重庆地区汉族人群CYP2C19基因多态性分布与不同种族间比较

摘要：目的：了解重庆地区汉族人群CYP2C19基因多态性分布,比较不同种族间CYP2C19代谢型的分布。 方法：用基因芯片法检测140例重庆地区汉族健康人群CYP2C19基因多态性,并比较分析不同种族间的CYP2C19代谢型分布。 结果：在140例重庆地区汉族人群中,*1/*1基因型（636GG,681GG）62例（44.3%）,*1/*2基因型（636GG,681GA）57例(40.7%)〖JP〗,*1/*3基因型（636GA,681GG）8例（5.7%）,*2/*2 基因型（636GG,681AA）10例（7.1%）,*3/*3基因型（636AA,681GG）0例,*2/*3基因型（636GA,681GA）3例（2.1%）;快代谢型62例（44.3 %）,中代谢型65例（46.4%）,慢代谢型13例（9.3 %）。CYP2C19代谢型（快、中、慢代谢型）与美洲印第安人、高加索血统种人、黑白混血人种分布比较差异有统计学意义（χ²分别为46.78, 24.45,12.29,P均<0.05）,与非洲人差异无统计学意义（χ²=3.21,P＞0.05）。 结论: 重庆地区汉族人群CYP2C19位点存在基因多态性,与其他种族比较,代谢型分布有差异。     

贵州地区汉族阿尔茨海默症患者CYP2C19 基因多态性及代谢表型分析

目的　探讨贵州地区汉族阿尔茨海默症患者细胞色素P450 2C19(CYP2C19) 基因多态性及代谢表型的分布,为临 床个体化用药提供理论依据。方法　以DNA 微阵列技术检测227 例贵州地区汉族阿尔茨海默症患者CYP2C19 基因多态 性及代谢表型（快代谢型, 中等代谢型, 慢代谢型）,用基因计数法计算基因频率和等位基因频率,同时分析基因多态 性与年龄、性别的相关性。结果　在227 例贵州地区汉族阿尔茨海默症患者中,CYP2C19*1/*1,*1/*2,*1/*3,*2/*2,*2/*3 基因型的频率分别为44.9%,38.3%,4.8%,8.8% 和3.1%,快代谢、中代谢和慢代谢3 种代谢表型所占比例分别为 44.9%,43.2% 和11.9%。不同性别及年龄基因型分布比较差异无统计学意义（χ2=4.314,4.435,均P>0.05）,不同年 龄段CYP2C19 代谢表型分布差异有统计学意义（χ2=32.053,P<0.001）。结论　贵州地区汉族阿尔茨海默症患者中有 较多的CYP2C19 代谢功能缺失基因,检测CYP2C19 基因多态性及代谢表型能为临床个体化用药提供依据,提高临床 疗效,减少不良反应发生。     

CYP2C19基因多态性与老年冠心病的关系研究

目的探讨CYP2C19基因多态性与老年冠心病的关系。方法选取2016年1月至2017年12月在我院治疗的冠心病患者89例(冠心病组),同时选取健康自愿者90例作为对照组,采用DNA微阵列芯片法检测冠心病组和对照组CYP2C19基因型表达情况。结果冠心病组CYP2C19基因*1/*2比例为51.69%,明显高于对照组(P0.05);冠心病组中代谢型比例为58.43%,明显高于对照组(P0.05);冠心病组不同临床分期CYP2C19基因型、代谢型差异比较无统计学意义(P0.05);经皮冠状动脉介入治疗(PCI)术后发生心血管事件(MACE)患者14例;MACE组和非MACE组CYP2C19基因型、代谢型差异比较有统计学意义(P0.05),MACE组慢代谢型比例为42.86%,明显高于非MACE组(P0.05)。结论 CYP2C19基因多态性可能与老年冠心病发生易感性有关,且与PCI术后MACE发生有关。     

