三氯乙烯药疹样皮炎代谢酶基因多态性的病例对照研究

目的 筛选三氯乙烯药疹样皮炎的易感基因。方法 比较43例病人和47例健康三氯乙烯接触工人细胞色素P450酶（CYP1A1）、谷胱甘肽S-转移酶（GSTM1、GSTP1、GSTT1）和N-乙酰基转移酶（NAT2）的基因多态性分布，并计算相对危险度，结果 NAT2基因Kpnl位点的变异可显著增加三氯乙烯皮炎的危险性；具有NAT2慢代谢基因型的个体患皮炎危险性显著高于快代谢基因型个体，未发现其它代谢酶基因多态性与三氯乙烯皮炎易感性的相关关系。结论 NAT2基因的变异可能是导致三氯乙烯皮炎个体易感性差异的原因之一。     

代谢酶基因多态性与结直肠癌易感性关系的病例对照研究

目的以自然随访人群为研究对象，研究Ⅰ、Ⅱ相代谢酶基因多态性与结直肠癌（CRC）易感性的关系。方法采用聚合酶链反应（PCR）-限制性片段长度多态性（RFLP）、等位基因特异性PCR（AS-PCR）和多重PCR分析技术，检测140例CRC患者和343名健康对照细胞色素P450氧化酶CYP1A16235T／C、CYP1A2734C／A、CYP2E1—12596／C和-1019C／T各位点多态性，谷胱甘肽转移酶GSTMu（GSTM1）和GSTTheta（GSTT1）缺陷型，以及N-乙酰基转移酶基因NAT1和NAT2各等位基因型分布频率，分析其对CRC易感性的影响。结果等位基因CYP1A16235C、CYP1A2734A、CYP2E1—1259C、CyP2E1—1019T、GSTM1缺陷型、GSTT1缺陷型、NAT1＊10和NAT2Mx（x=1，2，3）的分布频率在病例组依次为31．65％、63．77％、23．02％、32．61％、57．25％、17．39％、26．45％和39．21％，对照组依次为39．85％、66．62％、20．27％、28．61％、55．46％、20．35％、25．22％和39．36％，所有基因型分布均符合Hardy—Weinberg平衡定律。单基因、多基因联合分层分析表明，CYP1A16235CC突变纯合型可显著降低CRC风险（OR=0．79，95％CI=0．63～0．99）；在携带CYP1A2734A等位基因个体，CYP1A16235C等位基因也可显著降低CRC风险（OR=0．53．95％CI：0．34～0．83）；在GSTT1缺陷型个体，GSTM1缺陷型可使机体罹患CRC的风险显著升高（OR=4．41，95％CI=1．21～16．10）。结论CYP1A16235C等位基因、GSTM1和T1缺陷基因型可影响机体对CRC的遗传易感性，前者是CRC的保护因素，后两者可使机体罹患CRC的风险增高。     

GSTT1及CYP1A1基因多态性与肺癌易感性关系

目的 探讨细胞色素P4501A1(CYP1A1)和谷胱甘肽硫转移酶T1(GSTT1)基因多态性与肺癌易感性的关系.方法 用等位特异性PCR(AS-PCR)及多重PCR技术分析106例肺癌患者和250名健康人的CYP1A1、GSTT1基因多态性、基因型分布频率和交互作用.结果 携带CYP1A1(Val/Val)/GSTT1(-)基因型的人患肺癌的风险明显增加(P=0.025);吸烟与肺癌易感性有关(P=0.037),吸烟者患肺癌的风险明显增加(OR=1.628.95%CI=1.028～2.577);携带CYP1A1(Val/Val)基因的吸烟者较携带CYP1A1(Ile/Ile)基因型的不吸烟者易患肺癌(P=0.033);携带GSTT1(-)的吸烟者患肺癌的风险明显增加(P=0.045).结论 CYP1A1突变型和GSTT1(-)基因型是肺癌的可疑易患因素,二者对肺癌的发生有协同作用,但单独携带CYP1A1突变型或GSTT1(-)基因型肺癌易感性差异无统计学意义,吸烟与肺癌易感性有关;CYP1A1突变型、GSTT1(-)基因型与吸烟在肺癌的发生上有相互促进作用.     

