CYP11B2/B1基因多态性与醛固酮瘤临床表型及预后的相关研究
|
摘要
背景
原发性醛固酮增多症(简称原醛，Primarv Aldosteronism，PA)是最常见的内分泌高血压之一，两种常见临床亚型为醛固酮瘤(Aldosterone ProducingAdenoma，APA)和特发性醛固酮增多症(Idiopathic Hyperaldosteronism，IHA)。原醛主要的病理生理特点是过多醛固酮的自主分泌。APA多采用手术治疗；尽管大多数原醛患者术后血压恢复正常，但仍有33～44％术后持续性高血压。然而，目前过多醛固酮分泌的机制和术后血压恢复不均一的机制仍不清楚。影响高血压醛固酮代谢和血压调控的遗传因素是否与APA过多醛固酮分泌和术后持续高血压相关还仍不清楚。
CYP11B2基因编码合成醛固酮的醛固酮合酶；CYP11B1基因则编码合成皮质醇的11-β羟化酶，两基因位置相近，均位于染色体8q24。研究表明两基因座位上的许多DNA多态性位点处于完全连锁不平衡状态(Linkage Disequilibrium，LD)，且CYP11B2基因多态性位点(如rs1799998，intron2野生型／转位型和rs4539)与原发性高血压、11-β羟化酶活性降低、醛固酮分泌与代谢失调，心血管风险密切相关。上述研究提示CYP11B2／B1多态性位点可能与原醛临床表型及术后血压相关。在此假设基础上，本研究对6个DNA多态性位点，包括CYP11B2基因的rs1799998(C-344T)、intron2野生型／转位型、rs4539(A2718G)、rs6414和CYP11B1基因的rs6387(G225A)、rs6410(A2803G)进行基因分型和单体型分析，以判断它们对原醛中CYP11B2基因表达、临床表型的影响，并探讨它们在术后持续高血压中的作用。
方法
1．采用DNeasy Blood&Tissue试剂盒(Qiagen公司)提取93例随访到的APA患者的组织DNA；在公共SNP数据库(http：／／ncbi．nlm．nih．gov／SNP／和http：／／www．hapmap．org/)中选择CYP11B2和CYP11B1基因中频数≥0．05，且文献报道与醛固酮代谢和高血压相关的位点，包括CYP11B2基因的4个多态性位点：rs1799998、intron2野生型／转位型、rs4539和rs6416及CYP11B1基因的2个多态性位点：rs6410和rs6387。采用一对独立的PCR扩增intron2野生型／转位型位点，其余5个位点采用MGB-Taqman探针法进行基因分型。采用Haploview 4．0分析LD和Hardy-Weinberg平衡。
2．采用SYBR Green荧光定量RT-PCR法检测69例APA组织和20例正常肾上腺组织(取白手术的肾癌患者)中CYP11B2和CYP11B1基因的表达，2~(-△△C)T法计算APA组织中基因表达量相对正常肾上腺组织的变化。放射性免疫法检测血浆醛固酮的浓度(PAC)和血浆肾素活性(PRA)，并用Pearson相关分析它们与基因表达的关系。
3．在R statistics program 2．7．0程序包中使用SNPassoc 1．5-3和Haplo．stats 13．8分析CYP11B2和CYP11B1基因型及单体型与CYP11B2基因表达量和血浆醛固酮浓度、收缩压、舒张压等临床表型的关系。
4．在R statistics program 2．7．0程序包中使用SNPassoc 1．5-3和Haplo．stats 1．3．8分析CYP11B2和CYP11B1基因型及单体型与原醛术后血压恢复的相关性。
结果
1．检测了6个基因多态性位点，其中5个位点(包括CYP11B2基因的rs1799998、intron2野生型／转位型、rs4539和CYP11B1基因的rs6387、rs6410)在所有随访到的的APA患者中均获得成功检测，等位基因频数均＞0．2，基因型频数均＞0．01。所有位点基因型分布均符合Hardy-Weinberg平衡(对rs6387，rs6410，rs4539，intron2野生型／转位型，rs1799998：P分别为0．06，0．71，1．0，0．12，0．11)。配对的LD分析表明rs6387与rs6410和rs1799998存在着较强的LD(D′0．95，0．73)，rs4593和rs1799998及rs6410和intron 2野生型／转位型之间也有稍强的LD(D′0．52)。
2．在69例APA和20例正常肾上腺组织中均检测到CYP11B2 mRNA和CYP11B1mRNA的表达。相对正常肾上腺组织，APA组织中CYP11B2 mRNA表达明显上调，为正常肾上腺组织的3．58倍(p＜0．01)。且APA组织中CYP11B2 mRNA表达与血浆醛固酮水平有明显相关性(r=0．649，p＜0．01)，但与血浆肾素活性无关(r=-0．133，p=0．277)。APA组织CYP11B1 mRNA表达降低，是正常肾上腺组织的0．54倍，但两者差异无统计学意义(p=0．089)。APA组织中CYP11B1 mRNA表达与血浆肾素活性无相关性(r=-0．165，p=0．185)，与血浆醛固酮水平也无相关性(r=-0．08，p=0．946)。
3．单个位点分析中，未发现CYP11B2和CYP11B1基因的多态性位点包括rs1799998、intron2野生型／转位型、rs4539、rs410和rs6387与CYP11B2基因mRNA表达，血浆醛固酮浓度，术前收缩压、舒张压相关(p均＞0．05)。单体型分析中，GlobalScore统计显示：CYP11B2-CYP11B1单体型与CYP11B2mRNA表达量增加相关(global-stat=16．18，df=8，p=0．04)，与血浆醛固酮水平也相关(global-stat=20．41，df=8，P=0．009)；但与术前收缩压和舒张压不相关(分别P=0．34，P=0．54)。多元回归分析发现单体型H1和H3与CYP11B2基因mRNA的表达上调相关(经过Bonferroni校正后分别p=0．02；0．03)，H6、H10和H16与过多的醛固酮分泌相关(经过Bonferroni校正后分别p=0．015；0．003；p=0．049)；但未见有单体型与术前收缩压和舒张压相关(p均＞0．05)。
4．单个位点分析：上述五个位点包括rs1799998、intron2野生型／转位型、rs4539、rs410和rs6387中只有rs4539(AA)与术后持续性高血压相关(经过Bonferroni校正后p=0．01)。单体型分析中：Global Score统计显示CYP11B2-CYP11B1单体型与原醛术后血压恢复相关(Max-Stat sim．p=0．006)；多元回归分析中发现单体型H1和H3是预测术后持续性高血压的遗传性危险因子(经过Bonferroni校正后，分别p=0．02；0．03)。另外，传统因素包括高血压持续时间长，有高血压家族史和术前较高的收缩压是术后恢复不好的传统风险因素(经过Bonferroni校正后，分别p=0．002，=0．0015，＜0．00005)。
结论
1．对随访到的93位APA患者获得了较为完善的CYP11B2和CYP11B1基因多态性的遗传学资料，为后续证实CYP11B2／B1基因多态性和临床表型关系的研究提供了基础。
2．APA患者血浆醛固酮的过多分泌可能与CYP11B2基因的表达上调有关，而后者可能与APA组织中出现CYP11B1基因的表达相关。
3．尽管作用较弱，本研究显示APA患者CYP11B2和CYP11B1基因多态性可能通过上调CYP11B2的表达，导致血浆醛固酮水平的升高。
4．尽管作用较弱，本研究显示APA患者术后血压可能受到CYP11B2／CYP11B1基因多态性的影响。提示遗传因素在APA患者术后血压恢复不均一的机制中可能起一定的作用，单体型H1和H3可能成为预测术后持续性高血压的遗传指标。
Primary aldosteronism (PA) is the most common cause of endocrine hypertension.Two common subtypes of PA are idiopathic hyperaldosteronism (IHA) and aldosteroneproducing adenoma (APA).The main pathophysiological feature of PA is auto-secretion ofexcessive aldosterone.APA are always given surgically correction.Though most patientshad resolution of hypertension after adrenalectomy for PA,postoperative hypertensionoften persisted in a part of patients (account for 33～44%).However,the mechanisms ofauto-secretion of excessive aldosterone and heterogeneity of BP response to adrenalectomywere not clear nowadays.And,it was not clear whether the genetic variants that influencesteroid synthesis were also associated with auto-secretion of excessive aldosterone andpostoperative hypertension of patients with APA.
