N-乙酰基转移酶2基因型多态性与柳氮磺胺吡啶治疗炎症性肠病所产生不良反应的关系

目的探讨N-乙酰基转移酶2(NAT2)基因型多态性对柳氮磺胺吡啶(SASP)治疗炎症性肠病(IBD)时所产生不良反应的影响。方法在110例IBD患者及120例健康对照者中,采用聚合酶链反应-限制性片断长度多态性方法,检测NAT2野生型等位基因(NAT2*4)和3种突变型等位基因(NAT2*5B、*6A和*7B)频率,并对服用SASP的78例IBD患者进行NAT2基因型与SASP不良反应的相关性分析。结果慢型乙酰化基因型的IBD患者服用SASP后不良反应的发生率高于快型和中间型乙酰化基因型患者,差异有显著性(55%vs24.1%,OR=3.841,95%CI=1.322~11.161,P=0.011)。与磺胺吡啶(SP)剂量相关的不良反应在慢型乙酰化患者中的发生率也高于快型和中间型乙酰化患者(55%vs20%,OR=4.889,95%CI=1.625~14.704,P=0.003)。结论IBD患者SASP不良反应,特别是与SP剂量相关的不良反应,与NAT2慢型乙酰化基因型相关。     

NAT2基因型、抗结核药物治疗对患者血浆浓度及肝功能异常的相关性研究

目的：分析与探讨结核患者不同N－乙酰基转移酶2（NAT2）基因型分型和服用抗结核药物治疗后血浆浓度与肝功能异常的相关性,为临床根据NAT2基因分型指导抗结核药物合理用药提供依据。方法选取我院在2013年2月～2014年12月收治的肺结核患者50例为研究对象,回顾性分析患者的临床资料,并采用高效液相色谱法（HPLC）测定血浆中异烟肼（INH）的浓度,提取患者DNA,采用 PCR－直接测序法（PCR－DS）测定结核病患者NAT2基因型,记录肝功能检测结果,并进行相关性分析。结果患者接受氨基水杨酸异烟肼片（ PAS－INH）治疗后,肝功能异常组和正常组的血浆药物浓度分别是（2．37±0．47）mg? L－1、（1．78±0．52）mg? L－1,两组间差异具有统计学意义（P＜0．05）;20例 NAT2 RA（快速乙酰化）基因型,其中肝功能正常15例（75．0％）,肝功能异常4例,1例出现ATDILI;26例IA（中等乙酰化）基因型,其中肝功能正常10例,16例肝功能异常,0例出现ATDILI。4例SA（慢速乙酰化）基因型,肝功能正常1例,肝功能异常1例,其中2例出现ATDILI。 RA基因型肝功能异常率明显比SA基因型患者低（P＝0．02,P＜0．05）,具有统计学意义。结论 NAT2基因型、抗结核药物浓度和 ATDILI具有相关性,而且通过检测患者的NAT2基因型分型对其合理服用抗结核药物、预防抗结核药物导致的肝功能异常或者肝损伤等极具重要意义。检测血药浓度对结核药物造成肝功能异常或者肝损伤的预防意义仍有待考证。     

N-乙酰基转移酶2基因多态性与柳氮磺吡啶药物效应的相关性

<正>N-乙酰基转移酶2(N-acetyltransferase 2,NAT2)是柳氮磺吡啶(sulfasalazine,SASP)在人体内乙酰化代谢的关键酶。NAT2基因编码区的单核苷酸多态性可以造成氨基酸序列变化,进而影响酶含量[1]或活性[2],并对相关药物的代谢产生影响。近年来,NAT2编码基因的多态性与SASP药物效应的相关性备受关注,现将目前的研究进展综述如下。     

