C-反应蛋白的浓度对于经皮冠状动脉支架置入后心血管事件的发生有预测价值。冠状动脉内支架置入可显著升高血浆C-反应蛋白水平,所以应充分认识炎症反应及血浆C-反应蛋白、细胞因子的变化对防止心血管支架置入后再狭窄起到的重要作用,及早进行预防及干预,从而减少再狭窄率,提高介入治疗效果。     

药物基因组学和药物基因组计划

药物基因组学(Pharmacogenomics)和药物基因组计划(Pharmacogenomics prcoject,PGP)是在人类基因组(HGP )基础上发展起来的功能基因组内容之一.药物基因组学是研究影响药物吸收,转运、代谢和清除整个过程的个体差异的基因特性.由于基因多态性所致个体对药物的不同反应-药物反应的遗传基础,即有关基因和基因变异与药物效应个体差异之间的关系,并由此开发新药物 .以达到根据个体化的合理用药.所以,基因的多态性是药物基因组学的基础.药物基因组学是一个新型的交叉学科,使药物治疗的模式由诊断定向转为基因定向治疗.     

类风湿关节炎药物治疗基因多态性研究进展

类风湿关节炎(RA)是一种系统性疾病,可致关节破坏和残疾.治疗以传统DMARDs和生物制剂为主.药物疗效与患者基因多态性密切相关.药物主要包括甲氨蝶呤、来氟米特、柳氮磺胺吡啶和生物制剂如TNF拮抗剂、妥珠单抗、力妥昔单抗等.RA患者遗传背景是影响药物疗效的重要因素,必然对个体化治疗产生深远影响,因而研究基因多态性与RA患者疗效反应的相关机制具有重要意义.     

CYP2C9基因多态性与药物代谢

肝细胞色素CYP2C9催化一系列药物在体内的生物转化。CYP2C9基因多态性形成的个体差异是相关药物代谢差异的主要原因，本综述了CYP2C9基因的主要多态性类型在不同人群中的分布状况以及多态性与相关药物代谢的关系。     

药物基因组学和药物基因组计划

药物基因组学 (Ｐｈａｒｍａｃｏｇｅｎｏｍｉｃｓ)和药物基因组计划 (Ｐｈａｒｍａｃｏｇｅｎｏｍｉｃｓｐｒｃｏｊｅｃｔ,ＰＧＰ)是在人类基因组(ＨＧＰ)基础上发展起来的功能基因组内容之一 .药物基因组学是研究影响药物吸收 ,转运、代谢和清除整个过程的个体差异的基因特性 .由于基因多态性所致个体对药物的不同反应—药物反应的遗传基础 ,即有关基因和基因变异与药物效应个体差异之间的关系 ,并由此开发新药物 .以达到根据个体化的合理用药 .所以 ,基因的多态性是药物基因组学的基础 .药物基因组学是一个新型的交叉学科 ,使药物治疗的…     

药物代谢酶基因多态性与肿瘤易感性

药物代谢酶参与许多常见化学致宫物的代谢活化或解毒过程，且由于基因多态性，其活性存在个体及种族差异，有关药物代谢酶基因多态性与肿瘤易感性的研究正日益吸引了越来多的关注，本择其主要献作一简介。     

肿瘤化疗药物代谢酶遗传多态性的研究进展

肿瘤化疗的药物反应和毒性具有明显的个体差异，这种差异往往是由于药物代谢酶或受体表达在遗传上发生了变化。遗传多态性对药代动力学有重要的影响，它使一部分个体的毒性反应明显，而对另一部分病人则达不到理想治疗效果。本文对硫嘌呤甲基转移酶(TPMT)、细胞色素氧化酶(CYP450)、双氢嘧啶脱氢酶(DPD)、尿甘二磷酸--葡萄糖醛酸转移酶(UGTS)作了详细的综述，并阐明了其多态性对肿瘤化疗效果的意义。     