The terminal stages in the synthesis of steroid are catalyzed by the enzymesaldosterone synthase and 11β-hydroxylase respectively.CYP11B2 gene encodedaldosterone synthase and CYP11B1 gene encodes 11β-hydroxylase.The two genes areclosely adjacent on chromosome 8,band 8q24.The findings of studies demonstrate thatgenotypes at the CYP11B2-CYP11B1 locus are in strong linkage disequilibrium (LD).Thepolymorphisms of CYP11B2 gene such as rs1799998,intron2 wild/conversion and rs4539were suggested to associate with hypertension and cardiovascular disease risk.Thesesuggestion cued these genetic variations within CYP11B2/B1 might exert deleterious effect on clinical phenotype and postoperative resolution of hypertension for PA.On the basis ofthe above hypothesis,six DNA Polymorphisms at CYP11B2/CYP11B1 locus,includingrs1799998 (C-344T),intron2 wild/conversion (w/c),rs4539 (A2718G) and rs6414 ofCYP11B2 as well as rs6410 (G225A) and rs6387 (A2803G) of CYP11B1 were genotyedand analysed in the 93 follow-up patients with PA.The aim of this stduy was to investigatethe role of these polymorphisms/haplotype in CYP11B2 gene mRNA,clinical phenotype,and postoperative resolution of hypertension.
METHODS
1.DNA was extracted from tumorous tissue samples of 93 follow-up patients withAPA according to the manufacturer instructions with DNeasy Blood & Tissue Kit (Qiagen,Cat.No.69504,Germany).DNA polymorphisms at CYP11B2/CYP11B1 locus weresearched in public databases (http://ncbi.nlm.nih.gov/SNP/ and http://www.hapmap.org/).Selected potential loci had a minor allele frequency =0.05 based on data of Japanese andChinese population.In addition,previous studies produced the evidence of associationsbetween these variations and blood pressure regulation.Thus,above-mentioned six DNApolymorphisms including five single-nucleotide polymorphisms (SNPs) and intron2 w/cpolymorphism of CYP11B2 were included in the study.CYP11B2 intron 2 w/c wasgenotyped by two separate PCRs as described previously.And five SNPs were detected byTaqman SNP genotyping assays.Pairwise LD and Hardy-Weinberg equilibrium wasdetermined with Haploview 4.0.LD was estimated by D'.
2.The expressions of CYP11B1 and CYP11B2 gene were examined by SYBR Greenreal-time RT-PCR assay with 2~(-△△C)_T method in a series of adrenal tissues,including 69tumorous tissues of patients with APA and 20 normal adrenals from patientsadrenalectomized for renal cancer.PAC and PRA were measured by radioimmunoassaytechnique,and their associations with two above genes were analysed by Pearsoncorrelation.
3.The analysis of associations between polymorphisms at CYP11B1/CYP11B2 geneand clinical phenotypes or mRNA expression of CYP11B2 gene was performed withSNPassoc 1.5-3 for R statistics program 2.7.0.And the analysis of association betweenhaplotype and clinical phenotypes or mRNA expression was performed with Haplo.stats 1.3.8 for R statistics program 2.7.0.
4.The analysis of association between polymorphisms and postoperativehypertension was performed with SNPassoc 1.5-3 for R statistics program 2.7.0.And theanalysis of association between haplotype and postoperative hypertension was performedwith Haplo.stats 1.3.8 for R statistics program 2.7.0.
RESULTS
1.A total of 5 potentially genetic markers,including rs1799998,intron 2 w/c,andrs4539 within CYP11B2 and,rs6410 and rs6387 within CYP11B1 gene,were detected in93 follow-up patients with APA.It obtained full genotype data from 93 patients.The allelefrequencies (＞0.2) and Genotype frequencies (＞0.01) of the 5 genetic markers were seenhere.No marker exhibited a significant difference between Hardy-Weinberg equilibrium(for rs6387,rs6410,rs4539,intron2 w/c,rs1799998;P=0.06,0.71,1.0,0.12,0.11respectively).Pairwise LD was shown that rs6387 was in strong LD with rs6410 andrs1799998 (D' 0.95,0.73).Mild LD was also seen between rs4593 and rs1799998 (D' 0.50)as well as between rs6410 and intron 2 w/c (D' 0.52).