东莞地区汉族冠心病患者CYP2C19基因多态性分布特征分析

目的探讨东莞地区汉族冠心病患者CYP2C19基因多态性分布特征。方法选取该院2016年9月至2019年1月收治的800例汉族冠心病患者作为研究对象,采用等位基因特异PCR技术对患者CYP2C19基因多态性进行检测,了解CYP2C19基因多态性分布情况,并根据患者的年龄、性别进行分组分析。结果 CYP2C19基因型中*1/*1出现频率为38.50%,*1/*2频率为40.00%,*1/*3频率为6.38%,*2/*2频率为11.75%,*2/*3频率为3.00%,*3/*3频率为0.37%;其中快代谢型为38.50%、中代谢型为46.38%、慢代谢型为15.12%;等位基因分布中CYP2C19*1占61.69%,CYP2C19*2占33.25%,CYP2C19*3占5.06%。不同年龄、性别、患者CYP2C19各基因多态性分布虽存在一定的差异,但差异无统计学意义(P>0.05)。结论东莞地区汉族人群冠心病患者CYP2C19基因型中以快代谢型与中代谢型为主,基因分布以CYP2C19*1占比较高,不同性别、年龄患者CYP2C19基因型间差异不明显。     

CYP2C19基因多态性对幽门螺杆菌感染酸相关性疾病治愈率的影响

细胞色素P450（CYP450s）的同工酶有14种之多（CYPI-14），其基因多态性与药物代谢及其疗效密切相关。与质子泵抑制剂（PPI）代谢相关的P450同工酶主要为肝脏微粒体中的CYP2C19和CYP3A4。CYP2C19基因多态性对酶活性的影响显示基因剂量效应，表现为野生型纯合子（homEM）高于野生型杂合子（hetEM），更高于突变等位基因纯合子（PM）。PPI联合阿莫西林、克拉霉素或甲硝唑等抗生素组成的三联疗法治疗幽门螺杆菌（HP）感染酸相关性疾病的疗效与CYP2C19遗传多态性有关。     

CYP2C19基因多态性检测的临床实验室性能验证

目的对人细胞色素P450酶等位基因(CYP2C19)多态性检测试剂盒进行性能验证。方法根据中国合格评定国家认可委员会CNAS-GL039:2019《分子诊断检验程序性能验证指南》相关要求,结合试剂盒说明书,从符合率、精密度、检出限和抗干扰能力4个方面对“人CYP2C19基因多态性检测试剂盒(荧光PCR法)”进行性能验证。符合率验证采用荧光PCR法和Sanger测序法检测;精密度验证选择杂合突变CYP2C19 c.681GA、c.636GA样本进行检测;抗干扰能力验证判断基因型检测是否受影响。结果PCR法和Sanger测序法的检测符合率为100%;CYP2C19 c.681 G和A等位基因的FAM和ROX荧光通道精密度检测CV值分别为3.78%、1.76%、3.76%和3.56%;CYP2C19 c.636 G和A等位基因的FAM和ROX荧光通道精密度检测CV值分别为3.08%、2.81%、3.40%和3.73%;样本最低检出限为10 ng/μL;抗干扰能力验证显示基因型可以正常检测。结论人CYP2C19基因多态性检测试剂盒(荧光PCR法)符合ISO15189质量管理要求,可以为临床提供准确可靠的检测结果。     

