The role of polymorphic cytochrome P450 gene(CYP2B6)in B-chronic lymphocytic leukemia(B-CLL)incidence and outcome among Egyptian patients

Cytochromes P450(CYPs)play a prominent role in catalyzing phase I xenobiotic biotransformation and account for about 75%of the total metabolism of commercially available drugs,including chemotherapeutics.The gene expression and enzyme activity of CYPs are variable between individuals,which subsequently leads to different patterns of susceptibility to carcinogenesis by genotoxic xenobiotics,as well as differences in the efficacy and toxicity of clinically used drugs.This research aimed to examine the presence of the CYP2B6*9 polymorphism and its possible association with the incidence of B-CLL in Egyptian patients,as well as the clinical outcome after receiving cyclophosphamide chemotherapy.DNA was isolated from whole blood samples of 100 de novo B-CLL cases and also from 100 sex-and age-matched healthy individuals.The presence of the CYP2B6*9(G516T)polymorphism was examined by PCR-based allele specific amplification(ASA).Patients were further indicated for receiving chemotherapy,and then they were followed up.The CYP2B6*9 variant indicated a statistically significant higher risk of B-CLL under different genetic models,comprising allelic(T-allele vs.G-allele,OR=4.8,p<0.001)and dominant(GT+TT vs.GG,OR=5.4,p<0.001)models.Following cyclophosphamide chemotherapy,we found that the patients with variant genotypes(GT+TT)were less likely to achieve remission compared to those with the wild-type genotype(GG),with a response percentage of(37.5%vs.83%,respectively).In conclusion,our findings showed that the CYP2B6*9(G516T)polymorphism is associated with B-CLL susceptibility among Egyptian patients.This variant greatly affected the clinical outcome and can serve as a good therapeutic marker in predicting response to cyclophosphamide treatment.

Cytochrome P450 2E1 genetic polymorphism and gastric cancer in Changle,Fujian Province

AIM: Genetic polymorphism in enzymes of carcinogen metabolism has been found to have the influence on the susceptibility to cancer. Cytochrome P450 2E1 (CYP2E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitrosoamines and low molecular weight organic compounds. The purpose of this study is to determine whether CYP450 2E1 polymorphisms are associated with risks of gastric cancer. METHODS: We conducted a population based case-control study in Changle county, Fujian Province, a high-risk region of gastric cancer in China. Ninety-one incident gastric cancer patients and ninety-four healthy controls were included in our study. Datas including demographic characteristics, diet intake, and alcohol and tobacco consumption of individuals in our study were completed by a standardized questionnaire.PCR-RFLP revealed three genotypes:heterozygote (C1/C2) and two homozygotes (C1/C1 and C2/C2) in CYP2E1. RESULTS: The frequency of variant genotypes (C1/C2 and C2/C2) in gastric cancer cases and controls was 36.3% and 24.5%, respectively. The rare homozygous C2/C2 genotype was found in 6 individuals in gastric cancer group(6.6%), whereas there was only one in the control group (1.1%). However, there was no statistically significant difference between the two groups (two-tailed Fisher's exact test P=0.066). Individuals in gastric cancer group were more likely to carry genotype C1/C2 (odds ratio, OR=1.50) and C2/C2 (OR=7.34) than individuals in control group (chi(2) =4.597, for trend P=0.032). The frequencies of genotypes with the C2 allele (C1/C2 and C2/C2 genotypes) were compared with those of genotypes without C2 allele (C1/C1 genotype) among individuals in gastric cancer group and control group according to the pattern of gastric cancer risk factors. The results show that individuals who exposed to these gastric cancer risk factors and carry the C2 allele seemed to have a higher risk of developing gastric cancer. CONCLUSION: Polymorphism of CYP2E1 gene may have some effect in the development of gastric cancer in Changle county, Fujian Province.