2.The expressions of CYP11B1 and CYP11B2 gene were detected in all the tissues.Compared with that in normal adrenal tissue,the mRNA expression of CYP11B2 gene inAPA tissue up-regulated significantly (as 3.58 times as that in normal adrenal tissue,p＜0.01).And this increase of mRNA expression in APA was correlated with PAC (r=0.649,p＜0.01),but not with PRA (r=-0.133,p-0.277).The expression of CYP11B1 in APA tissuedown-regulated in APA (as 0.54 times as that in normal adrenal tissue),but it had nosignificence in statistics (p=0.089).The decreased expression of CYP11B1 has nevercorrelation with PRA (r=-0.165,p= 0.185) or PAC (r=-0.08,p= 0.946).
3.In the analysis of single locus,none of the five polymorphisms includingrs1799998,intron2w/c,rs4539,rs6410 and rs6387 were correlated with mRNA expressionsof CYP11B2,clinical phenotype including PAC,SBP and DBP (allp＞0.05).In the analysisof haplotype,global score statistics indicated CYP11B2-CYP11B1 haplotype wasassociated with mRNA expression of CYP11B2 (global-stat=16.18,df=8,p=0.04) and PAC(global-stat = 20.41,df = 8,p= 0.009),but not with SBP and DBP(p=0.34,p=0.54).Inregression models of haplo.glm,it was found that haplotype H1 and H3 were associated with upregulated mRNA expression of CYP11B2 (p=0.02;0.03 respectively afterBonferroni correction),while H6,H10 and H16 associated with PAC (p=0.015;0.003,0.049 respectively after Bonferroni correction).However none haplotype was foundassociation with SBP or DBP (allp＞0.05).
4.In the analysis of single locus,we found only rs4539AA of the five polymorphismsincluding rs1799998,intron2 wild/conversion,rs4539,rs6410and rs6387 were correlatedwith postoperative hypertension of patients with APA (p=0.01 after Bonferroni correction).In the analysis of haplotype,global score statistics indicated CYP11B2-CYP11B1haplotype was associated with postoperative hypertension (Max-Stat sim.p=0.006).Inregression models of haplo.glm,it was found that haplotype H1 and H3 were geneticpredictors for postoperative persisting hypertension of APA (p=0.02,p=0.03 respectivelyafter Bonferroni correction).In addition,the traditional risk factors such as duration ofpreoperative hypertension,family history of hypertension and preoperative higher level ofSBP were also identified for postoperative persisting hypertension (p=0.002,0.0015,＜0.00005 respectively after Bonferroni correction).
CONCLUSIONS
1.The full genotype data from 93 patients with APA provided help and basis for thesubsequent association study between genetic variation and clinical phenotype.
2.Excessive secretion of PAC in APA patients may correlated with up-regulatedmRNA expression of CYP11B2,whose behavior was related with abnormal mRNAexpression of CYP11B1 in APA tissue.
3.DNA polymorphisms at CYP11B1/CYP11B2 gene might impact PAC throughupregulation of mRNA expression of CYP11B2 gene in APA.
4.Postoperative persisting hypertension of patients with APA might be influenced byDNA Polymorphisms at CYP11B2/CYP11B1 locus.Genetic effect might play a role inheterogeneity of BP response to adrenalectomy.And H1 and H3 might be genetic predictorsfor postoperative persisting hypertension of APA.
原发性醛固酮增多症(简称原醛，Primarv Aldosteronism，PA)是最常见的内分泌高血压之一，两种常见临床亚型为醛固酮瘤(Aldosterone ProducingAdenoma，APA)和特发性醛固酮增多症(Idiopathic Hyperaldosteronism，IHA)。原醛主要的病理生理特点是过多醛固酮的自主分泌。APA多采用手术治疗；尽管大多数原醛患者术后血压恢复正常，但仍有33～44％术后持续性高血压。然而，目前过多醛固酮分泌的机制和术后血压恢复不均一的机制仍不清楚。影响高血压醛固酮代谢和血压调控的遗传因素是否与APA过多醛固酮分泌和术后持续高血压相关还仍不清楚。
CYP11B2基因编码合成醛固酮的醛固酮合酶；CYP11B1基因则编码合成皮质醇的11-β羟化酶，两基因位置相近，均位于染色体8q24。研究表明两基因座位上的许多DNA多态性位点处于完全连锁不平衡状态(Linkage Disequilibrium，LD)，且CYP11B2基因多态性位点(如rs1799998，intron2野生型／转位型和rs4539)与原发性高血压、11-β羟化酶活性降低、醛固酮分泌与代谢失调，心血管风险密切相关。上述研究提示CYP11B2／B1多态性位点可能与原醛临床表型及术后血压相关。在此假设基础上，本研究对6个DNA多态性位点，包括CYP11B2基因的rs1799998(C-344T)、intron2野生型／转位型、rs4539(A2718G)、rs6414和CYP11B1基因的rs6387(G225A)、rs6410(A2803G)进行基因分型和单体型分析，以判断它们对原醛中CYP11B2基因表达、临床表型的影响，并探讨它们在术后持续高血压中的作用。
方法
1．采用DNeasy Blood&Tissue试剂盒(Qiagen公司)提取93例随访到的APA患者的组织DNA；在公共SNP数据库(http：／／ncbi．nlm．nih．gov／SNP／和http：／／www．hapmap．org/)中选择CYP11B2和CYP11B1基因中频数≥0．05，且文献报道与醛固酮代谢和高血压相关的位点，包括CYP11B2基因的4个多态性位点：rs1799998、intron2野生型／转位型、rs4539和rs6416及CYP11B1基因的2个多态性位点：rs6410和rs6387。采用一对独立的PCR扩增intron2野生型／转位型位点，其余5个位点采用MGB-Taqman探针法进行基因分型。采用Haploview 4．0分析LD和Hardy-Weinberg平衡。
