The relationship between single nucleotide polymorphisms in estrogen-metabolizing genes CYP1A1,CYP17,COMT and estrogen receptor alpha and the risk of endometrial adenocarcinoma among the Chinese women

<正>Objective:To explore whether polymorphisms of the genes responsible for catechol estrogen(CE)formation via estrogen biosynthesis(CYP17)and hydroxylation (CYP1A1)and CE inactivation(COMT)and ERa are associated with an elevated risk for en- dometrial adenocarcinoma in Chinese women.Methods:A multigenic case-control study was conducted,eighty-seven endometrial adenocarcinoma patients and ninety controls were recrui- ted.PCR-RFLP assays were used to determine the genotypes of estrogen-metabolizing genes and ERa gene.Results:The endometrial adenocarcinoma risk associated with individual susceptibili- ty genotypes varied among the six polymorphic sites and was the highest for CYP17,followed by CYP1 A1 Ile-Val,CYP1A1 MspI,COMT,ERa XhaI and ERa PvuII.Multivariate logistic regres- sion showed the CYP1A1 MspI genotype was the most significant determinant for endometrial adenocarcinoma development and was associated with a 3.61 fold increase in risk(95% confi- dence interval,1.73～7.55).Furthermore,a trend of increasing risk for developing endometrial adenocarcinoma was found in women harboring higher numbers of high-risk genotypes.Conclu- sion:The CYP1A1,CYP17 and ERa XbaI genotypes are related to the susceptibility of endome- trial adenocarcinoma,they may be useful markers for predicting endometrial adenocarcinoma susceptibility.The allele encoding for low acticity COMT,ERa PvuII may not be a genetic risk factor for endometrial adenocarcinoma.     

CYP1A1基因多态性与宫颈鳞癌的关系

目的:检测宫颈鳞癌组织中CYP1A1等位基因的表达,探讨CYP1A1基因多态性在宫颈鳞癌发生中的作用。方法:收集宫颈鳞癌组织标本50例,以正常宫颈组织61例为阴性对照。采用等位基因特异性PCR法(ASA-PCR)和PCR扩增限制酶切法(RFLP-PCR)检测宫颈鳞癌组织中CYP1A1等位基因Exon7位点和MspⅠ位点多态性;用SPSS13.0软件建立数据库,进行χ2检验、logistic回归分析。结果:(1)CYP1A1Exon73种多态基因型在宫颈鳞癌组和对照组分布差异有统计学意义(P<0.005),宫颈鳞癌组Ile/Val、Val/Val基因型的分布频率明显高于对照组。Ile/Val和Val/Val基因型的个体发生宫颈鳞癌的OR值分别是Ile/Ile基因型个体的1.969倍和3.15倍,差异有统计学意义(P<0.05);(2)CYP1A1MspⅠ位点多态性分析:将MspⅠ位点的PCR产物行酶切分析,显示m1/m2杂合型、m2/m2突变型在宫颈鳞癌组和对照组表达差异无统计学意义(P>0.05)。结论:宫颈鳞癌组织中CYP1A1基因Exon7位点突变率升高,Ile/Val和Val/Val基因突变型个体发生宫颈鳞癌的危险性明显升高;CYP1A1基因MspⅠ位点的多态性可能与宫颈鳞癌易感性无关。     

CYP1B1基因多态性与卵巢癌易感性的研究

目的:研究CYP1B1基因外显子2密码子119(G-T)、外显子3密码子432(C-G)多态性与卵巢癌遗传易感性的关系。方法:应用等位基因特异性聚合酶链反应(AS-PCR)法对53例卵巢癌患者和30例对照者进行CYP1B1基因密码子119(G-T)、密码子432(C-G)突变分析,用免疫组化SP法进一步研究雌激素受体(ER)、孕激素受体(PR)的表达,分析其是否受CYP1B1基因多态性的影响。结果:CYP1B1基因密码子432中等位基因C、G在卵巢癌组和对照组分布的差异有统计学意义(P<0.05),其中等位基因G使卵巢癌发病风险增加2.71倍。CYP1B1基因密码子432C/G各基因型分布两组间差异有统计学意义(P<0.01),纯合突变(G/G)基因型、杂合突变(C/G)基因型与野生(C/C)基因型相比,患卵巢癌的危险度分别提高了4.53倍和4.43倍。此外,432G/G、C/G基因型者ER阳性表达率高于432(C/C)基因型,三者间有显著差异(P<0.05)。结论:CYP1B1基因密码子432突变等位基因与卵巢癌的发生有一定关系,突变基因型增加了卵巢癌的发病风险,且与ER的表达相关。     