Three new alternative splicing variants of human cytochrome P450 2D6 mRNA in human extratumoral liver tissue

AIM: To identify the new alternative splicing variants of human CYP2D6 in human extratumoral liver tissue with RT-PCR and sequencing. METHODS: Full length of human CYP2D6 cDNAs was amplificated by reverse transcription-polymerase chain reaction (RT-PCR) from a human extratumoral liver tissue and cloned into pGEM-T vector. The cDNA was sequenced. Exons from 1 to 4 of human CYP2D6 cDNAs were also amplificated by RT-PCR from extratumoral liver tissues of 17 human hepatocellular carcinomas. Some RT-PCR products were sequenced. Exons 1 to 4 of CYP2D6 gene were amplified by PCR from extratumoral liver tissue DNA. Two PCR products from extratumoral liver tissues expressing skipped mRNA were partially sequenced. RESULTS: One of the CYP2D6 cDNAs had 470 nucleotides from 79 to 548 (3' portion of exons 1 to 5' portion of exon 4), and was skipped. Exons 1 to 4 of CYP2D6 cDNA were assayed with RT-PCR in 17 extratumoral liver tissues. Both wild type and skipped mRNAs were expressed in 4 samples, only wild type mRNA was expressed in 5 samples, and only skipped mRNA was expressed in 8 samples. Two more variants were identified by sequencing the RT-PCR products of exons 1 to 4 of CYP2D6 cDNA. The second variant skipped 411 nucleotides from 175 to 585. This variant was identified in 4 different liver tissues by sequencing the RT-PCR products. We sequenced partially 2 of the PCR products amplified of CYP2D6 exon 1 to exon 4 from extratumoral liver tissue genomic DNA that only expressed skipped mRNA by RT-PCR. No point mutations around exon 1, intron 1, and exon 4, and no deletion in CYP2D6 gene were detected. The third variant was the skipped exon 3, and 153 bp was lost. CONCLUSION: Three new alternative splicing variants of CYP2D6 mRNA have been identified. They may not be caused by gene mutation and may lose CYP2D6 activity and act as a down-regulator of CYP2D6.

GSTT1,GSTM1 and CYP2E1 genetic polymorphisms in gastric cancer and chronic gastritis in a Brazilian population

AIM:To test the hypothesis that,in the Southeastern Brazilian population,the GSTT1,GSTM1 and CYP2E1 polymorphisms and putative risk factors are associated with an increased risk for gastric cancer. METHODS:We conducted a study on 100 cases of gastric cancer (GC),100 cases of chronic gastritis (CG),and 150 controls (C).Deletion of the GSTT1 and GSTM1 genes was assessed by multiplex PCR.CYP2E1/Pst1 genotyping was performed using a PCR-RFLP assay. RESULTS:No relationship between GSTT1/GSTM1 deletion and the c1/c2 genotype of CYP2E1 was observed among the three groups.However,a significant difference between CG and C was observed,due to a greater number of GSTT1/GSTM1 positive genotypes in the CG group.The GSTT1 null genotype occurred more frequently in Negroid subjects,and the GSTM1 null genotype in Caucasians,while the GSTM1 positive genotype was observed mainly in individuals with chronic gastritis infected with H pylori. CONCLUSION:Our findings indicate that there is no obvious relationship between the GSTT1,GSTM1 and CYP2E1 polymorphisms and gastric cancer.

Identification of the 2-tridecanone cis-acting element in the promoter of cytochrome P450 CYP6B7 in Helicoverpa armigera