ecNOS基因多态性与2型糖尿病心血管危险因素集簇的关系

目的：探讨内皮固有型一氧化氮合酶（ecNOS）基因G894T多态性与天津市汉族成年2型糖尿病（T2DM）患者心血管危险因素集簇的关联性。方法：随机抽取无心血管病并发症且无血缘关系的天津市汉族成年T2DM患者80例，静脉血提取基因组DNA，用聚合酶链反应-限制片段长度多态性（PCR—RFLP）法检测ecNOS基因G894T多态性。结果：（1）ecNOS基因第7外显子894位点基因型分布为GG基因型63例（78．75％）、GT基因型17例（21．25％）和TT基因型0例；（2）GG与GT基因型患者的各项临床及实验室指标差异均无统计学意义。（3）随着T2DM患者存在心血管危险因素的增多，GT基因型患者的比例逐渐升高，差别具有统计学意义（x^2=7．544，P〈0．05）。结论：ecNOS基因G894T多态性与T2DM患者心血管危险因素的集簇存在关联性．     

N-乙酰转移酶的多态性及其对肿瘤风险性的影响

N-乙酰转移酶是Ⅱ相药物代谢酶,在人体内由两个不同的基因编码,产生两个同酶NAT1和NAT2。NAT2的表达具有多态性,其慢乙酰化表型为NAT2基因编码区点突变所致。NAT1亦具有基因结构上的变异,不同的突变等位基因其酶表达水平不同。生化学研究表明NAT1和NAT2在致癌物质的代谢激活或灭活过程中起重要作用。流行病学研究则提示NATs的多态性与某些肿瘤的风险性有关,代谢基因型/表现型将通过影响DNA结合物的水平进而影响肿瘤的发生。如果肿瘤的遗传易感性这一生物标记能够成功地建立起来,将有助于更好地预防和控制人类疾病。     

SUR1基因多态性与2型糖尿病的相关性研究

目的：探讨2型糖尿病（T2DM）与磺脲类药物受体1（SUR1）基因多态性的关系。方法：随机抽取正常人136例（正常组）及2型DM患者173例（T2DM组）外周血白细胞基因组DNA，PCR扩增SUR1基因31号外显子多态性位点的区域．用限制性酶切片段长度多态性分析其基因型，并用测序证实不同酶切图形基因型的准确性。结果：T2DM组和正常组SUR1基因31号外显子基因型及等位基因分布差别有统计学意义（P〈0．05）。结论：SUR1基因可能是中国天津地区2型糖尿病发生的易感基因。     

广西地区汉族2型糖尿病患者脂联素基因多态性研究

目的：研究脂联素基因外显子2单核苷酸多态性（SNP）＋45T→G多态性与广西地区汉族2型糖尿病（T2DM）、肥胖及胰岛素抵抗（ IR）的关系。方法：运用聚合酶链反应-限制性片段长度多态性（ PCR-RFLP）的方法,对313例无亲缘关系的广西地区汉族人群的正常糖耐量（NGT95例）、糖耐量减低（IGT103例）和T2DM115例检测脂联素基因外显子2的多态性,并与代谢值进行相关性研究。结果：广西地区汉族人群中含脂联素基因外显子2的SNP＋45GG基因型的人群高密度脂蛋白（ HDL-C）水平低于TT、TG基因型的人群（P〈0.05）,HOMA-IR高组的GG基因型相对于TT基因型的OR为2.876（95%CI：1.141~7.248）,即GG基因型发生IR的相对危险度是TT基因型的2.876倍。结论：汉族人群中,脂联素基因SNPs＋45 TT基因型的HDL-C较GG基因型频率高;GG基因型较TT基因型人群易产生IR。但汉族人群SNPs＋45基因型与T2DM及肥胖无关。     