2．采用SYBR Green荧光定量RT-PCR法检测69例APA组织和20例正常肾上腺组织(取白手术的肾癌患者)中CYP11B2和CYP11B1基因的表达，2~(-△△C)T法计算APA组织中基因表达量相对正常肾上腺组织的变化。放射性免疫法检测血浆醛固酮的浓度(PAC)和血浆肾素活性(PRA)，并用Pearson相关分析它们与基因表达的关系。
3．在R statistics program 2．7．0程序包中使用SNPassoc 1．5-3和Haplo．stats 13．8分析CYP11B2和CYP11B1基因型及单体型与CYP11B2基因表达量和血浆醛固酮浓度、收缩压、舒张压等临床表型的关系。
4．在R statistics program 2．7．0程序包中使用SNPassoc 1．5-3和Haplo．stats 1．3．8分析CYP11B2和CYP11B1基因型及单体型与原醛术后血压恢复的相关性。
结果
1．检测了6个基因多态性位点，其中5个位点(包括CYP11B2基因的rs1799998、intron2野生型／转位型、rs4539和CYP11B1基因的rs6387、rs6410)在所有随访到的的APA患者中均获得成功检测，等位基因频数均＞0．2，基因型频数均＞0．01。所有位点基因型分布均符合Hardy-Weinberg平衡(对rs6387，rs6410，rs4539，intron2野生型／转位型，rs1799998：P分别为0．06，0．71，1．0，0．12，0．11)。配对的LD分析表明rs6387与rs6410和rs1799998存在着较强的LD(D′0．95，0．73)，rs4593和rs1799998及rs6410和intron 2野生型／转位型之间也有稍强的LD(D′0．52)。
2．在69例APA和20例正常肾上腺组织中均检测到CYP11B2 mRNA和CYP11B1mRNA的表达。相对正常肾上腺组织，APA组织中CYP11B2 mRNA表达明显上调，为正常肾上腺组织的3．58倍(p＜0．01)。且APA组织中CYP11B2 mRNA表达与血浆醛固酮水平有明显相关性(r=0．649，p＜0．01)，但与血浆肾素活性无关(r=-0．133，p=0．277)。APA组织CYP11B1 mRNA表达降低，是正常肾上腺组织的0．54倍，但两者差异无统计学意义(p=0．089)。APA组织中CYP11B1 mRNA表达与血浆肾素活性无相关性(r=-0．165，p=0．185)，与血浆醛固酮水平也无相关性(r=-0．08，p=0．946)。
3．单个位点分析中，未发现CYP11B2和CYP11B1基因的多态性位点包括rs1799998、intron2野生型／转位型、rs4539、rs410和rs6387与CYP11B2基因mRNA表达，血浆醛固酮浓度，术前收缩压、舒张压相关(p均＞0．05)。单体型分析中，GlobalScore统计显示：CYP11B2-CYP11B1单体型与CYP11B2mRNA表达量增加相关(global-stat=16．18，df=8，p=0．04)，与血浆醛固酮水平也相关(global-stat=20．41，df=8，P=0．009)；但与术前收缩压和舒张压不相关(分别P=0．34，P=0．54)。多元回归分析发现单体型H1和H3与CYP11B2基因mRNA的表达上调相关(经过Bonferroni校正后分别p=0．02；0．03)，H6、H10和H16与过多的醛固酮分泌相关(经过Bonferroni校正后分别p=0．015；0．003；p=0．049)；但未见有单体型与术前收缩压和舒张压相关(p均＞0．05)。
4．单个位点分析：上述五个位点包括rs1799998、intron2野生型／转位型、rs4539、rs410和rs6387中只有rs4539(AA)与术后持续性高血压相关(经过Bonferroni校正后p=0．01)。单体型分析中：Global Score统计显示CYP11B2-CYP11B1单体型与原醛术后血压恢复相关(Max-Stat sim．p=0．006)；多元回归分析中发现单体型H1和H3是预测术后持续性高血压的遗传性危险因子(经过Bonferroni校正后，分别p=0．02；0．03)。另外，传统因素包括高血压持续时间长，有高血压家族史和术前较高的收缩压是术后恢复不好的传统风险因素(经过Bonferroni校正后，分别p=0．002，=0．0015，＜0．00005)。
结论
1．对随访到的93位APA患者获得了较为完善的CYP11B2和CYP11B1基因多态性的遗传学资料，为后续证实CYP11B2／B1基因多态性和临床表型关系的研究提供了基础。
2．APA患者血浆醛固酮的过多分泌可能与CYP11B2基因的表达上调有关，而后者可能与APA组织中出现CYP11B1基因的表达相关。
3．尽管作用较弱，本研究显示APA患者CYP11B2和CYP11B1基因多态性可能通过上调CYP11B2的表达，导致血浆醛固酮水平的升高。
4．尽管作用较弱，本研究显示APA患者术后血压可能受到CYP11B2／CYP11B1基因多态性的影响。提示遗传因素在APA患者术后血压恢复不均一的机制中可能起一定的作用，单体型H1和H3可能成为预测术后持续性高血压的遗传指标。
Primary aldosteronism (PA) is the most common cause of endocrine hypertension.Two common subtypes of PA are idiopathic hyperaldosteronism (IHA) and aldosteroneproducing adenoma (APA).The main pathophysiological feature of PA is auto-secretion ofexcessive aldosterone.APA are always given surgically correction.Though most patientshad resolution of hypertension after adrenalectomy for PA,postoperative hypertensionoften persisted in a part of patients (account for 33～44%).However,the mechanisms ofauto-secretion of excessive aldosterone and heterogeneity of BP response to adrenalectomywere not clear nowadays.And,it was not clear whether the genetic variants that influencesteroid synthesis were also associated with auto-secretion of excessive aldosterone andpostoperative hypertension of patients with APA.
The terminal stages in the synthesis of steroid are catalyzed by the enzymesaldosterone synthase and 11β-hydroxylase respectively.CYP11B2 gene encodedaldosterone synthase and CYP11B1 gene encodes 11β-hydroxylase.The two genes areclosely adjacent on chromosome 8,band 8q24.The findings of studies demonstrate thatgenotypes at the CYP11B2-CYP11B1 locus are in strong linkage disequilibrium (LD).Thepolymorphisms of CYP11B2 gene such as rs1799998,intron2 wild/conversion and rs4539were suggested to associate with hypertension and cardiovascular disease risk.Thesesuggestion cued these genetic variations within CYP11B2/B1 might exert deleterious effect on clinical phenotype and postoperative resolution of hypertension for PA.On the basis ofthe above hypothesis,six DNA Polymorphisms at CYP11B2/CYP11B1 locus,includingrs1799998 (C-344T),intron2 wild/conversion (w/c),rs4539 (A2718G) and rs6414 ofCYP11B2 as well as rs6410 (G225A) and rs6387 (A2803G) of CYP11B1 were genotyedand analysed in the 93 follow-up patients with PA.The aim of this stduy was to investigatethe role of these polymorphisms/haplotype in CYP11B2 gene mRNA,clinical phenotype,and postoperative resolution of hypertension.