The expression level of cytochrome P450 genes in insects can be induced by plant allelochemicals,which is important for insects to adapt to host plants.Cytochrome P450CYP6B 7has been reported to be involved in pyethroid insecticide resistance in Heli- coverpa armigera,and its transcription level was induced by some inducers.Currently,the regulatory mechanism of the induced expression of CYP6B7remains unknown,although it is very important for understanding the detoxification mechanism to allelochemicals in host plants.The objective of the present study was to investigate the eis-acting ele- ment in the promoter of CYP6B7 mediating the inducible up-regulation of CYP6B7in H.armigera by 2-tridecanone.The promoter region of CYP6B7was cloned by genome walking technique and analyzed by transient transfeetion assay.Progressive 5'deletion of the promoter region of CYP6B7revealed that the relative luciferase activity of construct -320/+232could be significantly induced by 2-trideeanone.Further stepwise deletion between -320 and -238 bp found that construct -292/+232 could also be significantly induced by 2-tridecanone,but the adjacent construct -256/+232could not,suggesting the essential role of the sequence between -292 and --257 bp for 2-tridecanone induction. Nucleotide mutations between -292 and -281 bp had no influence on the induction ef- fect by 2-tridecanone,but nucleotide mutations between -280 and -257 bp significantly decreased the induction effect.These results demonstrated that the cis-acting element for 2-trideeanone induction was between -280 and -257 bp in the promoter of CYP6B7.

CYP1A1,CYP2E1 and EPHX1 polymorphisms in sporadic colorectal neoplasms

AIM To investigate the contribution of polymorphisms in the CYP1A1, CYP2E1 and EPHX1 genes on sporadic colorectal cancer(SCRC) risk. METHODS Six hundred forty-one individuals(227 patients with SCRC and 400 controls) were enrolled in the study. The variables analyzed were age, gender, tobacco and alcohol consumption, and clinical and histopathological tumor parameters. The CYP1A1 *2A, CYP1A1 *2C CYP2E1 *5B and CYP2E1 *6 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The EPHX1 Tyr113 His, EPHX1 His139 Arg and CYP1A1 *2C polymorphisms were detected by real-time PCR. Chisquared test and binary logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the Haploview program, version 2.05.RESULTS Age over 6 2 years was a risk factor for SCRC development(OR = 7.54, 95%CI: 4.94-11.50, P < 0.01). Male individuals were less susceptible to SCRC(OR = 0.55, 95%CI: 0.35-0.85, P < 0.01). The CYP2E1*5B polymorphism was associated with SCRC in the codominant(heterozygous genotype: OR = 2.66, 95%CI: 1.64-4.32, P < 0.01), dominant(OR = 2.82, 95%CI: 1.74-4.55, P < 0.01), overdominant(OR = 2.58, 95%CI: 1.59-4.19, P < 0.01), and log-additive models(OR = 2.84, 95%CI: 1.78-4.52, P < 0.01). The CYP2E1*6 polymorphism was associated with an increased SCRC risk in codominant(heterozygous genotype: OR = 2.81, 95%CI: 1.84-4.28, P < 0.01; homozygous polymorphic : OR = 7. 3 2, 9 5 % C I : 1.85-28.96, P < 0.01), dominant(OR = 2.97, 95%CI: 1.97-4.50, P < 0.01), recessive(OR = 5.26, 95%CI: 1.35-20.50, P = 0.016), overdominant(OR = 2.64, 95%CI: 1.74-4.01, P < 0.01), and log-additive models(OR = 2.78, 95%CI: 1.91-4.06, P < 0.01). The haplotype formed by the minor alleles of the CYP2E1*5B(C) and CYP2E1*6(A) polymorphisms was associated with SCRC(P = 0.002). However, the CYP1A1 *2A, CYP1A1 *2C, EPHX1 Tyr113 His and EPHX1 His139 Arg polymorphisms were not associated with SCRC.CONCLUSION In conclusion, the results demonstrated that CYP2E1*5B and CYP2E1*6 minor alleles play a role in the development of SCRC.

Polymorphism of genes encoding drug-metabolizing and inflammation-related enzymes for susceptibility to cholangiocarcinoma in Thailand