Nutrigenetics and nutraceuticals: the next wave riding on personalized medicine

The Human Genome Project and subsequent identification of single nucleotide polymorphisms (SNPs) within populations has played a major role in predicting individual response to drugs (pharmacogenetics) leading to the concept of "personalized medicine." Nutritional genomics is a recent off-shoot of this genetic revolution that includes (1) nutrigenomics: the study of interaction of dietary components with the genome and the resulting proteonomic and metabolomic changes; and (2) nutrigenetics: understanding the gene-based differences in response to dietary components and developing nutraceuticals that are most compatible with health based on individual genetic makeup. Despite the extensive data on genetic polymorphisms in humans, its translation into medical practice has been slow because of the time required to accumulate population data on SNP incidence, understand the significance of a given SNP in disease, and develop suitable diagnostic tests. Nutrigenomics revitalized the field by showing that nutrients and botanicals can interact with the genome and modify subsequent gene expression, which has provided a great impetus for nutrigenetic research and nutraceutical development based on nutrigenetics. Polymorphisms in methlyene tetrahydrofolate reductase (MTHFR) (involved in folate metabolism), apolipoprotein E (Apo E) and ApoA1 (in cardiovascular disease), and leptin/leptin receptor (obesity) genes are some good examples for understanding basic nutrigenetics. Developing nutraceuticals to prevent and manage thrombosis risk in women with thrombophilic gene mutations are discussed in the context of the opportunities that exist at the nutrigenetic/pharmacogenetic interphase leading to "personalized nutrition." Further research on individual differences in genetic profiles and nutrient requirements will help establish nutrigenetics as an essential discipline for nutrition and dietetics practice.     

Effect of pharmacogenetics on medicine

Pharmacogenetics is moving rapidly to assemble a large set of polymorphisms that define the influence of genetic diversity on human drug response. Scientific and technological advances of the last 10 years have led to new approaches to the discovery of genetic drug susceptibility loci, the development of high-tech analytical strategies for drug susceptibility profiling, and a flood of new gene discoveries in the area of receptors and receptor polymorphisms. Extension and refinement of our knowledge of human genetic diversity is essential to the use of drugs in more of an individualized manner and to the discovery of better therapies, but knowledge of the functional consequences of this diversity, the next great challenge in pharmacogenetics, provides the best chance to profit from this diversity.     

Genetic polymorphism and cancer

The clinical pathological significance of genetic polymorphism in cancer is reviewed from the following standpoint. 1) Genetic diagnosis of cancer, especially for loss of heterozygosity 2) Interference with laboratory data: For example, the polymorphisms in secretor and Lewis genes make effect on the serum levels of CA19-9. 3) Cancer susceptibility: Molecular epidemiological studies revealed some genetic polymorphisms were related with cancer susceptibility and were useful for biomarkers of cancer risk. 4) Drug sensitivity: The differences in drug toxicity are sometimes attributed to genetic variability in some enzymes responsible for drug metabolism. When the polymorphisms related with drug degradation were examined, the exact drug would have been selected for each individual. Genetic polymorphisms are strongly related with clinical practice of cancer. After the information about genetic polymorphisms is accumulated, tailor-made medicine(therapy/prevention/diagnosis) will be applicable to medical care of individuals.     

中国不同人群常见药物代谢相关基因遗传多态性的研究进展

遗传背景的差异会导致不同人群对同一种药物产生药物效应差异。随着药物基因组学的研究与发展,探讨药物基因组学与群体遗传差异的关系有助于阐明药物代谢相关基因多态性在中国不同人群药物效应异质性中的重要作用。本文总结了常见药物代谢相关基因多态性在中国不同人群中的研究情况,旨在为中国不同人群的个体化治疗提供有价值的理论依据。     

Human genetic variability and HIV treatment response

Access to potent antiretroviral medications greatly reduces morbidity and mortality due to HIV/AIDS, but drug toxicity limits treatment success in many individuals. The field of pharmacogenomics strives to understand the influence of human genetic variants in response to medications. Investigators have begun to identify associations among human genetic variants, predisposition to HIV drug toxicities, and likelihood of virologic response. These include associations among abacavir hypersensitivity reactions, HLA type, and hsp70-hom genotypes, and among CYP2B6 polymorphisms, efavirenz pharmacokinetics, and central nervous system symptoms. Pharmacogenomics also holds great promise to suggest novel targets for drug development. The discovery that a naturally occurring, nonfunctional variant of the HIV receptor gene CCR5 protected against HIV infection encouraged the development of CCR5 antagonists. Through continued translational and applied research, pharmacogenomics will ultimately benefit persons living with HIV worldwide by identifying new therapeutic targets and through individualized drug prescribing that is informed by human genetic testing.     