赤峰地区蒙古族冠心病患者CYP2C19基因多态性分布研究

目的分析赤峰地区蒙古族冠心病患者CYP2C19基因多态性分布状况。方法选取2018年3-12月于该院确诊为冠心病并行经皮冠状动脉介入术治疗的患者558例为研究对象,其中蒙古族患者299例为研究组,汉族患者259例为对照组。抽取两组患者的外周血2 mL,提取基因组DNA,采用实时荧光定量PCR方法检测CYP2C19基因多态性,比较两组间CYP2C19基因型、代谢型分布情况。结果研究组患者CYP2C19*1/*1、*1/*2、*2/*3型所占比例均高于对照组(P<0.05);两组CYP2C19*1/*3、*2/*2、*3/*3型所占比例比较,差异无统计学意义(P>0.05)。研究组中间代谢型和慢代谢型基因所占比例低于对照组(P<0.05),快代谢型基因所占比例高于对照组(P<0.05)。结论赤峰地区蒙古族冠心病患者CYP2C19基因存在不同基因型和代谢型,与汉族冠心病患者间存在差异。掌握CYP2C19基因的多态性分布情况对冠心病患者抗凝药物的选择具有重要意义。     

DNA测序法检测CYP2C19基因多态性指导氯吡格雷用药的临床价值

目的评估DNA测序法检测细胞色素氧化酶P450 2C19(CYP2C19)多态性以指导氯吡格雷临床用药。方法选取2010年11月至2013年11月武汉大学人民医院心血管内科诊断为急性冠状动脉综合征,并首次接受经皮冠状动脉介入治疗术(PCI)的140例患者为研究对象,随机分为试验组及对照组各70例。试验组采集外周血标本并提取基因组DNA,根据已知的CYP2C19基因序列,设计针对CYP2C19*2、CYP2C19*3位点的特异性引物,聚合酶链反应扩增包含CYP2C19基因多态性位点的DNA片段;并以DNA测序法进行鉴定,分析不同CYP2C19基因型在试验组患者中的分布频率。对照组患者使用氯吡格雷药物但未检测相关基因。比较两组患者随访过程中发生冠状动脉血栓事件的差异。结果 DNA测序结果显示,试验组中共有4种基因型组合被检测到:*1/*1(636GG,681GG)、*1/*2(636GG,681GA)、*2/*2(636GG,681AA)、*1/*3(636GA,681GG),分布频率分别为33例(47.1%)、29例(41.4%)、4例(5.7%)、4例(5.7%),而*3/*3(636AA,681GG)和*2/*3(636GA,681GA)未检测到。经基因型指导氯吡格雷用药的试验组患者发生支架冠状动脉血栓事件的比例为0.0%,明显低于对照组的7.1%,差异有统计学意义(P0.05)。结论基因型指导氯吡格雷用药有助于患者用药剂量的调整,可降低冠状动脉血栓事件的发生率。     

CYP2C19、CYP2D6基因多态性与精神分裂症患者氯氮平代谢的关联研究

目的 探讨精神分裂症患者CYP2C19、CYP2D6基因多态性对氯氮平(CZ)代谢的影响.方法 采用实时荧光定量PCR检测224例精神分裂症患者的CYP2C19与CYP2D6基因型,根据CYP2C19的代谢类型,将患者分为快代谢型、中间代谢型和慢代谢型,根据CYP2D6的代谢类型,将患者分为快代谢、中间代谢型和中低代谢...     

Effects of CYP2C19 genetic polymorphism on the pharmacokinetics and pharmacodynamics of omeprazole in Chinese people

BACKGROUND: To investigate whether the pharmacodynamics and pharmacokinetics of omeprazole (OPZ) are dependent of the CYP2C19 genotype status in Chinese people. METHODS: Eighteen healthy subjects were voluntary to participate in the study, whose CYP2C19 genotype status were determined by polymerase chain reaction-restriction fragment length polymorphism method. There were six homozygous extensive metabolizers, six heterozygous extensive metabolizers and six poor metabolizers (PMs). All subjects were Helicobacter pylori-negative, determined by serology method and (13)C-urea breath test. After d1 and d8 orally received OPZ 20 mg once daily in the morning, intragastric pH values were monitored for 24 h by Digitrapper pH. Meanwhile, blood samples were collected at various time-points until 24 h after administration. The serum concentrations of OPZ were measured by liquid chromatography. RESULTS: After single or repeated doses, the PMs showed a significantly higher mean area under the serum concentration-time curves (AUC) values than that observed in the homozygous extensive metabolizers or the heterozygous extensive metabolizers, with a relative ratio of 1.0 : 1.1 : 4.2 and 1.0 : 1.3 : 3.3 (homozygous extensive metabolizers:heterozygous extensive metabolizers:poor metabolizers), respectively. After a single dose of OPZ, significant differences in intragastric pH median, pH > 3 holding time and pH > 4 holding time were observed among the three groups. After repeated doses, the PMs showed a significantly higher intragastric pH values than that observed in the homozygous extensive metabolizers or the heterozygous extensive metabolizers. CONCLUSION: The pharmacodynamic effects of OPZ and its pharmacokinetics depend on the CYP2C19 genotype status in Chinese people.     

CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian population

The aim of the study was to establish the frequencies of CYP2C9*1, *2, *3 and CYP2C19*1, *2 and *3 in the south Indian population and to compare them with the inter-racial distribution of the CYP2C9 and CYP2C19 genetic polymorphisms. Genotyping analyses of CYP2C9 and CYP2C19 were conducted in unrelated, healthy volunteers from the three south Indian states of Andhra Pradesh, Karnataka and Kerala, by the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). The allele frequencies of the populations of these three states were then pooled with our previous genotyping data of Tamilians (also in south India), to arrive at the distribution of CYP2C9 and CYP2C19 alleles in the south Indian population. Frequencies of CYP2C9 and CYP2C19 alleles and genotypes among various populations were compared using the two-tailed Fisher's exact test. The frequencies of CYP2C9*1, *2 and *3 in the south Indian population were 0.88 (95% CI 0.85-0.91), 0.04 (95% CI 0.02-0.06) and 0.08 (95% CI 0.06-0.11), respectively. The frequencies of CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 were 0.78 (95% CI 0.74-0.82), 0.05 (95% CI 0.03-0.07), 0.15 (95% CI 0.12-0.18), 0.01 (95% CI 0.0-0.02), 0.01 (95% CI 0.0-0.02) and 0.0, respectively. CYP2C19*1, *2 and *3 frequencies were 0.64 (95% CI 0.60-0.68), 0.35 (95% CI 0.31-0.39) and 0.01 (95% CI 0.0-0.03), respectively. As a result of a significant heterogeneity, the data on CYP2C19 genotype frequencies were not pooled. The frequency of CYP2C9*2 mutant alleles in south Indians was higher than in Chinese and Caucasians, while CYP2C9*3 was similar to Caucasians. CYP2C19*2 was higher than in other major populations reported so far. The relatively high CYP2C19 poor-metabolizer genotype frequency of 12.6% indicates that over 28 million south Indians are poor metabolizers of CYP2C19 substrates.     

Assessment of CYP2C19 genetic polymorphisms in a Korean population using a simultaneous multiplex pyrosequencing method to simultaneously detect the CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles

Background and objective: CYP2C19 is a drug‐metabolizing enzyme showing various genetic polymorphisms that may cause marked interindividual and interethnic variability in the disposition of its substrates. We assessed CYP2C19 genetic polymorphisms in a Korean population using a newly developed multiplex pyrosequencing method. Method: A multiplex pyrosequencing method to simultaneously detect CYP2C19*2, *3, and *17 alleles was designed. We established the frequency of these CYP2C19 alleles in 271 Korean subjects using the multiplex pyrosequencing method. Results: The results showed 100% concordance between single and multiplex pyrosequencing methods. We also validated the polymorphisms identified by pyrosequencing with direct sequencing method. The allele frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 were 0·284, 0·101 and 0·015 respectively. These frequencies are similar to that reported for other Asian populations including Japanese and Chinese but different from that of Caucasians and Africans. Conclusions: The multiplex pyrosequencing method to detect CYP2C19*2, CYP2C19*3, and CYP2C19*17 concurrently, seems to be a rapid and reliable genotyping method for the detection of important CYP2C19 genetic polymorphisms. Similar to studies conducted on other Asian populations, this study reported that in the Korean population tested, the CYP2C19*2 and CYP2C19*3 alleles were relatively frequently found, whereas the frequency of CYP2C19*17 was very low.     