METHODS
1.DNA was extracted from tumorous tissue samples of 93 follow-up patients withAPA according to the manufacturer instructions with DNeasy Blood & Tissue Kit (Qiagen,Cat.No.69504,Germany).DNA polymorphisms at CYP11B2/CYP11B1 locus weresearched in public databases (http://ncbi.nlm.nih.gov/SNP/ and http://www.hapmap.org/).Selected potential loci had a minor allele frequency =0.05 based on data of Japanese andChinese population.In addition,previous studies produced the evidence of associationsbetween these variations and blood pressure regulation.Thus,above-mentioned six DNApolymorphisms including five single-nucleotide polymorphisms (SNPs) and intron2 w/cpolymorphism of CYP11B2 were included in the study.CYP11B2 intron 2 w/c wasgenotyped by two separate PCRs as described previously.And five SNPs were detected byTaqman SNP genotyping assays.Pairwise LD and Hardy-Weinberg equilibrium wasdetermined with Haploview 4.0.LD was estimated by D'.
2.The expressions of CYP11B1 and CYP11B2 gene were examined by SYBR Greenreal-time RT-PCR assay with 2~(-△△C)_T method in a series of adrenal tissues,including 69tumorous tissues of patients with APA and 20 normal adrenals from patientsadrenalectomized for renal cancer.PAC and PRA were measured by radioimmunoassaytechnique,and their associations with two above genes were analysed by Pearsoncorrelation.
3.The analysis of associations between polymorphisms at CYP11B1/CYP11B2 geneand clinical phenotypes or mRNA expression of CYP11B2 gene was performed withSNPassoc 1.5-3 for R statistics program 2.7.0.And the analysis of association betweenhaplotype and clinical phenotypes or mRNA expression was performed with Haplo.stats 1.3.8 for R statistics program 2.7.0.
4.The analysis of association between polymorphisms and postoperativehypertension was performed with SNPassoc 1.5-3 for R statistics program 2.7.0.And theanalysis of association between haplotype and postoperative hypertension was performedwith Haplo.stats 1.3.8 for R statistics program 2.7.0.
RESULTS
1.A total of 5 potentially genetic markers,including rs1799998,intron 2 w/c,andrs4539 within CYP11B2 and,rs6410 and rs6387 within CYP11B1 gene,were detected in93 follow-up patients with APA.It obtained full genotype data from 93 patients.The allelefrequencies (＞0.2) and Genotype frequencies (＞0.01) of the 5 genetic markers were seenhere.No marker exhibited a significant difference between Hardy-Weinberg equilibrium(for rs6387,rs6410,rs4539,intron2 w/c,rs1799998;P=0.06,0.71,1.0,0.12,0.11respectively).Pairwise LD was shown that rs6387 was in strong LD with rs6410 andrs1799998 (D' 0.95,0.73).Mild LD was also seen between rs4593 and rs1799998 (D' 0.50)as well as between rs6410 and intron 2 w/c (D' 0.52).
2.The expressions of CYP11B1 and CYP11B2 gene were detected in all the tissues.Compared with that in normal adrenal tissue,the mRNA expression of CYP11B2 gene inAPA tissue up-regulated significantly (as 3.58 times as that in normal adrenal tissue,p＜0.01).And this increase of mRNA expression in APA was correlated with PAC (r=0.649,p＜0.01),but not with PRA (r=-0.133,p-0.277).The expression of CYP11B1 in APA tissuedown-regulated in APA (as 0.54 times as that in normal adrenal tissue),but it had nosignificence in statistics (p=0.089).The decreased expression of CYP11B1 has nevercorrelation with PRA (r=-0.165,p= 0.185) or PAC (r=-0.08,p= 0.946).
3.In the analysis of single locus,none of the five polymorphisms includingrs1799998,intron2w/c,rs4539,rs6410 and rs6387 were correlated with mRNA expressionsof CYP11B2,clinical phenotype including PAC,SBP and DBP (allp＞0.05).In the analysisof haplotype,global score statistics indicated CYP11B2-CYP11B1 haplotype wasassociated with mRNA expression of CYP11B2 (global-stat=16.18,df=8,p=0.04) and PAC(global-stat = 20.41,df = 8,p= 0.009),but not with SBP and DBP(p=0.34,p=0.54).Inregression models of haplo.glm,it was found that haplotype H1 and H3 were associated with upregulated mRNA expression of CYP11B2 (p=0.02;0.03 respectively afterBonferroni correction),while H6,H10 and H16 associated with PAC (p=0.015;0.003,0.049 respectively after Bonferroni correction).However none haplotype was foundassociation with SBP or DBP (allp＞0.05).
4.In the analysis of single locus,we found only rs4539AA of the five polymorphismsincluding rs1799998,intron2 wild/conversion,rs4539,rs6410and rs6387 were correlatedwith postoperative hypertension of patients with APA (p=0.01 after Bonferroni correction).In the analysis of haplotype,global score statistics indicated CYP11B2-CYP11B1haplotype was associated with postoperative hypertension (Max-Stat sim.p=0.006).Inregression models of haplo.glm,it was found that haplotype H1 and H3 were geneticpredictors for postoperative persisting hypertension of APA (p=0.02,p=0.03 respectivelyafter Bonferroni correction).In addition,the traditional risk factors such as duration ofpreoperative hypertension,family history of hypertension and preoperative higher level ofSBP were also identified for postoperative persisting hypertension (p=0.002,0.0015,＜0.00005 respectively after Bonferroni correction).
CONCLUSIONS
1.The full genotype data from 93 patients with APA provided help and basis for thesubsequent association study between genetic variation and clinical phenotype.
2.Excessive secretion of PAC in APA patients may correlated with up-regulatedmRNA expression of CYP11B2,whose behavior was related with abnormal mRNAexpression of CYP11B1 in APA tissue.
3.DNA polymorphisms at CYP11B1/CYP11B2 gene might impact PAC throughupregulation of mRNA expression of CYP11B2 gene in APA.
4.Postoperative persisting hypertension of patients with APA might be influenced byDNA Polymorphisms at CYP11B2/CYP11B1 locus.Genetic effect might play a role inheterogeneity of BP response to adrenalectomy.And H1 and H3 might be genetic predictorsfor postoperative persisting hypertension of APA.
引文
[1] CONN JW. Presidential address. Ⅰ. Painting background. Ⅱ. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med, 1955,45:3-17.