内皮细胞固有型一氧化氮合成酶基因G894T变异与糖尿病肾病的关系

目的：观察内皮细胞固有型一氧化氮合成酶（ecNOS）基因外显子7的Glu298Asp基因多态性与2型糖尿病肾病（DN）的关系。方法：利用聚合酶链反应限制性片段长度多态性（PCR-RFLP）技术检测了天津地区299例2型糖尿病患者和100例正常对照者的ecNOS基因外显子7的基因型，比较各组间的等位基因频率与基因型频率。结果：（1）2型糖尿病合并持续性微量白蛋白尿组（DN1组）的GT基因型和T等位基因频率高于糖尿病非肾病组（DM组）和正常对照组（C组），差异有统计学意义（P〈0．05）。（2）在2型糖尿病患者中GT基因型者较GG基因型者的DN患病率高（X^2=5．252，P=0.022）。（3）高血压、血纤维蛋白原（FIB）、ecNOS外显子7的GT基因型是2型糖尿病合并DN的独立危险因素。（4）2型糖尿病合并高血压组（DMEH组）、糖尿病非高血压组（DM1组）和C组间ecNOS基因外显子7的基因型分布和等位基因频率差异无统计学意义（P〉0．05）。结论：ecNOS基因外显子7的基因G894T（Glu298Asp）的变异可能是天津地区2型糖尿病患者DN易感性的基因标志之一，可能参与DN的启动；该基因多态性不是通过促进高血压的发生而增加DN的易感性。     

氯吡格雷对冠心病患者PCI术后CYP2C19、PON1 基因多态性与FIB、D-二聚体水平的相关性研究

目的：分析冠心病患者经皮冠状动脉介入治疗(PCI)术后,规律服用氯吡格雷治疗时CYP2C19、PON1基因多态性与血浆纤维蛋白原（FIB）、D-二聚体水平的相关性研究。方法：选取在某三甲医院确诊为冠心病且行PCI术的患者217例,对217例患者行CYP2C19*2、CYP2C19*3、CYP2C19*17、PON1基因监测,观察患者在规律服用氯吡格雷治疗（75 mg·d-1）1个月以上的血浆FIB、D-二聚体指标。结果：在217名患者中CYP2C19* 17基因未检测出突变型等位基因,因此对超快代谢型基因不做统计分析。CYP2C19基因的快代谢型、中间代谢型、慢代谢型之间的FIB指标对比均无统计学差异（P>0.05）;快代谢型与中间代谢型、快代谢性与慢代谢型之间的D-二聚体指标均无统计学差异（P>0.05）;中间代谢型与慢代谢型之间D-二聚体指标有统计学差异（P<0.05）。PON1基因GG型与GA型、GG型与AA型、GA型与AA型的FIB和D-二聚体指标水平均无统计学差异（P>0.05）。结论：携带CYP2C19慢代谢基因型的患者使用常规氯吡格雷剂量治疗,增加血栓风险,可考虑适当增加氯吡格雷服药剂量或改服替格瑞洛进行溶栓治疗。PON1基因多态性与氯吡格雷治疗血小板反应性差异并无关联性。     

冠心病伴抑郁与5-羟色胺转运体基因多态性的关系

目的：探讨5-羟色胺转运体基因多态性对冠心病伴抑郁的影响。方法：选择冠心病伴抑郁患者70例，以冠心病不伴抑郁患者70例作对照。采用聚合酶链反应技术检测受试对象5-羟色胺转运体基因上游调控区多态性位点（5-HTTLPR）与内含子2区（VNRT）2种基因多态性的分布频率。均经社会支持评定量表与应对方式问卷进行心理评定。结果：抑郁组5-HTFLPR的SS基因型及S等位基因频率显著高于对照组（均P〈0．01），VNRT基因型及等位基因频率分布2组差别无统计学意义（均P〉0．05）。SS基因型冠心病患者社会支持总分和积极应对分显著低于L5型及LL型（均P〈0．01）：消极应对分显著高于15型及LL型（均P〈0．01）。多元Logistic回归分析结果显示5-HTTLPR基因SS型与冠心病伴抑郁独立相关。结论：5-HTTLPR的SS基因型可能是冠心病患者伴发抑郁的易感基因之一。     