CYP1A1基因多态性与子宫内膜癌易感性关系的研究

目的:研究细胞色素P4501A1(CYP1A1)基因MspⅠ位点多态性与子宫内膜癌发生的关系。方法:用PCR-RFLP法检测174例子宫内膜腺癌患者和114例对照者CYP1A1基因MspI位点多态性。结果:合并杂合型T/C和突变型C/C后与野生型T/T比较,两组差异有统计学意义(P=0.047,OR=1.635)。在绝经年龄<50岁的病例组,T和C等位基因频率与对照组相比差异有统计学意义(P=0.032);初潮年龄≤14岁,等位基因频率在两组中差异有统计学意义(P=0.036);经BMI分层分析,未发现MspI多态性与子宫内膜癌有关。结论:CYP1A1基因MspI多态中突变等位基因C可显著增加子宫内膜癌的发病风险,且绝经年龄越早、初潮年龄越早携带等位基因C的个体越易感子宫内膜癌。     

CYP1A1基因多态性与子宫内膜腺癌发生的关系研究

目的研究细胞色素P4501A1(CYP1A1)基因MspI位点和Ile-Val位点多态性与子宫内膜腺癌发生的关系。方法以病例-对照研究,采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)方法和等位基因特异性PCR(AS-PCR)技术检测84例子宫内膜腺癌患者和66例对照者CYP1A1基因MspI位点和Ile-Val位点的多态性。结果Ile-Val三种多态基因型在对照组和子宫内膜腺癌组中的分布在显著性差异(P<0.05),其中Ile/Val和Val/Val基因型在子宫内膜腺癌组中的分布频率明显高于对照组。与Ile/Ile基因型相比,Ile/Val基因型个体发生子宫内膜腺癌的相对危险度(OR)是2.682,两者差异有统计学意义(P<0.05);而MspI位点的多态性在对照组和子宫内膜腺癌组中的分布差异无统计学意义(P>0.05)。结论CYP1A1基因第7外显子的Ile/Val基因型与子宫内膜腺癌的发生有关,可以作为子宫内膜腺癌易感人群筛查的重要指标,MspI位点多态性与子宫内膜腺癌的发生无相关性。     

CYP1A1基因MspⅠ位点多态性与子宫肌瘤易感性的研究

目的:探讨细胞色素P450(cytochrome P450,CYP)1A1基因MspⅠ位点多态性与鲁北地区汉族女性子宫肌瘤的关系。方法:以病例-对照的研究方法,采用PCR-RFLP方法检测了123例子宫肌瘤患者和123例匹配对照者的CYP1A1基因MspⅠ位点的基因多态性。应用Logistic回归等方法分析基因多态性与子宫肌瘤的关系。结果:(1)CYP1A1基因MspⅠ位点的基因型在子宫肌瘤组与对照组中分布的差异无统计学意义(P=0.927);(2)杂合型(T/C)和突变型(C/C)与野生型(T/T)在子宫肌瘤组与对照组的分布差异均无统计学意义(P=0.738,P=0.947);(3)合并杂合型(T/C)和突变型(C/C)与野生型(T/T)比较,在子宫肌瘤组与对照组分布的差异无统计学意义(P=0.925)。结论:CYP1A1MspⅠ等位基因多态性与鲁北地区汉族女性子宫肌瘤的易感性无显著相关性。     