BACKGROUND Cholangiocarcinoma(CCA)is an intractable cancer,and its incidence in north eastern Thailand is the highest worldwide.Infection with the liver fluke Opisthorchis viverrini(OV)has been associated with CCA risk.However,animal experiments have suggested that OV alone does not induce CCA,but its combination with a chemical carcinogen like nitrosamine can cause experimentally induced CCA in hamsters.Therefore,in humans,other environmental and genetic factors may also be involved.AIM To examine relations between risk for CCA and genetic polymorphisms in carcinogenmetabolizing and inflammation-related genes.METHODS This hospital-based case-control study enrolled 95 case-control pairs matched by age(±5 years)and sex.We examined relations between risk for CCA and genetic polymorphisms in carcinogenmetabolizing and inflammation-related genes,serum anti-OV,alcohol consumption,and smoking.Polymorphisms of CYP2E1,IL-6(-174 and-634),IL-10(-819),and NF-κB(-94)and their cooccurrence with polymorphisms in the drug-metabolizing enzyme gene GSTT1 or GSTM1 were also analyzed.RESULTS Although CCA risk was not significantly associated with any single polymorphism,persons with the GSTT1 wild-type and CYP2E1 c1/c2+c2/c2 genotype had an increased risk(OR=3.33,95%CI:1.23-9.00)as compared with persons having the GSTT1 wild-type and CYP2E1 c1/c1 wild genotype.The presence of anti-OV in serum was associated with a 7-to 11-fold increased risk,and smoking level was related to an OR of 1.5-1.8 in multivariable analyses adjusted for each of the seven genetic polymorphisms.CONCLUSION In addition to infection with OV,gene-gene interactions may be considered as one of the risk factors for CCA development.

Preferential expression of cytochrome CYP CYP2R1 but not CYP1B1 in human cord blood hematopoietic stem and progenitor cells

Cytochrome P450(CYP)enzymes metabolize numerous endogenous substrates,such as retinoids,androgens,estrogens and vitamin D,that can modulate important cellular processes,including proliferation,differentiation and apoptosis.The aim of this study is to characterize the expression of CYP genes in CD34+human cord blood hematopoietic stem and early progenitor cells(CBHSPCs)as a first step toward assessment of the potential biological functions of CYP enzymes in regulating the expansion or differentiation of these cells.CD34+CBHSPCs were purified from umbilical cord blood via antibody affinity chromatography.Purity of CD34+CBHSPCs was assessed using fluorescence-activated cell sorting.RNA was isolated from purified CD34+CBHSPCs and total mononuclear cells(MNCs)for RNA-PCR analysis of CYP expression.Fourteen human CYPs were detected in the initial screening with qualitative RT-PCR in CD34+CBHSPCs.Further quantitative RNA-PCR analysis of the detected CYP transcripts yielded evidence for preferential expression of CYP2R1 in CD34+CBHSPCs relative to MNCs;and for greater expression of CYP1B1 in MNCs relative to CD34+CBHSPCs.These findings provide the basis for further studies on possible functions of CYP2R1 and CYP1B1 in CBHSPCs'proliferation and/or differentiation and their potential utility as targets for drugs designed to modulate CD34+CBHSPC expansion or differentiation.

溴氰菊酯对大鼠脑中苄氧基试卤灵O-脱烷基化酶活力及CYP2B1/2B2蛋白水平的影响

目的 研究溴氰菊酯 (deltamethrin ,DM)对大鼠脑组织中苄氧基试卤灵O 脱烷基化酶(benzyloxyresorufinO dealkylatase,BROD)活力及CYP2B1 / 2B2蛋白水平的影响。方法 采用荧光分光光度法 ,在体内、体外研究了DM对大鼠脑组织中BROD活力的影响 ,并用Western blot法检测了DM对CYP2B1 / 2B2蛋白水平的影响。结果 大鼠连续 5d腹腔注射DM 1 2 .5mg·kg- 1 ·d- 1 染毒后 ,其全脑、大脑皮层及小脑BROD活力明显被抑制 ,其抑制率分别是 2 6 .7%、2 3 .8%和 33 .3 % ,差异均有显著性(P <0 .0 5) ;在体外 ,DM浓度在 2× 1 0 - 8～ 2× 1 0 - 4mol/L范围内对BROD活力无明显影响 ;DM在体内明显降低小脑中CYP2B1 / 2B2蛋白水平 ,其酶蛋白合成抑制率为 42 .6 %。结论 DM在体内能明显抑制脑内BROD活力 。