肺癌易感性与4种代谢酶基因多态性关系的研究

目的 探讨4种代谢酶基因多态性与肺癌易感性的关系.方法 采用病例对照研究的方法,209例肺癌患者为病例组,256例健康体检者为对照组,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测Ⅰ相代谢酶基因细胞色素P450 1A1 (CYP1A1),Ⅱ相代谢酶基因谷胱甘肽S-转移酶M1 (GSTM1)、谷胱甘肽S-转移酶T1 (GSTT1)及环氧化物水化酶(mEH)基因的多态性.结果 CYP1A1基因Ⅱe462Val位点纯和突变型、GSTM1缺失型、mEH基因Tyr113His位点纯和突变型在病例组与对照组中的分布频率差异均有统计学意义(P＜0.05),这3种变异基因型携带者与野生型携带者相比发生肺癌危险度分别为1.968倍(OR=1.968,95％CI 1.197～3.236)、1.775倍(OR=1.775,95％CI1.226～2.568)、1.983倍(OR=1.983,95％CI 1.260～3.121).CYP1A1基因Msp1位点、GSTT1及mEH基因His139Arg位点多态基因型在病例组与对照组中的分布频率差异均无统计学意义(P＞0.05).Logistic多元回归分析表明CYP1A1Ile462Val突变基因型与GSTM1缺失型、CYP1A1 Ile462Val突变基因型与mEH Tyr113His突变基因型之间在肺癌的发生中具有交互作用,这两种联合基因型携带者患肺癌的危险度分别为4.86、3.27 (P＜ 0.05).结论 代谢酶基因变异及基因间的交互作用与肺癌患癌危险度增高有关,其在肺癌的发生过程中起一定作用.     

基因多态性在肺癌发生中交互作用

目的探讨代谢酶基因与修复酶基因多态性在肺癌发生中的交互作用。方法采用1：1配对病例一对照研究，收集原发性肺癌患者227例和相应非肿瘤对照227例，对CYP1B1、CYP2C19、CYP2D6、CYP2E1、GSTM1、GSTT1、GSTP1、mEH、NQ01、XRCC1、XRCC3、hOGG1、NAT2、XPD基因多态性进行检测，应用Logistic回归对基因一基因交互作用进行分析。结果CYP2C19突变基因型与NQ01突变基因型。mEH-exon3突变基因型与NQ01突变基因型之间对肺癌的发生存在交互作用，可导致肺癌易感性的增高。未见其他代谢酶基因与修复酶基因在汉族人群肺癌发生中存在交互作用。结论对基因多态性的联合检测更有利于筛选易感人群。今后应加大样本含量，进行多基因之间的联合作用分析。     

毒物代谢酶基因多态性与胃癌易感性

简要综述毒物代谢酶一相酶细胞色素P4502E1（CYP4502E1）、二相酶谷胱甘肽S－转硫酶M1、T1GSTM1、GSTT1）、N－乙酰化转移酶（NAT）的基因多态性与胃癌的遗传易感性的国内外研究进展。     