[2] Conn JW. Part Ⅰ. Painting background. Part Ⅱ. Primary aldosteronism, a new clinical syndrome, 1954. J Lab Clin Med, 1990,116:253-67.
[3] Ganguly A. Primary aldosteronism. N Engl J Med, 1998,339:1828-34.
[4] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[5] Mosso L, Carvajal C, Gonzalez A, et al. Primary aldosteronism and hypertensive disease. Hypertension, 2003,42:161-5.
[6] Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab, 2000,85:2854-9.
[7] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[8] Mulatero P, Dluhy RG, Giacchetti G, et al. Diagnosis of primary aldosteronism: from screening to subtype differentiation. Trends Endocrinol Metab, 2005,16:114-9.
[9] Plouin PF, Amar L, Chatellier G Trends in the prevalence of primary aldosteronism,aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant, 2004,19:774-7.
[10] Suzuki J, Otsuka F, Inagaki K, et al. Primary aldosteronism caused by a unilateral adrenal adenoma accompanied by autonomous cortisol secretion. Hypertens Res,2007,30:367-73.
[11] Omura M, Saito T, Sasano H, et al. [Primary aldosteronism due to unilateral adrenal hyperplasia]. Nippon Rinsho, 2006,Suppl 1:635-7.
[12] Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med, 2001,135:258-61.
[13] Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg, 2005,29:155-9.
[14] Celen O, O'Brien MJ, Melby JC, et al. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg, 1996,131:646-50.
[15] Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas: multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg, 2005,71:864-9.
[16] Harris DA, Au-Yong I, Basnyat PS, et al. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. Eur J Surg Oncol, 2003,29:467-74.
[17] Rossi GP, Bolognesi M, Rizzoni D, et al. Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients.Hypertension, 2008,51:1366-71.
[18] Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism,including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab, 2004,89:1045-50.
[19] Mattsson C, Young WF Jr. Primary aldosteronism: diagnostic and treatment strategies.Nat Clin Pract Nephrol, 2006,2:198-208; quiz, 1 p following 230.
[20] Inglis GC, Plouin PF, Friel EC, et al. Polymorphic differences from normal in the aldosterone synthase gene (CYP11B2) in patients with primary hyperaldosteronism and adrenal tumour (Conn's syndrome). Clin Endocrinol (Oxf), 2001,54:725-30.
[21] Mulatero P, Schiavone D, Fallo F, et al. CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism. Hypertension, 2000,35:694-8.
[22] Tanahashi H, Mune T, Takahashi Y, et al. Association of Lysl73Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab, 2005,90:6226-31.
[23] Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension. Hypertension, 2003,41:993-9.
[24] Kloppenborg PW, Drayer JI, Van Haelst AJ, et al. Primary aldosteronism, idiopathic aldosteronism and "low-renin" benign essential hypertension. A retrospective study.Neth J Med, 1974,17:239-47.
[25] Gordon RD, Jackson RV. Idiopathic aldosteronism: diagnostic artifact. Lancet, 1980,1:1422.
[26] Giacchetti G, Mulatero P, Mantero F, et al. Primary aldosteronism, a major form of low renin hypertension: from screening to diagnosis. Trends Endocrinol Metab,2008,19:104-8.
[27] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[28] Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[29] Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab,2005,90:1220-5.
[30] Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the llbeta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[31] Mulatero P, Morello F, Veglio F. Genetics of primary aldosteronism. J Hypertens,2004,22:663-70.
[32] Higaki J, Miya A, Miki T, et al. Contribution of the activation of the ras oncogene to the evolution of aldosterone- and renin-secreting tumors. J Hypertens, 1991,9:135-7.
[33] Gordon RD. Primary aldosteronism: a new understanding. Clin Exp Hypertens,1997,19:857-70.
[34] Zwermann O, Beuschlein F, Mora P, et al. Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol,2000,142:689-95.
[35] Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors.J Clin Endocrinol Metab, 1998,83:2585-8.
[36]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001,25:402-8.
[1] Conn JW. Part Ⅰ. Painting background. Part Ⅱ. Primary aldosteronism, a new clinical syndrome, 1954. J Lab Clin Med, 1990,116:253-67.
[2] Ganguly A. Primary aldosteronism. N Engl J Med, 1998,339:1828-34.
[3] Gordon RD, Klemm SA, Tunny TJ, et al. Genetics of primary aldosteronism. Clin Exp Pharmacol Physiol, 1994,21:915-8.
[4] Mulatero P, Morello F, Veglio F. Genetics of primary aldosteronism. J Hypertens,2004,22:663-70.
[5] Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature, 1992,355:262-5.
[6] Lafferty AR, Torpy DJ, Stowasser M, et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J Med Genet, 2000,37:831-5.
[7] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[8] Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[9] Curnow KM, Mulatero P, Emeric-Blanchouin N, et al. The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme. Nat Struct Biol, 1997,4:32-5.
[10]Higaki J, Miya A, Miki T, et al. Contribution of the activation of the ras oncogene to the evolution of aldosterone- and renin-secreting tumors. J Hypertens, 1991,9:135-7.
[11] Gordon RD. Primary aldosteronism: a new understanding. Clin Exp Hypertens,1997,19:857-70.
[12] Zwermann O, Beuschlein F, Mora P, et al. Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol, 2000,142:689-95.
[13] Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors. J Clin Endocrinol Metab, 1998,83:2585-8.
[14]Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab,2005,90:1220-5.
[15]Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the llbeta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[16] Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone.J Am Soc Nephrol, 2004,15:1993-2001.
[17] Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension. Hypertension, 2003,41:993-9.
[18]Lim PO, Macdonald TM, Holloway C, et al. Variation at the aldosterone synthase(CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio. J Clin Endocrinol Metab, 2002,87:4398-402.
[19]White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med,1994,331:250-8.
[20]Inglis GC, Plouin PF, Friel EC, et al. Polymorphic differences from normal in the aldosterone synthase gene (CYP11B2) in patients with primary hyperaldosteronism and adrenal tumour (Conn's syndrome). Clin Endocrinol (Oxf), 2001,54:725-30.
[21]Mulatero P, Schiavone D, Fallo F, et al. CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism. Hypertension, 2000,35:694-8.
[22]Tanahashi H, Mune T, Takahashi Y, et al. Association of Lysl73Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab, 2005,90:6226-31.
[23]Tsukada K, Ishimitsu T, Teranishi M, et al. Positive association of CYP11B2 gene polymorphism with genetic predisposition to essential hypertension. J Hum Hypertens,2002,16:789-93.