CYP2B6基因多态性与异维A酸人体代谢动力学差异关联性研究

目的 探讨细胞色素P450（CYP2B6）基因多态性与异维A酸人体代谢动力学的关系.方法 21例健康受试者单次口服40mg异维A酸胶丸（商品名泰尔丝）,提取外周血基因组DNA进行PCR及限制性核酸内切酶片段分析方法（RFLP）分析CYP2B6第四外显子exon4及第五外显子exon5基因分型.高效液相色谱-质谱法（LC/MS）分析受试者异维A酸血药浓度并计算相关药动学参数.结果 21例健康受试者CYP2B6 exon4及exon5存在明显的连锁不平衡性.等位基因CYP2B6^＊4野生型^＊1/^＊1为12例（57.14%）,杂合型^＊1/^＊4为6例（28.57%）,突变型^＊4/^＊4为3例（14.29%） 等位基因CYP2B6^＊6野生型^＊1/^＊1为13例（61.90%）,杂合型^＊1/^＊6为5例（23.81%）,变异型^＊6/^＊6为3例（14.29%）.等位基因CYP2B6^＊4野生型体内消除参数t1/2及MRT高于突变型（P值均＜0.05）,吸收参数Cmax、Tmax及AUC等两组差异无统计学意义.等位基因为CYP2B6^＊6的野生型与突变型各项药动学参数差异均未见有统计学意义（P＞0.05）.结论 代谢酶CYP2B6等位基因^＊4突变与异维A酸体内代谢相关.CYP2B6^＊4突变型可能为异维A酸快代谢型人群.

Genetic polymorphisms of CYP2D6 in Chinese mainland

OBJECTIVE: To observe the significant differences in the frequencies of the cytochrome P450 2D6 (CYP2D6) alleles in Chinese popoulations. METHODS: Tetra-primer polymerase chain reaction (PCR), allele specific amplification (ASA) PCR and multiplex long PCR were developed to detect the CYP2D6 alleles * 2, * 3, * 4, * 5, * 6, * 8, * 10 and * 14 in 223 subjects from Chinese mainland. RESULTS: The CYP2D6 * 5 allele was the most frequent poor metabolizer (PM) allele in Chinese (7.2%), followed by CYP2D6 * 14 (2.0%) which was only detected in orientals. There was only 0.2% CYP2D6 * 4, and no CYP2D6 * 3, * 6 and * 8 were detected. In contrast to the Caucasians, the most frequent allele in Chinese was the * 10 allele with a frequency of 51.6%. CONCLUSION: The frequencies of PM alleles, CYP2D6 * 5 and CYP2D6 * 14, were higher; but the frequency of CYP2D6 * 10 was lower in mainland Chinese population than that in other orientals.

原发性高血压患者醛固酮合酶基因-344T/C多态性与心房颤动的相关性研究

目的探讨中国河南豫北地区原发性高血压人群醛固酮合酶（CYP11B2）基因-344T／C多态性与心房颤动（房颤）的关系。方法运用病例对照法，选择803例原发性高血压患者，运用PCR—RFLP技术对405例伴房颤者（房颤组）和398例窦性心律者（窦律组）的CYP11B2基因-344T／C多态性进行基因分型，并进行分析。结果2组T和C等位基因分布，差异无统计学意义（x2=1．32，P=0．25）；房颤组CC基因频率明显高于窦律组（x2=21．29，P〈0．05）。与携带TT或TC基因型者比较，携带CC基因型高血压患者患房颤的风险增加（OR=1．96，95％CI：1．23～2．67），携带CC基因型的高血压合并房颤患者左心房内径明显增高（P〈0．05）。结论CYP11B2基因-344T／C多态性与原发性高血压患者房颤的发生相关。