N-Acetyltransferase 2 Genotype-Related Efficacy of Sulfasalazine in Patients with Rheumatoid Arthritis

PURPOSE: For the individual optimization of drug therapy with sulfasalazine (SASP), we studied the influence of the N-acetyltransferase 2 (NAT2) genotype on the pharmacokinetics, efficacy, and incidence of adverse reactions of SASP in patients. METHODS: Ninety-six rheumatoid arthritis (RA) patients were treated or had been treated with 0.5 and/or 1.0 g/day of SASP. The wild-type allele (NAT2*4) and three variant alleles (NAT2*5B, *6A, and *7B) of NAT2 were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Plasma concentrations of SASP and its two metabolites, sulfapyridine (SP) and N-acetylsulfapyridine (AcSP), were estimated by HPLC. Therapeutic efficacy and incidence of adverse reactions were also monitored as recommended by the American College of Rheumatology. RESULTS: Patients were classified into three groups by NAT2 genotyping: Rapid Type (homozygote for NAT2*4), Intermediate Type (heterozygote for NAT2*4 and variant alleles), and Slow Type (homozygote for variant alleles). There was no clear difference in the genotype frequencies between RA patients and healthy subjects. NAT2 genotypes significantly affected both the plasma concentration ratios of SP to AcSP (SP/AcSP) and the efficacy of SASP (p < 0.05). Adverse reactions to SASP were found in 26 (27.1%) out of 96 patients, and there was no difference among the three genotype groups. CONCLUSIONS: NAT2 gene polymorphism is related to the plasma SP/AcSP ratio and the efficacy of SASP.     

美沙拉嗪与柳氮磺胺吡啶治疗活动期轻、中度溃疡性结肠炎的临床观察

目的:比较美沙拉嗪与柳氮磺胺吡啶治疗活动期轻、中度溃疡性结肠炎(UC)的疗效和安全性。方法:将80例活动期轻、中度UC患者随机均分为观察组和对照组,观察组患者口服美沙拉嗪1.0 g,tid;对照组患者口服柳氮磺胺吡啶(SASP)1.0 g,4次/d,4周后视情况可剂量减半。两组患者疗程均为6周。观察两组患者的临床疗效和不良反应发生情况,并比较两组患者治疗前、后的结肠黏膜组织学积分。结果:治疗后,观察组患者的总有效率为90.00%,显著高于对照组(72.50%),两组比较差异有统计学意义(P<0.05);两组患者治疗后结肠黏膜组织学积分均较治疗前显著下降,治疗前、后比较差异均有统计学意义(P<0.05)。观察组患者的不良反应发生率为2.50%,显著低于对照组(17.50%),两组比较差异有统计学意义(P<0.05)。结论:美沙拉嗪治疗活动期轻、中度UC患者的疗效和安全性均优于SASP。     

痛泻宁颗粒治疗肝郁脾虚型溃疡性结肠炎30例

目的观察痛泻宁颗粒治疗肝郁脾虚型溃疡性结肠炎(UC)的临床疗效与安全性。方法将61例溃疡性结肠炎患者随机分成治疗组和对照组。治疗组30例,采用口服痛泻宁颗粒治疗,每日3次,每次5 g;对照组31例,采用口服柳氮磺胺吡啶(SASP)治疗,每次1.0 g,每日4次。两组疗程均为8周。结果治疗组总有效率为90.00%,明显高于对照组的80.65%;中医证候缓解率,治疗组为90.00%,明显高于对照组的74.19%(P<0.05);两组总有效率、中医证候缓解率比较,差异均有统计学意义(P<0.05);服药后的不良反应,治疗组明显少于对照组(P<0.05)。结论痛泻宁颗粒治疗肝郁脾虚型溃疡性结肠炎疗效明显优于柳氮磺胺吡啶,且不良反应少。     

Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil

Purpose  To determine the frequency of N-acetyltransferase 2 (NAT2) polymorphisms, the NAT2 acetylation profile and its relation to the incidence of gastrointestinal adverse drug reactions (ADRs), anti-tuberculosis (TB) drug-induced hepatotoxicity, and the clinical risk factors for hepatotoxicity in a population from Brazil. Methods  Two hundred and fifty-four Brazilian TB patients using isoniazid (INH), rifampicin (RMP), and pirazinamide (PZA) were tested in a prospective cohort study. NAT2 genotyping was performed by direct PCR sequencing. The association between gastrointestinal ADRs/hepatotoxicity and the NAT2 profile genotype was evaluated by univariate analysis and multiple logistic regression. Results  Of the 254 patients analyzed, 69 (27.2%) were slow acetylators and 185 (72.8%) were fast acetylators. Sixty-five (25.6%) patients were human immunodeficiency virus (HIV)-positive. Thirty-three (13%) and 14 (5.5%) patients developed gastrointestinal ADR and hepatotoxicity, respectively. Of the 14 hepatotoxicity patients, nine (64.3%) were slow acetylators and five (35.7%) were fast acetylators. Sex, age, presence of hepatitis C virus, alcohol abuse, and baseline aminotransferases were not found to be risk factors for hepatotoxicity. However, logistic regression analysis revealed that slow acetylator status and the presence of HIV (p < 0.05) were independent risk factors for hepatotoxicity. Conclusions  Our findings show that HIV-positive patients that have the slow acetylation profile are significantly associated with a higher risk of developing hepatotoxicity due to anti-TB drugs. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Discordance between N-acetyltransferase 2 phenotype and genotype in a population of Hmong subjects

Polymorphisms of N-acetyltransferase 2 (NAT2) acetylation may influence drug toxicities and efficacy and are associated with a differential susceptibility to select cancers. Acetylation phenotype may have clinical implications. The purposes of this study were to determine the genetic basis of an apparent predominance of slow acetylation phenotype and to assess concordance with genotype in a population of Hmong residing in Minnesota. Urine and DNA obtained from unrelated Hmong 18 to 65 years of age were used to determine phenotype from caffeine metabolites, whereas direct nucleotide sequencing of the NAT2 coding region, followed by cloning, identified all known allelic variants. From 61 subjects (27 men, 30 +/- 11 years), analysis of 50 urine-DNA pairs identified 46 (92%) slow acetylators and 4 (8%) rapid acetylators by phenotype. Genotypic analysis inferred 5 (10%) slow acetylators and 45 (90%) rapid acetylators. There is 86% discordance between phenotype and genotype. A predominance of NAT2 slow acetylation phenotype in the Hmong is confirmed, and a significant discordance between NAT2 phenotype and genotype is identified. In this population, slow acetylation phenotype determined by a metabolic probe would not have been predicted by genotype alone. Environmental, genetic, or phenotypic anomalies that may contribute to this discordance should be considered and evaluated in future studies within this unique population.     

N-acetyltransferase 2 single-nucleotide polymorphisms and risk of gastric carcinoma

OBJECTIVE: To explore whether an association exists between the NAT2 genotype and the risk of developing gastric cancer.METHODS. Ninety-nine patients with gastric adenocarcinoma and 258 healthy subjects were analysed for single-nucleotide polymorphisms at the NAT2 gene locus, which give rise to gene variants known to be associated with slow-acetylation status.RESULTS: The functional NAT2*4 (wild-type) allele is over-represented among patients (40.4% of all allelic variants) compared with control subjects [25.8%, odds ratio (OR) 1.95, 95% confidence interval (CI) 1.36, 2.8]. According to the NAT2 genotype, 69 patients (69.9%) and 119 healthy subjects (46%) were classified as rapid acetylators (OR 2.69, 95% CI 1.6, 4.54).CONCLUSIONS: Our results, which need independent confirmation, suggest that individuals with NAT2 genotypes leading to high levels of NAT2 enzyme activity are at increased risk of developing gastric carcinoma.     