[24]Nicod J, Bruhin D, Auer L, et al. A biallelic gene polymorphism of CYP11B2 predicts increased aldosterone to renin ratio in selected hypertensive patients. J Clin Endocrinol Metab, 2003, 88:2495-2500.
[1] Conn JW. Part Ⅰ. Painting background. Part Ⅱ. Primary aldosteronism, a new clinical syndrome, 1954. J Lab Clin Med, 1990,116:253-67.
[2] CONN JW. Presidential address. Ⅰ. Painting background.Ⅱ. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med, 1955,45:3-17.
[3] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[4] Mosso L, Carvajal C, Gonzalez A, et al. Primary aldosteronism and hypertensive disease. Hypertension, 2003,42:161-5.
[5] Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab, 2000,85:2854-9.
[6] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[7] Mulatero P, Dluhy RG, Giacchetti G, et al. Diagnosis of primary aldosteronism: from screening to subtype differentiation. Trends Endocrinol Metab, 2005,16:114-9.
[8] Plouin PF, Amar L, Chatellier G Trends in the prevalence of primary aldosteronism,aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant, 2004,19:774-7.
[9] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[10]Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[11]Curnow KM, Tusie-Luna MT, Pascoe L, et al. The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. Mol Endocrinol,1991,5:1513-22.
[12]Sasano H, Okamoto M, Sasano N. Immunohistochemical study of cytochrome P-450 11 beta-hydroxylase in human adrenal cortex with mineralo-and glucocorticoid excess. Virchows Arch A Pathol Anat Histopathol, 1988,413:313-8.
[13]Takasaki H, Miyamori I, Nagai K, et al. Mitochondrial P-450 activities in aldosteronoma tissues. J Steroid Biochem Mol Biol, 1991,38:533-5.
[14]Ogishima T, Shibata H, Shimada H, et al. Aldosterone synthase cytochrome P-450 expressed in the adrenals of patients with primary aldosteronism. J Biol Chem,1991,266:10731-4.
[15] Suzuki H, Shibata H, Maruyama T, et al. Significance of steroidogenic enzymes in the pathogenesis of hyperfunctioning and non-hyperfunctioning adrenal tumor. Steroids,1995,60:42-7.
[16]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001,25:402-8.
[17]Fallo F, Pezzi V, Barzon L, et al. Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas. Eur J Endocrinol, 2002,147:795-802.
[18]Tanahashi H, Mune T, Takahashi Y, et al. Association of Lysl73Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab, 2005,90:6226-31.
[19]Cover CM, Wang JM, St LE, et al. Molecular variants in the P450c11AS gene as determinants of aldosterone synthase activity in the Dahl rat model of hypertension. J Biol Chem, 1995,270:16555-60.
[20]Fardella CE, Rodriguez H, Hum DW, et al. Artificial mutations in P450c11AS(aldosterone synthase) can increase enzymatic activity: a model for low-renin hypertension. J Clin Endocrinol Metab, 1995,80:1040-3.
[21]Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[22]Mulatero P, Glorioso N, Fallo F, et al. Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production. Eur J Endocrinol, 2001,144:397-400.
[23]Nicod J, Dick B, Frey FJ, et al. Mutation analysis of CYP11B1 and CYP11B2 in patients with increased 18-hydroxycortisol production. Mol Cell Endocrinol, 2004,214:167-74.
[24] Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension. Hypertension, 2003,41:993-9.
[25]Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone.J Am Soc Nephrol, 2004,15:1993-2001.
[26]Kem DC, Gomez-Sanchez C, Kramer NJ, et al. Plasma aldosterone and renin activity response to ACTH infusion in dexamethasone-suppressed normal and sodium-depleted man. J Clin Endocrinol Metab, 1975,40:116-24.
[27]Lehoux JG, Fleury A, Ducharme L. The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. Endocrinology, 1998,139:3913-22.
[28]Erdmann B, Gerst H, Bulow H, et al. Zone-specific localization of cytochrome P45011B1 in human adrenal tissue by PCR-derived riboprobes. Histochem Cell Biol,1995,104:301-7.
[29]Denner K, Doehmer J, Bernhardt R. Cloning of CYP11B1 and CYP11B2 from normal human adrenal and their functional expression in COS-7 and V79 Chinese hamster cells. Endocr Res, 1995,21:443-8.
[30]Zhou M, Xue D, Foecking MF, et al. Stable expression of rat cytochrome P450 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) in MA-10 cells. J Steroid Biochem Mol Biol, 1995,52:523-8.
[1] Curnow KM, Tusie-Luna MT, Pascoe L, et al. The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. Mol Endocrinol,1991,5:1513-22.
[2] Kawamoto T, Mitsuuchi Y, Toda K, et al. Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans. Proc Natl Acad Sci USA, 1992,89:1458-62.
[3] Kojima I, Ogata E, Inano H, et al. Oxygenation of 18-hydroxycorticosterone as the final reaction for aldosterone biosynthesis. Acta Endocrinol (Copenh),1984,107:395-400.
[4] Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[5] Cover CM, Wang JM, St LE, et al. Molecular variants in the P450cllAS gene as determinants of aldosterone synthase activity in the Dahl rat model of hypertension. J Biol Chem, 1995,270:16555-60.
[6] Fardella CE, Rodriguez H, Hum DW, et al. Artificial mutations in P450c11AS(aldosterone synthase) can increase enzymatic activity: a model for low-renin hypertension. J Clin Endocrinol Metab, 1995,80:1040-3.
[7] Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[8] Mulatero P, Glorioso N, Fallo F, et al. Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production. Eur J Endocrinol, 2001,144:397-400.
[9] Nicod J, Dick B, Frey FJ, et al. Mutation analysis of CYP11B1 and CYP11B2 in patients with increased 18-hydroxycortisol production. Mol Cell Endocrinol,2004,214:167-74.
[10] Higaki J, Miya A, Miki T, et al. Contribution of the activation of the ras oncogene to the evolution of aldosterone-and renin-secreting tumors. J Hypertens, 1991,9:135-7.
[11] Gordon RD. Primary aldosteronism: a new understanding. Clin Exp Hypertens, 1997,19:857-70.
[12]Zwermann O, Beuschlein F, Mora P, et al. Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol,2000,142:689-95.
[13] Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors.J Clin Endocrinol Metab, 1998,83:2585-8.