雌激素代谢酶CYP1A1及COMT基因多态性与子宫肌瘤相关性研究

目的:探讨雌激素代谢酶CYP1A1和COMT基因多态性与子宫肌瘤发生的关系。方法:应用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)技术,对100例子宫肌瘤患者和100例对照组人群CYP1A1基因Msp I位点多态和COMT基因外显子4密码子158(G-A)多态性进行分析。结果:1两组均存在CYP1A1基因Msp I位点多态,但两组基因型TT、TC、CC频率和等位基因T、C频率的比较差异均无统计学意义(P0.05);2两组均存在COMT基因G-A多态,但两组基因型GG、GA、AA频率和等位基因G、A频率的比较差异均无统计学意义(P0.05)。结论:CYP1A1基因Msp I位点多态性和COMT基因外显子4密码子158(G-A)多态性与子宫肌瘤发病风险无相关性。     

卵巢癌细胞系A2780紫杉醇体外化疗后CYP1B1基因表达差异研究

目的探讨卵巢癌细胞系A2780紫杉醇(PTX)体外化疗后细胞色素P4501B1(CYP1B1)表达的变化,研究CYP1B1基因表达与肿瘤细胞耐药的关系。方法2004年天津医科大学总医院采用四甲基偶氮唑蓝(MTT)比色法观察不同质量浓度PTX(50、25、12.5、6.25、3.13、1.56、0.78mg/L)对A2780细胞体外生长的抑制作用。应用RT-PCR技术检测5mg/L PTX分别处理A2780细胞24h、48h、72h和50mg/L PTX处理A2780细胞24h后存活的卵巢癌细胞中CYP1B1 mRNA的表达。Western blot检测5mg/L PTX处理不同时间后和50mg/L PTX处理A2780细胞后CYP1B1蛋白表达。结果PTX抑制卵巢癌细胞生长,不同浓度PTX作用A2780细胞72h后的抑制率分别为90.45%、78.63%、66.77%、58.38%、45.90%、36.41%、15.38%,随药物质量浓度的下降,细胞受抑制程度明显降低(P<0.05)。PTX处理后存活的卵巢癌细胞中CYP1B1 mRNA及蛋白的表达量增加,高于未加药的对照组;5mg/L处理48h、72h和50mg/L组CYP1B1的表达量高于5mg/L处理24h组(P<0.05)。结论CYP1B1基因在卵巢癌细胞系中呈高表达,在卵巢癌细胞系A2780体外化疗中起抑制作用。     

CYP1A1 MspI多态性及其合并GSTM1基因缺失与子宫内膜异位症的关系

目的:探讨新疆维吾尔族、汉族人群中解毒酶细胞色素P4501A1(CYP1A1)基因MspI多态性、CYP1A1/MspI合并GSTM1基因缺失基因型与子宫内膜异位症(内异症)的关系。方法:用聚合酶链反应限制性片段长度多态性技术,检测维吾尔族107例正常妇女与41例内异症患者、汉族105例正常妇女与80例内异症患者CYP1A1基因限制性内切酶MspI位点的3种基因型的分布频率。结果:CYP1A1基因MspI位点基因型在维吾尔族正常对照组的分布频率为TT(48.6%)、TC(42.9%)、CC(8.5%),等位基因分布频率为T(70.1%)、C(29.9%),内异症组的基因型分布频率为TT(39.1%)、TC(46.3%)、CC(14.6%),等位基因分布频率为T(62.2%)、C(37.8%),差异无显著性(P>0.05);在汉族正常对照组基因型分布频率为TT(41.9%)、TC(46.7%)、CC(11.4%),等位基因分布频率为T(65.2%)、C(34.8%),内异症组基因型分布频率为TT(42.5%)、TC(51.2%)、CC(6.3%),等位基因分布频率为T(68.1%)、C(31.9%),差异无显著性。两个民族对照组之间与内异症组之间基因型频率与等位基因频率比较差异无显著性。在CYP1A1/MspI合并GSTM1(/)基因型的人群中,维吾尔族对照组与内异症组的基因型频率与等位基因频率分布比较均有显著差异(P<0.05),其TC+CC与TT比较,OR值为3.556(P<0.05)。汉族对照组与内异症组的比较无统计学差异。结论:解毒酶CYP1A1基因MspI多态性本身可能与维吾尔族及汉族内异症发病无关,而CYP1A1/MspI合并GSTM1(/)基因型可能与维吾尔族内异症发病有关。     