CYP1A1基因多态性与肺癌个体易感性研究

[目的 ]探讨CYP1A1Msp1和Ile/Val多态性单独或联合作用 ,对肺癌易感性的影响。 [方法 ]以病例一对照研究的方法 ,采用PCR扩增限制酶切法 (PCR -RFLP)和等位基因特异性扩增 (Allele SpecificAmplification ,ASA)检测 92例肺癌病人 (病例组 )和 98例非肿瘤病人 (对照组 )CYP1A1基因Msp1和Ile/Val基因型。 [结果 ]Msp1多态性位点 :具有B和C基因型者患肺癌的危险性是A基因型者的 1 85倍 (χ2 =4 3 6,P <0 0 5 ,OR =1 85 ,95 %CI 1 0 4～ 3 3 0 )。Ile/Val多态性位点 :Val/Val基因型者患肺癌的危险性是Ile/Ile基因型者的 3 3倍 (χ2 =4 12 ,P <0 0 5 ,OR =3 3 ,95 %CI 1 0 2～10 72 )。Ile/Val基因型联合B基因型、C基因型或Val/Val基因型联合C基因型与Ile/Ile基因型联合A基因型相比 ,患肺癌的危险性增加 ,其相对危险度分别为 3 0 9(χ2 =5 81,P <0 0 5 ,95 %CI 1 7～ 9 96) ;4 74(χ2 =4 74,P <0 0 5 ,95 %CI1 11～ 2 0 9) ;5 5 (χ2 =4 42 ,P <0 0 5 ,95 %CI 1 2 7～ 2 3 6)。 [结论 ]CYP1A1基因的B、C和Val/Val基因型可能是肺癌的易感基因型 ,两种易感基因型同时存在 ,更增加对肺癌的易感性     

吸烟者CYP1A1和GSTM1基因多态性与DNA损伤关系

[目的]探讨吸烟者Ⅰ相代谢酶CYP1A1和Ⅱ相代谢酶GSTM1基因多态性与DNA损伤的关系。[方法]选择吸烟量、性别、年龄、生活方式基本相同的吸烟者123例,应用Pyrosequencing技术进行个体基因型测定,彗星试验测定外周血淋巴细胞DNA损伤程度。[结果]在123名吸烟者中,CYP1A1突变型(CYP1A1Val/Val)占CYP1A1等位基因型的28.5%,GSTM1缺失型(GSTM1null)占GSTM1等位基因型的56.1%。具有CYP1A1Val/Val和GSTM1null基因型的个体有19名,占吸烟者总数的15.4%。同时具CYP1A1突变型和GSTM1缺失型纯合个体,淋巴细胞的拖尾形成率为97.5%,尾长达120.9μm,尾矩为42.4μm,显著高于野生型个体(P<0.05),且尾部DNA的荧光强度明显升高,而突变杂合型个体DNA损伤无明显加重。[结论]CYP1A1突变型与GSTM1缺失型共同携带者对DNA损伤敏感,多个突变基因对DNA损伤可能具有协同作用。     

吉林市汉族妇女GSTM1基因和CYP1A1基因Exon7位点多态性与 子宫内膜异位症易感性的研究

目的:探讨在吉林地区汉族妇女中细胞色素P450(CYP1A1)基因Exon7位点多态性即Ile-Val位点的多态性及GSTM1基因多态性和子宫内膜异位症易感性的相关关系。方法:以病例对照的研究方法,采用PCR技术检测216例子宫内膜异位症和216例对照人群的CYP1A1基因Ile-Val位点及GSTM1基因多态性的表达。结果:吉林地区汉族人群中GSTM1空白基因型分布频率0.463,内异症人群中空白基因型分布频率0.667,两组差异有统计学意义(P<0.05),空白基因型患内异症的危险是功能基因型的1.896倍;Ile-Val三种多态基因型在内异症组和对照组分布差异有统计学意义(P<0.05),Ile/Val、Val/Val基因型患内异症的危险分别是Ile/Ile基因型的1.901倍和3.056倍;CYP1A1 Ile/Val联合GSTM1空白基因型个体的OR值为3.409(95%C I 1.897~6.125,P<0.01),而CYP1A1Val/Val联合GSTM1空白基因型个体的OR值增高至7.143(95%C I 2.584~19.742,P<0.01)。结论:CYP1A1 Exon7的Ile/Val、Val/Val基因型及GSTM1空白基因型与内异症的易感性有关,二者联合效应具有协同作用,可望作为内异症易感人群筛选的重要指标。     