CYP2E1基因多态性与客家人群胃癌易感性的研究

目的：通过研究细胞色素P4502E1（CYP2E1）基因多态性位点rs2031920与客家人群胃癌遗传易感性的相关性，探讨遗传和环境因素在胃癌发病中的作用。方法采取病例-对照研究，选择经胃镜和病理检查确诊的梅州地区客家人群51例胃癌患者（胃癌组）和52例正常对照（对照组），对CYP2E1 rs2031920（C-1053T）位点进行基因型及等位基因检测，分析其在两组间的分布特征。结果CYP2E1 rs2031920位点在梅州地区客家人群中存在 CC、CT、TT 多态性，各基因型在胃癌组的分布频率为62．75％（32／51）、33．33％（17／51）、3．92％（2／51），在对照组的分布频率为59．62％（31／52）、34．61％（18／52）、5．77％（3／52），两组之间的差异无统计学意义（χ2＝0．235，P ＝0．889）。CYP2E1基因rs2031920位点的等位基因 C、T 在胃癌组和对照组构成比分别为79．41％（81／102）、20．59％（21／102）和76．92％（80／104）、23．08％（24／104），差异无统计学意义（χ2＝0．186，P ＝0．666）。经性别、年龄分层分析结果显示也无统计学意义（χ2＝4．412，P ＝0．129；χ2＝0．898，P ＝0．473）。结论 CYP2E1的基因多态性位点 rs2031920与客家人群胃癌的易感性不相关。

醛固酮合成酶基因-344C/T多态性与高血压左室肥厚相关性研究

目的观察醛固酮合成酶(CYP11B2)基因-344C/T多态性与高血压左室肥厚(LVH)的相关性。方法按心脏超声特点将314例原发性高血压患者分为左室肥厚[LVH(+)]组157例,无左室肥大[LVH(-)]组157例。使用常规方法提取白细胞DNA,采用多聚酶链式反应(PCR),限制性内切酶方法测定CYP11B2基因多态性。结果CYP11B2基因-344C/T多态性显示在LVH(+)组与LVH(-)组之间各基因型分布及等位基因频率显著不同,其中LVH(+)组TT基因型频率显著高于LVH(-)组(分别为0.66、0.51,P<0.01),而在CT基因型频率LVH(+)组显著低于LVH(-)组(分别为0.27、0.41,P<0.01);T等位基因频率LVH(+)组显著高于LVH(-)组(分别为0.79、0.72,P<0.05)。结论CYP11B2基因-344C/T多态性与高血压LVH密切相关,TT基因型频率和T等位基因频率可能是高血压LVH发生的机制之一。

大鼠肾小球系膜细胞合成分泌醛固酮并表达醛固酮受体研究

目的探讨培养的大鼠肾小球系膜细胞能够自身合成分泌醛固酮及存在醛固酮受体的可能性。方法应用反转录-聚合酶链反应(RT-PCR)法检测培养的大鼠肾小球系膜细胞表达醛固酮合成酶基因CYP11B2 mRNA及醛固酮受体mRNA;用放射免疫分析法测定肾小球系膜细胞培养上清中醛固酮的含量。结果大鼠肾小球系膜细胞表达醛固酮合成酶基因CYP11B2 mRNA及醛固酮受体mRNA,且细胞培养上清中能够检测到醛固酮。结论大鼠肾小球系膜细胞自身能够合成分泌醛固酮并存在醛固酮受体。