CYP17A1 gene mutations and hypertension variations found in 46, XY females with combined 17α-hydroxylase/17, 20-lyase deficiency

The aim of this study was to analyze the structural consequences of the mutations in CYP17A1 gene and their relationship with the variations of clinical manifestations in three patients who presented with complete or partial combined 17α-hydroxylase/17,20-lyase deficiency (17OHD). DNA sequences of the coding exons and intron/exon boundaries of the CYP17A1 gene were analyzed for mutations. In silico analysis with computational three-dimensional model of human P450c17 and multiple alignments analysis were performed to evaluate the spatial conformational changes by missense mutations. Five mutations p.S117fs (c.351_352delCT), p.H373L (c.1184 A>T), p.Y329fs (c.985_987delTACinsAA), p.A82D (c.245 C>A) and p.L209P (c.626 T>C) were identified in three patients, respectively. The novel mutation p.S117fs (c.351_352delCT) has not been reported previously. In silico analysis explained the conformational changes by the described mutations, which resulted in different severe 17OHD. Our studies also suggest that molecular data accompanying with in silico analysis of the CYP17A1 gene are much helpful for the diagnosis, management and genetic counseling of 17OHD.     

Gene–gene-environment interactions of prenatal exposed to environmental tobacco smoke,CYP1A1 and GSTs polymorphisms on full-term low birth weight: relationship of maternal passive smoking,gene polymorphisms,and FT-LBW

Objective: To examine the interaction effects of prenatal exposed to environmental tobacco smoke (ETS) and genotypes of cytochrome P4501A1 (CYP1A1), glutathione S-transferases (GSTs) on the risk of full-term low birth weight (FT-LBW).

Study design: We conducted a case-control study among pregnant women at two Women and Children’s Hospitals in Guangdong, China (n?=?910). Information was collected through interview, medical records review, and blood lab tests. Maternal selfreport and serum cotinine concentration were combined to define prenatal exposed to ETS. Logistic regression approach was applied for statistical analysis.

Results: Our results showed that regardless of genotypes, prenatal exposed to ETS significantly increased the risk of FT-LBW. Then, two-way interactions showed increased prevalence of FT-LBW in prenatal exposed to ETS mothers with the CYP1A1 variant genotype (MspI “CC”), or with GSTT1-null genotype. Furthermore, three-way interactions showed that women with CYP1A1 variant (MspI “TC” or BsrDI “AG”) genotypes and GSTT1 “null” genotype had higher risk to give birth of FT-LBW. Additionally, among nonexposed ETS mothers, genotype did not independently confer adverse effects on FT-LBW.

Conclusions: Our results revealed that prenatal exposed to ETS is independently associated with FT-LBW while gene polymorphisms of CYP1A1 and GSTs merely play modified roles in this process. This study extends understanding of three-way interaction, and stresses the need to tobacco control toward pregnant women for better pregnant outcomes.     

CYP1A1基因MspI位点和SULT1A1基因Arg213His位点多态性与子宫肌瘤的关联性研究

目的 探讨细胞色素P450 (cytochrome P450, CYP)1A1 基因MspⅠ位点和硫酸氨基转移酶(sulfotransferase, SULT) 1A1 基因 Arg213His位点多态性与鲁北地区汉族女性子宫肌瘤的关系。 方法 采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法检测123例子宫肌瘤患者和123例健康对照组的CYP1A1 基因 MspⅠ位点的基因型和SULT1A1 基因 Arg213His位点的基因型,分析基因多态性与子宫肌瘤的关系。 结果 子宫肌瘤组CYP1A1基因MspⅠ位点的基因型与对照组中的分布比较,差异无统计学意义(P=0.927); 而子宫肌瘤组SULT1A1 基因Arg213His位点的基因型与对照组中的分布比较,差异有统计学意义( P=0.011)。CYP1A1基因MspI位点和SULT1A1基因Arg213His位点多态性在子宫肌瘤的发生过程中的交互作用比较,差异有统计学意义( P=0.024 )。 结论 CYP1A1 基因MspⅠ位点多态性与鲁北地区汉族女性子宫肌瘤的易感性无显著相关;SULT1A1 基因Arg213His位点多态性与鲁北地区汉族女性子宫肌瘤的发生有关,并增加了子宫肌瘤的患病风险;CYP1A1基因MspI位点和SULT1A1基因Arg213His位点多态性在子宫肌瘤的发生过程中具有交互作用。     