肾移植患者CYP3A4基因多态性对他克莫司疗效和不良反应的影响

目的:研究肾移植术后患者CYP3A4基因多态性对他克莫司(FK506)血药浓度/剂量比(C/D)及急性排斥反应和不良反应的影响。方法:采用聚合酶链反应(PCR)和限制性内切片段长度多态性(RFLP)方法检测肾移植患者CYP3A4*18B基因型,比较不同基因型患者之间FK506的C/D值及急性排斥反应、不良反应的差异。结果:肾移植术后3个月内,*18B/*18B型、*1/*18B型和*1/*1型患者FK506的C/D值分别为(82.03±4.93)、(104.4±7.58)、(160.2±8.69)ng.mL-1permg.kg-1,3组间差异具有统计学意义(P<0.05或P<0.01)。移植术后3个月内,*18B/*18B型患者急性排斥反应发生率为21.4%,高于*1/*1型患者的7.6%(P<0.05);而术后*1/*1型患者肝功能异常、高血糖、药物肾毒性等不良反应发生率显著高于*1/*18B型和*18B/*18B型患者(P<0.05)。结论:肾移植患者CYP3A4*18B基因多态性与FK506的C/D值、急性排斥反应及不良反应均密切相关。     

三种氨基水杨酸制剂治疗溃疡性结肠炎的安全性和有效性研究

目的观察美沙拉嗪、奥沙拉嗪和柳氮磺吡啶治疗溃疡性结肠炎的临床疗效和不良反应。方法选择120例轻中度溃疡性结肠炎患者,随机分为美沙拉嗪组（n=40）、奥沙拉嗪组（n=39）和柳氮磺吡啶组（n=41）,分别接受上述三种药物治疗。美沙拉嗪组和奥沙拉嗪组患者口服药物剂量均为每次1．0g,每日3次;而柳氮磺吡啶组患者服用剂量为每次1．0g,每日4次。治疗12周后观察治疗疗效和不良反应发生情况。结果美沙拉嗪组、奥沙拉嗪组和柳氮磺吡啶组临床有效率分别为30．0％、28．2％和51．2％,总有效率分别为75．0％、76．9％和92．7％。柳氮磺吡啶组疗效优于美沙拉嗪组、奥沙拉嗪组（P〈0．05）。结论与美沙拉嗪、奥沙拉嗪相比,柳氮磺吡啶治疗溃疡性结肠炎有效性更高,但不良反应发生率稍高。     

Genotyping of the N-acetyltransferase2 polymorphism in the prediction of adverse drug reactions to isoniazid in Japanese patients

To investigate the association between NAT2 genotypes and the incidence of isoniazid (INH)-induced adverse reactions, in the hope of identifying a pharmacogenetic approach that could be useful in the prediction and prevention of adverse reactions in Japanese patients, we retrospectively studied the genotypes of NAT2 in 102 Japanese patients treated with INH (without rifampicin co-administration). The subjects were classified into three groups according to their genotypes: rapid-type, intermediate-type, and slow-type. The clinical conditions of the patients were followed-up in order to evaluate the development of any adverse drug reactions (ADRs) and correlate them with patient genotypes. Six out of the 102 patients (5.9%) developed various ADRs following INH treatment. These reactions included nausea/vomiting, fever, visual impairment, and peripheral neuritis. We found a statistically significant difference between the incidence of ADRs and NAT2 genotype. The incidence of ADRs was significantly higher in the slow type than in the other two types, as 5 out of the 6 ADR patients were of the slow-type, and the other one was of the intermediate-type, while no patients of the rapid-type developed any ADRs. The results indicated that the genes coding for slow acetylation were associated with the incidence of serious ADRs following INH treatment. Our findings suggest that determination of NAT2 genotype might be clinically useful in the evaluation of patients at high risk of developing ADRs induced by INH.