老年高血压患者血管紧张素转换酶和醛固酮合酶基因多态性与肾素血管紧张素醛固酮的关系

目的分析老年高血压晨峰患者血管紧张素转换酶(ACE)基因I/D、醛固酮合酶(CYP11B2)基因-344C/T多态性与肾素-血管紧张素-醛固酮系统(RAAS)的相关性。方法选择2016年2月~2017年12月云南省第一人民医院老年病科门诊及住院的老年原发性高血压患者200例,根据清晨血压水平分为晨峰增高组58例和非晨峰增高组142例。分析2组患者ACE基因I/D、CYP11B2基因-344C/T多态性和血浆RAAS参数的差异。结果 2组ACE基因型和等位基因频率比较,差异有统计学意义(χ^2=38.020,P=0.000;χ^2=42.040,P=0.000)。2组CYP11B2基因型和等位基因频率比较,差异无统计学意义(χ^2=0.261,P=0.878;χ^2=0.198,P=0.656)。晨峰增高组DD+TC、DD+TT基因型比例明显高于非晨峰增高组,差异有统计学意义(22.4%vs 3.5%,12.1%vs 2.1%,P<0.01);晨峰增高组II+TT、II+TC基因型比例明显低于非晨峰增高组,差异有统计学意义(13.8%vs 29.6%,P<0.05;5.2%vs 22.5%,P<0.01)。晨峰增高组血浆肾素、血管紧张素Ⅱ和醛固酮水平明显高于非晨峰增高组,差异有统计学意义(P<0.05,P<0.01)。logistic回归分析显示,DD+CC、DD+TC、DD+TT、肾素、血管紧张素Ⅱ为血压晨峰的重要影响因素(OR=8.084,95%CI:1.261~51.832,P=0.027;OR=14.459,95%CI:3.804~54.964,P=0.000;OR=9.753,95%CI:2.255~42.181,P=0.002;OR=1.816,95%CI:1.258~2.620,P=0.001;OR=0.634,95%CI:0.437~0.921,P=0.017)。结论 ACE基因DD型、肾素、血管紧张素Ⅱ是血压晨峰形成的主要影响因素。

Effect and safety of anaprazole in the treatment of duodenal ulcers:a randomized,rabeprazole-controlled,phase Ⅲ non-inferiority study

Background:The pharmacokinetic and clinical behaviors of many proton pump inhibitors(PPIs)in peptic ulcer treatment are altered by CYP2C19 genetic polymorphisms.This non-inferiority study evaluated the efficacy and safety of the novel PPI anaprazole compared with rabeprazole.We also explored the influence of Helicobacter pylori(H.pylori)infection status and CYP2C19 polymorphism on anaprazole.Methods:In this multicenter,randomized,double-blind,double-dummy,positive-drug parallel-controlled,phase Ⅲ study,Chinese patients with duodenal ulcers were randomized 1:1 to receive rabeprazole 10 mg+anaprazole placebo or rabeprazole placebo+anaprazole 20 mg once daily for 4 weeks.The primary efficacy endpoint was the 4-week ulcer healing rate assessed by blinded independent review.Secondary endpoints were the proportion of patients with improved overall and individual duodenal ulcer symptoms at 4 weeks.Furthermore,exploratory subgroup analysis of the primary endpoint by H.pylori status and CYP2C19 polymorphism was conducted.Adverse events were monitored for safety.Non-inferiority analysis was conducted for the primary endpoint.Results:The study enrolled 448 patients(anaprazole,n=225;rabeprazole,n=223).The 4-week healing rates were 90.9%and 93.7%for anaprazole and rabeprazole,respectively(difference,-2.8%[95%confidence interval,-7.7%,2.2%]),demonstrating non-inferiority of anaprazole to rabeprazole.Overall duodenal ulcer symptoms improved in 90.9%and 92.5%of patients,respectively.Improvement rates of individual symptoms were similar between the groups.Healing rates did not significantly differ by H.pylori status or CYP2C19 genotype for either treatment group.The incidence of treatment-emergent adverse events was similar for anaprazole(72/220,32.7%)and rabeprazole(84/219,38.4%).Conclusions:The efficacy of anaprazole is non-inferior to that of rabeprazole in Chinese patients with duodenal ulcers.Registration:ClinicalTrials.gov,NCT04215653.