广东东莞地区心血管疾病患者CYP2C19基因多态性分析

目的研究广东东莞地区心血管病患者CYP2C19基因的多态性分布。方法选取心内科心血管疾病患者1 662例,抽取外周血并提取基因组DNA,用PCR技术结合基因芯片技术检测患者的CYP2C19基因型。对年龄45岁和年龄≥45岁冠心病患者CYP2C19等位基因频率和代谢表型频率进行比较。结果在1 662例患者中,CYP2C19代谢型713例(42.90%),中间代谢型740例(44.52%),慢代谢209例(12.58%)。CYP2C19*1、CYP2C19*2、CYP2C19*3等位基因频率分别为65.16%、30.08%、4.75%。45岁组检出快代谢型104例(40.00%),中间代谢型104例(45.38%),慢代谢型38例(14.62%)。≥45岁冠心病组检出快代谢型609例(43.44%),中间代谢型622例(44.37%),慢代谢171例(12.20%)。45岁与≥45岁组各基因型的比例比较,差异无统计学意义(P0.05)。结论通过检测CYP2C19基因型确定患者遗传特征,可以评估其氯吡格雷抵抗风险,为患者制订个体化的抗血小板治疗方案。     

细胞色素酶CYP2C19代谢对沙利度胺体外抗骨髓瘤作用的影响

目的 研究人肝微粒体代谢对沙利度胺体外抗骨髓瘤作用的影响,并探讨细胞色素酶CYP2C19在其中的作用.方法 以沙利度胺或与人肝微粒体在体外孵育后分别处理多发性骨髓瘤(MM)细胞株U266、NCI-H929、RPMI 8226、LP-1和CZ-1细胞,采用MTT法检测细胞活力,流式细胞术测定细胞周期和细胞凋亡.结果 沙利度胺对MM细胞活力无明显抑制作用,10、50和100μg/ml沙利度胺处理5株MM细胞后的细胞活力分别为96.2%～103.7%、96.3%～103.7%和97.9%～106.5%,与对照组比较差异无统计学意义(P>0.05).但与人肝微粒体孵育后,沙利度胺明显抑制MM细胞活力,且该作用呈剂量依赖性.10、50和100μg/ml沙利度胺与人肝微粒体共孵育后对5株MM细胞活力抑制率分别为12.2%～22.9%、25.9%～36.4%和34.9%～46.3%,与对照组比较差异均具有统计学意义(P<0.05).100μg/ml沙利度胺与人肝微粒体孵育后,5株MM细胞凋亡的比例增加达18.5%～32.5%.在孵育体系中加入CYP2C19特异性抑制剂奥美拉唑后,沙利度胺与人肝微粒体孵育后对MM细胞活力的抑制作用减弱,5 μmol/L和10μmol/L奥美拉唑对100μg/ml沙利度胺经肝微粒体孵育后抑制细胞活力的逆转率分别为7.5%～21.9%和19.1%～38.3%,差异有统计学意义(P<0.05).结论 沙利度胺的体外抗骨髓瘤作用需要人肝脏代谢,细胞色素酶系中的CYP2C19参与了这一过程.     

Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population

The aim of the present study was to determine the prevalence of the most common allelic variants of the polymorphic cytochrome P450 (CYP) enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 and to predict the genotype frequency for each polymorphism in the Greek population. DNA isolated from peripheral blood samples derived from 283 non-related Greek ethnic subjects was used to determine the frequency of CYP2D6*3, CYP2D6*4, CYP2C9*2, CYP2C9*3 and CYP3A5*3 allelic variants by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method, CYP2C19*2 and CYP2C19*3 with allelic specific amplification (PCR-ASA), and CYP2D6*2 (gene duplications) by long PCR analysis. The allelic frequencies (out of a total of 566 alleles) for CYP2D6*3 and CYP2D6*4, were 2.3% and 17.8%, respectively, while gene duplications (CYP2D6*2) were found in 7.4% of the subjects tested. For CYP2C9*2 and CYP2C9*3 polymorphisms the allelic frequencies were 12.9% and 8.13% respectively. For CYP2C19, the *2 polymorphism was present at an allelic frequency of 13.1%, while no subjects were found carrying the CYP2C19*3 allele. Finally, the CYP3A5*3 allele was abundantly present in the Greek population with an allelic frequency of 94.4%. Overall our results show that the frequencies of the common defective allelic variants of CYP2C9, CYP2C19 and CYP3A5 in Greek subjects are similar to those reported for several other Caucasian populations. Finally, a high prevalence of CYP2D6 gene duplication among Greeks was found, a finding that strengthens the idea that a South/North gradient exists in the occurrence of CYP2D6 ultrarapid metabolizers in European populations.     

细胞色素酶CYP2C19介导的沙利度胺体外抗血管生成作用研究

本研究探讨人肝细胞微粒体代谢系统对治疗多发性骨髓瘤的沙利度胺体外抗血管生成的影响及细胞色素酶CYP2C19在其中的作用。采用沙利度胺原药或与人肝细胞微粒体在体外共孵育后用MTY法检测人脐带静脉内皮细胞（human umbilical cord vein endothelial cells，hUCVEC）增殖活力，用流式细胞术测定hUVCEC细胞周期和细胞凋亡，以改良的Boyden小室法检测hUCVEC细胞迁移力，以体外小管形成实验检测hUCVEC分化。结果表明：沙利度胺原药对hUCVEC活力无明显抑制作用，细胞凋亡比例也无明显增加，轻度影响细胞迁移，无抗小管形成作用；当与人肝细胞微粒体共孵育后hUCVEC增殖活力明显受抑。100μg／ml沙利度胺与肝细胞微粒体共孵育后hUCVEC增殖活力的抑制率达（11．7±3．9）％，凋亡细胞增加达27．2％，明显下调细胞迁移力并抑制体外小管形成。在共孵育体系中加入CYP2C19特异性抑制剂奥美拉唑，可减弱沙利度胺抑制hUCVEC增殖活力和诱导凋亡的作用，减低细胞迁移力和部分逆转抗小管形成的作用。结论：沙利度胺的体外抗血管生成作用依赖于人细胞微粒体的作用，细胞色素酶系中的CYP2C19可能参与了这一过程。     

CYP2C19基因多态性与维吾尔族冠心病相关性

目的:探讨细胞色素P450(CYP)2C19基因多态性与新疆维吾尔族人群冠心痛的相关性.方法:采用聚合酶链反应-限制性片段长度多态性方法,对234例冠心痛患者(冠心病组)和132例健康受试者(对照组)CYP2C19基因rs6583954位点进行多态性分析.结果:CYP2C19基因rs6583954住点等住基因CT在冠心病组分别为84.83%和15.17%,在对照组分别为78.79%和21.21%,2组等位基因频率差异有统计学意义(P<0.05);冠心痛组CC基因型为73.1%,对照组为61.4%,2组比较差异有统计学意义(P=0.0201);Logistic回归分析显示在调整了年龄、性别、高血压、糖尿痛、高胆固醇血症等传统危险因素之后,CYP2C19基因多态性仍是维吾尔族冠心病发生的重要危险因素,基因型CC:OR值=3.25,95%CI为0.73～14.36;基因型CT:OR值=1.59,95%CI为0.34～7.35.结论:CYP2C19基因多态性可增加维吾尔族吸烟者冠心病的发生风险.