Implications of pharmacogenetics for individualizing drug treatment and for study design

Adverse drug reactions and ineffective drug treatment are responsible for a large health care burden. Considerable variability in drug response makes the prediction of the individual reaction difficult. Pharmacogenetics can help to individualize drug treatment in accordance with the genetic make-up of the patient. Drug response is best understood as a complex interplay between pharmacokinetics, pharmacodynamics, and other disease-associated factors. There are a large number of genetic variants in the enzymes of phase I and phase II drug metabolism, in drug transporters, and drug targets, all of which account for differences in drug response. The polymorphisms in the cytochrome P450 enzyme system have been investigated most extensively. Genotype-based dose adjustment which should ensure "bioequivalent" drug concentrations in all patients has been derived from pharmacokinetic parameters, but this approach will have to be verified in prospective studies. Drug transport has recently been recognized as a further crucial determinant in pharmacokinetics. The effect of genetics on disease susceptibility and drug treatment has been studied quite extensively; however, hardly any of this progress is at present reflected in routine health care. The integration of pharmacogenetic factors in clinical trials requires novel considerations for study design and data interpretation. It is to be hoped that the new science bioinformatics will (a) help us identify the contribution of genetics to disease and treatment response and will (b) create data-processing devices which help the physician in the face of the enormously expanding scientific knowledge in selecting the best individually adapted treatment for the patient.     

Pharmacogenomics: the future of drug therapy

Pharmacogenomics aims to optimize patient management by customizing and synthesizing drugs based on genetic variations in drug response. Polymorphisms affecting metabolism, receptors, and absorption can influence drug sensitivity, toxicity, and dosing. The Human Genome Project, DNA chips, and bioinformatics advance the practice of this field by, respectively, identifying polymorphisms related to drug response, determining an individual's profile of polymorphisms, and integrating data to facilitate clinical decision making. Potential benefits of pharmacogenomics include increasing efficacy and preventing adverse drug reactions, thus improving patient care and decreasing costs. These factors imply that a thorough understanding of the principles and applications of pharmacogenomics will be an indispensable part of the future of drug therapy in clinical medicine.     

Pharmacogenetics in HIV therapy

Administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, as well as different rates of drug-associated toxicity. The reasons for the large interindividual variability in drug levels are multifactorial, and involve differences in gender metabolism, concomitant medications, drug compliance, underlying diseases, and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the interindividual variation in the body disposition of drugs. One of the main goals is to give grounds to individualized therapy. The majority of pharmacogenetic traits so far have involved drug metabolism. An example of this is the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid. This variation is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which may split the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretrovirals have focused on metabolizing enzymes and transporter proteins in the cell membrane. Herein, we review the genetic polymorphisms known to be associated with altered pharmacokinetics of antiretrovirals, which may influence the efficacy and toxicity of these drugs.     

New insights into the genetic history of Tunisians: data from Alu insertion and apolipoprotein E gene polymorphisms

BACKGROUND: Among polymorphisms of non-transcribed DNA sequences and functional genes, those of Alu insertions and that of the APOE gene have been widely used to clarify the degree of genetic relationships between human populations. AIM: APOE gene and eight Alu insertion polymorphisms were investigated in Tunisians and compared with data from neighbour populations in order to gain new insights into the genetic position of Tunisia in the Mediterranean region. SUBJECTS AND METHODS: A total of 121 individuals from the North and Centre-South regions were sampled. RESULTS: No significant genetic differences were found between Tunisians and North Africans when samples representative of wide areas were considered. APOE gene variation seemed slightly less powerful than the Alu polymorphisms in detecting North-South Mediterranean differences. CONCLUSION: North African populations show a substantial degree of genetic homogeneity, which may reflect the similarity of their origins, mainly when samples from large geographical areas are compared. The relative genetic homogeneity of the whole Mediterranean region probably reflects a common origin and/or remarkable levels of gene flow. However, this gene flow has not yet erased the differentiation between the two Mediterranean shores, as revealed by Alu insertion polymorphisms.