醛固酮合成酶基因多态性与多囊卵巢综合征相关性的研究

目的 探讨醛固酮合成酶 (CYP11B2 )基因多态性与多囊卵巢综合征 (PCOS)发病的关系。方法 采用聚合酶链反应、限制性内切酶消化及电泳技术 ,对 92例PCOS患者和 60例正常妇女的CYP11B2基因 3 44T位点基因多态性进行检测 ,并测定基础状态下促卵泡激素、促黄体生成素、雌二醇、睾酮、孕酮、泌乳素、血肾素活性、血管紧张素Ⅱ及醛固酮水平 ,比较不同基因型PCOS患者及正常妇女的肾素、血管紧张素、醛固酮及雄激素水平差异。结果 ( 1)正常妇女、PCOS患者中 ,CYP11B2基因 3 44T位点C基因频率分别为 2 2 %和 3 6%。 ( 2 )PCOS患者T→C(TC、CC)出现率为 5 7% ,明显高于正常妇女的 3 7% (P <0 0 5 )。 ( 3 )PCOS患者CYP11B2基因型及基因频率的分布与正常妇女比较 ,差异有显著性 (P <0 0 5 ) ;CYP11B2基因 3 44TC、 3 44CC基因型的PCOS患者及正常妇女的肾素、血管紧张素、醛固酮及雄激素水平 ,均明显高于CYP11B2基因 3 44TT基因型者 (P <0 0 1)。结论 ( 1)CYP11B2基因 3 44T位点变异 (T→C)的出现 ,可能增大了患PCOS的风险 ,并与PCOS发病有关。 ( 2 )CYP11B2基因 3 44CC、 3 44TC基因型可能是PCOS的易患基因型 。

血管紧张素转换酶和醛固酮合成酶基因多态性与氢氯噻嗪降压疗效的关系

目的研究血管紧张素转换酶(ACE)基因I/D多态性和醛固酮合成酶(CYP11B2)基因-344T/C多态性与氢氯噻嗪降压疗效的关系。方法829例高血压病(EH)患者同时服用氢氯噻嗪12·5mg(1次/d),6周后资料完整的785例患者按不同ACE基因型和CYP11B2基因型分组,比较不同基因型和不同基因型组合间血压下降值有无差别。结果服用氢氯噻嗪6周后,ACE基因II、ID、DD型患者收缩压分别下降(5·1±14·8)mmHg(1mmHg=0·133kPa)、(4·8±16·3)mmHg和(9·4±15·7)mmHg,DD型患者下降值大于II、ID型患者,组间比较差异有统计学意义(P<0·00);CYP11B2基因TT、TC、CC型患者收缩压下降值分别为(5·8±16·2)mmHg、(5·5±14·9)mmHg和(7·6±16·1)mmHg,组间比较差异无统计学意义。DD+CC基因型患者收缩压下降值为(10·6±12·3)mmHg,高于其他基因型组合患者,但差异无统计学意义(P>0·05)。多因素分析结果表明DD基因型和治疗前醛固酮浓度是影响患者坐位收缩压下降的主要因素。结论ACE基因的DD型与氢氯噻嗪的降压疗效相关,CYP11B2基因CC型、DD+CC型患者对氢氯噻嗪的降压反应可能优于其他基因组合患者。

醛固酮合成酶基因多态性与小动脉顺应性的研究

目的探讨醛固酮合成酶(CYP11B2)基因-344C/T多态性与小动脉顺应性(C2)的关系及其临床意义.方法 (1) 用CVProfilor DO-2020动脉脉搏分析仪测量大小动脉顺应性,共224例,其中C2异常组123例,对照组101例.(2) 用多聚酶链反应-限制性片段长度多态性分析方法检测CYP11B2 基因-344C/T 多态性. 结果 (1) C2异常组TT基因型、T等位基因频率均高于对照组,但差异无统计学意义(55.3%比41.6 %,P>0.05, 75.6%比66.8%, P>0.05).(2) CC型与CT型合并分析,显示C2异常组TT型频率显著高于对照组(30.3%比18.8%,P<0.05).(3) 协方差分析显示,与CT/CC型比较,TT型者C2显著降低.(4) Logistic 回归分析表明,TT型是导致C2减退重要的基因型(P=0.043,OR=1.93 95%CI 1.02～3.63 ). 结论 CYP11B2基因-344C/T多态性与小动脉顺应性C2密切相关,TT型是C2减退的敏感基因型.