NAT2,CYP2B6和GSTP1基因多态性与苯乙烯生物监测的关系

目的：探讨NAT2，CYP2B6和GSTP1基因多态性与苯乙烯生物监测之间的关系。方法：选择58名接触苯乙烯的工人为研究对象，应用PCR-RFLP法判定基因型；应用高效液相色谱法测定其尿中三种代谢产物（苯乙醇酸、苯乙醛酸和苯乙烯巯基尿酸）的含量；并分析NAT2，CYP2B6和GSTP1基因多态性对接触不同水平苯乙烯工人尿中代谢产物含量有无显著影响（P〈0.05）。结果：CYP2B6（BsrI）不同基因型苯乙烯尿中代谢产物含量有显著性差异；GSTP1（BsmAI）和NAT2 M3基因型在苯乙烯代谢中的作用差异均无统计学意义。结论：除传统生物检测指标如尿中化学代谢物和早期生物效应等，某些苯乙烯代谢酶基因多态性对其生物监测指标具有一定影响，因此也可作为遗传易感性生物标志物，用来评价苯乙烯接触人群的遗传易感性。     

The CYP1A1 genotype may alter the association of meat consumption patterns and preparation with the risk of colorectal cancer in men and women

We hypothesized that the risk of colorectal cancer associated with meat preparation methods producing heterocyclic amines or polycyclic aromatic hydrocarbons is modified by the CYP1A1 genotype alone or in combination with the GSTM1 genotype or the NAT2 imputed phenotype. A total of 952 rectal cancer cases and 1205 controls (between September 1997 and February 2002) and 1346 colon cancer cases and 1544 controls (between October 1991 and September 1994) from Utah and Northern California were recruited from a population-based case-control study. Detailed interviews ascertained lifestyle, medical history, and diet and we extracted DNA from whole blood. Risk of colorectal cancer decreased among men with the CYP1A1 *2 any variant genotype and the lowest intake of poultry and men and women with high use of white meat drippings. Risk increased among men with the CYP1A1 *1 (no variant) allele and high white meat mutagen index, but decreased among those with the CYP1A1 *2 genotype. Risk increased with a high white meat mutagen index among women with the CYP1A1 *2 genotype and the GSTM1 present genotype. Risk of colorectal cancer decreased with the CYP1A1 *2 genotype, the NAT2 slow phenotype, and the use of white meat or its drippings. The association of risk for colorectal cancer and selected red and white meat mutagen indices and the use of white meat drippings, or fried white meat variables was more evident within select combinations of the CYP1A1 genotype and either the GSTM1 genotype or NAT2 than with the CYP1A1 alone. Genetic susceptibility may modify the associations of some meat or meat preparation factors with the risk of colorectal cancer.     

代谢酶基因多态性与结直肠癌的易感性

目的研究代谢酶细胞色素P450（cytochrome P450s,CYP）1A1、谷胱甘肽转移酶（glutathione—S-transferase,GST）M1和T1、尿苷二磷酸葡萄糖醛酸转移酶（UDPglucumnosyltransferase,UGT）1A7基因多态性与结直肠癌的易感性及其交互作用。方法2002年5月在浙江省嘉善县开展的现场病例对照研究及单纯病例研究,获得140例结直肠癌患者和343名健康对照,用PCR-限制性片段长度多态性等方法检测CYP1A1、GSTM1、GSTT1和UGT1A7的基因多态,并应用非条件logistic回归方法进行数据分析。结果CYPIA1 MspI多态（非编码区T6235C）C／C基因型、T／C和C／C基因型者相对于T／T基因型者的OR值分别为0．493（95％CI：0．254—0．956）和0．638（95％CI：0．427—0．952）,具有统计学意义;GSTM1、GSTT1非缺陷型与缺陷型的分布频率对照组和病例组比较差异无统计学意义;对照组和病例组UGT1A7变异／变异型基因与野生纯合型基因比较差异有统计学意义（OR=2．501,95％CI：1．456—4．296）。单纯病例研究分析,CYP1A1与GSTT1、GSTM1与GSTT1对结直肠癌的发生存在交互作用,COR值分别为2．617（95％CI：1．015—6．752）和3．935（95％CI：1．323—11．706）;而CYPlAl与GSTM1、CYP1A1与UGT1A7之间无交互作用。结论CYP1A1 MspI变异型可降低机体对结直肠癌的易感性,而UGT1A7的变异／变异基因型可增加结直肠癌的罹患风险,CYP1A1与GSTT1、GSTM1与GSTT1对结直肠癌的发生存在交互作用。     