CYP1A1基因MspⅠ位点和SULT1A1基因Arg213His位点多态性与子宫肌瘤的关联性研究

目的 探讨细胞色素P450(cytochrome P450,CYP)1A1基因MspⅠ位点和硫酸氨基转移酶(sulfotransferase,SULT)1A1基因Arg213His位点多态性与鲁北地区汉族女性子宫肌瘤的关系.方法 采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法检测123例子宫肌瘤患者和123例健康对照组的CYP1A1基因MspⅠ位点的基因型和SULT1A1基因Arg213His位点的基因型,分析基因多态性与子宫肌瘤的关系.结果 子宫肌瘤组CYP1A1基因MspⅠ位点的基因型与对照组中的分布比较,差异无统计学意义(P=0.927);而子宫肌瘤组SULT1A1基因Arg213His位点的基因型与对照组中的分布比较,差异有统计学意义(P=0.011).CYP1A1基因MspⅠ位点和SULT1A1基因Arg213His位点多态性在子宫肌瘤的发生过程中的交互作用比较,差异有统计学意义(P=0.024).结论 CYP1A1基因MspⅠ位点多态性与鲁北地区汉族女性子宫肌瘤的易感性无显著相关;SULT1A1基因Arg213His位点多态性与鲁北地区汉族女性子宫肌瘤的发生有关,并增加了子宫肌瘤的患病风险;CYP1A1基因MspⅠ位点和SULT1A1基因Arg213His位点多态性在子宫肌瘤的发生过程中具有交互作用.     

GSTM1、CYP2E1基因多态性与新疆维吾尔族妇女宫颈癌及癌前病变关联性的研究

目的:探讨谷胱甘肽硫转移酶基因GSTM1和细胞色素氧化酶P4502E1(CYP2E1)的基因多态性与新疆维吾尔族妇女宫颈癌前病变与癌的关联性。方法:用聚合酶链反应(PCR)方法及聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法为21例浸润性宫颈癌(ICC)、41例宫颈上皮内瘤变(CIN)及45例慢性宫颈炎标本进行GSTM1和CYP2E1RsaⅠ位点基因分型。结果:ICC组和CIN组的GSTM1空白基因型频率明显高于慢性宫颈炎组(对照组),差异有统计学意义(χ2=7.56,P<0.05;χ2=13.30,P<0.05),携带GSTM1(-)的个体患宫颈癌的危险性比携带GSTM1(+)的个体升高3.47倍(OR=4.47,95%CI=1.5～13.0),患CIN的危险性升高4.30倍(OR=5.30,95%CI=2.2～13.0)。CYP2E1基因RsaⅠ位点多态在3组的频率差异无统计学意义(χ2=2.28,P>0.05)。联合分析3组病例CYP2E1基因RsaⅠ多态性和GSTM1基因多态性,未发现两者之间的交互作用与ICC及CIN易感性有关(χ2=4.47,P>0.05)。结论:GSTM1基因空白型可能与维吾尔族宫颈癌及癌前病变风险增加有关,CYP2E1基因RsaⅠ多态性与宫颈癌及癌前病变无关。     

CYP11A与多囊卵巢综合征

CYP11A编码胆固醇侧链裂解酶P450scc是固醇类激素合成的第一步关键限速酶,几乎存在于所有动植物中。CYP11A受激素水平和自身启动子区域某些特定结构调控,其启动子区域的基因多态性可能与转录活性和基因表达相关。多囊卵巢综合征(PCOS)是一种很常见的女性生殖内分泌疾病,高雄激素是PCOS的主要特征。CYP11A基因是PCOS的一个重要遗传易感位点,在PCOS发病机制中其多态性表现的作用仍有争论,并未完全阐明,值得进一步深入研究。     