胃癌易感基因筛选及多基因危险度分析

[目的]探讨我国汉族人群胃癌患者遗传易感基因,并进行多基因危险度分析。[方法]采用1：1配对病例对照研究方法,收集南京市汉族人群原发性胃癌患者585例和相应非肿瘤及非消化道疾病患者为研究对象,应用限制性片段长度多态性聚合酶链反应（PCR-RFLP）和基因特异性聚合酶链反应（AS-PCR）技术分析CYP2E1、GSTM1、GSTT1、NAT2、ALDH2、MTHFR、XRCC1、IL-1β、VDR、TNF等基因型别;以条件logistic回归模型对基因及基因间的交互作用进行分析,选出易感基因,多基因联合作用危险度分析统计模型对选出的危险因素进行多基因危险度评价。[结果]原发性胃癌遗传易感因素有8项,分别是CYP2E1（c1／c1）、NAT2表型（慢乙酰化型）、MTHFRA1298C（A／C）、IL-1β（C/T）、NAT2M2（A／A）、XRCC1194（T／T）、NAT2M1（T/T）、VDR TaqI（T/T）。利用多基因联合作用危险度分析模型对多基因危险度评价分析,可以更直观地发现多基因组合的OR值与其基因频率存在高度相关性,即随易感基因的增加,易感基因组合危险度分布曲线会向更加危险的方向移动。并呈现一定的量化关系。[结论]通过对筛选出的易感基因进行多基因危险度分析,可更有效地推进对汉族人群中胃癌的高危人群识别及对其采取预防和干预措施。     

Polymorphisms in Xenobiotic Metabolizing Genes,Intakes of Heterocyclic Amines and Red Meat,and Postmenopausal Breast Cancer

Heterocyclic amines (HCAs) are mutagenic compounds generated when meats are cooked at high temperature and for long duration. The findings from previous studies on the relation between HCAs and breast cancer are inconsistent, possibly because of genetic variations in the enzymes metabolizing HCAs. To evaluate whether the associations of intakes of estimated HCAs, meat-derived mutagenicity (MDM), and red meat with risk of postmenopausal breast cancer were modified by N-acetyltransferase 2 (NAT2) acetylator genotype or cytochrome P450 1A2-164 A/C (CYP1A2) polymorphism, we conducted a nested case-control study with 579 cases and 981 controls within a prospective cohort, the Nurses’ Health Study. HCAs and MDM intakes were derived using a cooking method questionnaire administered in 1996. NAT2acetylator genotype, the CYP1A2 polymorphism, and intakes of HCAs, MDM, and red meat were not associated with risk of postmenopausal breast cancer. There was also no interaction between NAT2 acetylator genotype or CYP1A2 polymorphism and HCAs and MDM and red meat intake in relation to breast cancer. These results do not support the hypothesis that genetic polymorphisms of xenobiotic enzymes involved in the metabolism of HCAs may modify the associations between intakes of red meat or meat-related mutagens and breast cancer risk.     

Genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of colorectal cancer

Environmental factors such as smoking cigarette, diets and alcohol may interact with genetic factors, which put one individual at a greater or lesser risk of a particular cancer than another. Advances in molecular biology have allowed many allelic variants of several drug metabolizing enzymes so that individuals with the susceptible genotypes can be determined easily. Many pieces of research have focused on the relationship between the distribution of polymorphic variants of different forms of the metabolic enzymes and colorectal cancer susceptibility because of importance roles of the metabolic enzymes in the activation of many procarcinogens or chemicals. In this respect five groups of the metabolic enzymes, cytochrome P450 (CYP) 1A1/CYP1A2, glutathione S-transferases (GSTs), N-acetyltransferases (NATs), aldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR), have been discussed here. A positive association between development of colorectal cancer and the mutant homozygous genotype in Msp1 polymorphism of CYP1A1 gene has been reported in Japanese in Hawaii. The relation between genetic polymorphisms in GSTs and cancer risk has also taken an interest. At least nine studies have demonstrated the relation between the GST polymorphisms and colorectal cancer. Two of these studies suggested an increased risk of approximately 2-fold among those with the GSTM1 null genotype, while others found no risk increase. None of these studies examined the combined effect of CYP1A1 and GST polymorphisms. Either NAT2 or CYP1A2 alone have been slightly associated with colorectal cancer. When CYP1A2 and NAT2 phenotype were combined, a significant increased risk (odds ratio of 2.8) was seen among well done meat consumers with the rapid-rapid phenotype. Two published studies have found that the risk of colorectal cancer can be enhanced (2-3 fold) in alcohol drinkers with heterozygous genotype of ALDH2 in two Japanese populations recently. Findings from three published studies suggested that the mutant genotype of MTHFR inversely slightly associated with colorectal cancer. Although some of genetic polymorphisms discussed here have not shown statistically significant increase/decrease in risk, individuals with differing genotypes may have different susceptibilities to colorectal cancer, based on environmental factors. Further studies are needed to identify risk groups more specific and to determine factors of importance in colorectal cancer development.     

CYP1A1, cigarette smoking, and colon and rectal cancer

Cytochrome P-450 (CYP) is involved in the activation and metabolism of polycyclic aromatic hydrocarbons in tobacco products. The authors evaluated the association of two polymorphisms in the CYP1A1 gene--the noncoding Msp I polymorphism in the 3'-untranslated region and the Ile462Val polymorphism in exon 7--with colon and rectal cancer. The authors used data from two incident case-control studies of colon cancer (1,026 cases and 1,185 controls) and rectal cancer (820 cases and 1,036 controls) conducted in California and Utah (1991-2002). CYP1A1 genotype was not associated with colon or rectal cancer. Having GSTM1 present, a CYP1A1 variant allele, and the rapid-acetylator NAT2 imputed phenotype was associated with increased risk of colon cancer (odds ratio = 1.7, 95% confidence interval: 1.2, 2.3). Among men, the greatest colon cancer risk was observed for having any CYP1A1 variant allele and currently smoking (odds ratio = 2.5, 95% confidence interval: 1.3, 4.8; Wald chi(2)test: p < 0.01). Assessment of GSTM1 and CYP1A1 and rectal cancer in men showed a twofold elevation in risk for more than 20 pack-years of smoking, except among those with GSTM1 present who had a variant CYP1A1 allele. These data support the association between smoking and colon and rectal cancer. Smoking may have a greater impact on colorectal cancer risk based on CYP1A1 genotype; this might further be modified by GSTM1 for rectal cancer risk.     

N-乙酰基转移酶2基因型与结核病患者发生药物性肝损害的关系

目的 研究N-乙酰基转移酶2(N-acetyltransferase 2,NAT2)基因型与抗结核药物性肝损害的关系,阐明抗结核药物性肝损害的分子机制.方法 通过病例-对照研究和聚合酶链反应-直接测序(PCR-DS)技术,收集抗结核药物所致肝损害患者101例和无药物性肝损害的结核患者107例,分别作为肝损害组和对照组,...