孕37周,发现血压升高1~+月,头痛1周,恶心、呕吐1天

<正>1 病历摘要患者,26岁,G2P0,因孕37周,发现血压升高1+月,头痛1周,恶心、呕吐1天,于2020年7月11日2时30分入院。孕妇于2019年12月20日至当地某三甲医院建卡,后旅居西藏,未做任何产前检查,2020年5月返回当地不定期产前检查。未行唐氏筛查、胎儿系统超声及胎儿心脏超声筛查。孕晚期行口服葡萄糖耐量试验（OGTT）,因空腹血糖5.34 mmol/L,考虑诊断为妊娠期糖尿病,行糖尿病饮食及运动指导,血糖监测正常。     

子宫内膜异位症与CYP19基因多态性

子宫内膜异位症(EMs)是妇科常见疾病之一,该病在病理上呈良性形态学改变.但具有类似恶性肿瘤的种植、侵袭及远处转移能力.EMs是一种雌激索依赖性疾病.CYP19基因的表达与雌激素的产生密切相关,其突变可能会改变雌激素的暴露情况.影响EMs的发病风险.目前关于CYPl9基因多态性与EMs之间的关系仍存在争论,尚需深入研究...     

子宫内膜异位症与CYP19基因多态性

子宫内膜异位症（EMs）是妇科常见疾病之一,该病在病理上呈良性形态学改变,但具有类似恶性肿瘤的种植、侵袭及远处转移能力。EMs是一种雌激素依赖性疾病,CYP19基因的表达与雌激素的产生密切相关,其突变可能会改变雌激素的暴露情况,影响EMs的发病风险。目前关于CYP19基因多态性与EMs之间的关系仍存在争论,尚需深入研究以明确芳香化酶的基因多态性在EMs发生中的作用。     

Homozygous CYP17A1 mutation (H373L) identified in a 46,XX female with combined 17α-hydroxylase/17,20-lyase deficiency

Background: Defects in cytochrome P450c17 are uncommon forms of congenital adrenal hyperplasia caused by CYP17A1 mutations. An H373L mutation in the CYP17A1 gene has been identified in Japanese and Chinese patients. This mutation impairs 17α-hydroxylase and 17,20-lyase activity. Case: A 23-year-old Korean female (46,XX) presented with absent spontaneous puberty and hypertension. Hormonal findings were consistent with combined 17α-hydroxylase/17,20-lyase deficiency. Very high levels of progesterone and 11-deoxycorticosterone were detected, coincident with normal 17-hydroxysteroid levels. Plasma levels of dehydroepiandrosterone, androstenedione and testosterone were extremely low. Mutation analysis of the CYP17A1 gene identified a homozygous missense mutation changing His (CAC) to Leu (CTC) at codon 373. This mutation is known to completely abolish both 17α-hydroxylase and 17,20-lyase activity. The patient’s nonconsanguineous parents were heterozygous for this mutation. Of note, her serum steroid levels indicated decreased, but still present, 17α-hydroxylase activity in vivo. Conclusion: We detected a homozygous H373L mutation in a patient with combined 17α-hydroxylase/17,20-lyase deficiency. Our findings demonstrate minimally preserved 17α-hydroxylase activity in vivo and contribute to our knowledge of the regional prevalence of this mutation in Northeast Asia.     

腹胀、血压升高3天,加重1天,顺产后1天

1病历摘要患者,41岁。因“腹胀、血压升高3天,加重1天,顺产后1天”于2006年3月4日入院。患者末次月经2005年6月26日。怀孕期间未作正规产前检查,自诉无头痛、眼花等症状。3天前无诱因出现阵发性腹胀、解粘液样便、中上腹胀痛。呕吐胃内容物数次,伴食欲减退。在当地镇医院诊治时