[14]Fallo F, Pezzi V, Barzon L, et al. Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas. Eur J Endocrinol, 2002,147:795-802.
[15]Miyamori I, Inaba S, Hatakeyama H, et al. Idiopathic hyperaldosteronism: analysis of aldosterone synthase gene. Biomed Pharmacother, 2000,54 Suppl l:77s-79s.
[16]Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[17]Mulatero P, Morello F, Veglio F. Genetics of primary aldosteronism. J Hypertens,2004,22:663-70.
[18] Gordon RD, Klemm SA, Tunny TJ, et al. Genetics of primary aldosteronism. Clin Exp Pharmacol Physiol, 1994,21:915-8.
[19]Pilon C, Mulatero P, Barzon L, et al. Mutations in CYP11B1 gene converting 11beta-hydroxylase into an aldosterone-producing enzyme are not present in aldosterone-producing adenomas. J Clin Endocrinol Metab, 1999,84:4228-31.
[20]Davies E, Holloway CD, Ingram MC, et al. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension, 1999,33:703-7.
[21]Staessen JA, Wang JG, Brand E, et al. Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population. J Hypertens, 2001,19:1349-58.
[22]Hautanena A, Lankinen L, Kupari M, et al. Associations between aldosterone synthase gene polymorphism and the adrenocortical function in males. J Intern Med,1998,244:11-8.
[23]Bassett MH, Zhang Y, Clyne C, et al. Differential regulation of aldosterone synthase and 11beta-hydroxylase transcription by steroidogenic factor-1. J Mol Endocrinol,2002,28:125-35.
[24]Nicod J, Bruhin D, Auer L, et al. A biallelic gene polymorphism of CYP11B2 predicts increased aldosterone to renin ratio in selected hypertensive patients. J Clin Endocrinol Metab, 2003,88:2495-500.
[25] Portrat-Doyen S, Tourniaire J, Richard O, et al. Isolated aldosterone synthase deficiency caused by simultaneous E198D and V386A mutations in the CYP11B2 gene.J Clin Endocrinol Metab, 1998,83:4156-61.
[26]Tanahashi H, Mune T, Takahashi Y, et al. Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab, 2005,90:6226-31.
[27]Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the 11beta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[28]Keavney B, Mayosi B, Gaukrodger N, et al. Genetic variation at the locus encompassing 11-beta hydroxylase and aldosterone synthase accounts for heritability in cortisol precursor (11-deoxycortisol) urinary metabolite excretion. J Clin Endocrinol Metab, 2005,90:1072-7.
[29]Barr M, MacKenzie SM, Friel EC, et al. Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency.Hypertension, 2007,49:113-9.
[30]Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab,2005,90:1220-5.
[31]Kem DC, Gomez-Sanchez C, Kramer NJ, et al. Plasma aldosterone and renin activity response to ACTH infusion in dexamethasone-suppressed normal and sodium-depleted man. J Clin Endocrinol Metab, 1975,40:116-24.
[32]Lehoux JG, Fleury A, Ducharme L. The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. Endocrinology, 1998,139:3913-22.
[33]Tamaki S, Iwai N, Tsujita Y, et al. Genetic polymorphism of CYP11B2 gene and hypertension in Japanese. Hypertension, 1999,33:266-70.
[34]Matsubara M, Sato T, Nishimura T, et al. CYP11B2 polymorphisms and home blood pressure in a population-based cohort in Japanese: the Ohasama study. Hypertens Res,2004,27:1-6.
[35]Davies E, Holloway CD, Ingram MC, et al. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension, 1999,33:703-7.
[36] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[37] Staessen JA, Wang JG, Brand E, et al. Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population. J Hypertens, 2001,19:1349-58.
[38]Russo P, Siani A, Venezia A, et al. Interaction between the C(-344)T polymorphism of CYP11B2 and age in the regulation of blood pressure and plasma aldosterone levels:cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study. J Hypertens, 2002,20:1785-92.
[39]Barbato A, Russo P, Siani A, et al. Aldosterone synthase gene (CYP11B2) C-344T polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population. J Hypertens, 2004,22:1895-901.
[40]Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone.J Am Soc Nephrol, 2004,15:1993-2001.
[41] Mulatero P, Williams TA, Milan A, et al. Blood pressure in patients with primary aldosteronism is influenced by bradykinin B(2) receptor and alpha-adducin gene polymorphisms. J Clin Endocrinol Metab, 2002,87:3337-43.
[1] Mosso L, Carvajal C, Gonzalez A, et al. Primary aldosteronism and hypertensive disease. Hypertension, 2003,42:161-5.
[2] Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab, 2000,85:2854-9.
[3] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[4] Suzuki J, Otsuka F, Inagaki K, et al. Primary aldosteronism caused by a unilateral adrenal adenoma accompanied by autonomous cortisol secretion. Hypertens Res,2007,30:367-73.
[5] Omura M, Saito T, Sasano H, et al. [Primary aldosteronism due to unilateral adrenal hyperplasia]. Nippon Rinsho, 2006,Suppl 1:635-7.
[6] Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med, 2001,135:258-61.
[7] Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg, 2005,29:155-9.
[8] Celen O, O'Brien MJ, Melby JC, et al. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg, 1996,131:646-50.
[9] Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas: multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg, 2005,71:864-9.
[10] Harris DA, Au-Yong I, Basnyat PS, et al. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. Eur J Surg Oncol, 2003,29:467-74.
[11] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[12]Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[13]Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab,2005,90:1220-5.
[14]Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the 11 beta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[15]Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension. Hypertension, 2003,41:993-9.
[16]Kloppenborg PW, Drayer JI, Van Haelst AJ, et al. Primary aldosteronism, idiopathic aldosteronism and "low-renin" benign essential hypertension. A retrospective study.Neth J Med, 1974,17:239-47.
[17] Gordon RD, Jackson RV. Idiopathic aldosteronism: diagnostic artifact. Lancet,1980,1:1422.
[18]Balkestein EJ, Wang JG, Struijker-Boudier HA, et al. Carotid and femoral intima-media thickness in relation to three candidate genes in a Caucasian population. J Hypertens,2002,20:1551-61.
[19]Kupari M, Hautanen A, Lankinen L, et al. Associations between human aldosterone synthase (CYP11B2) gene polymorphisms and left ventricular size, mass, and function.Circulation, 1998,97:569-75.
[20] Schaid DJ, Rowland CM, Tines DE, et al. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet, 2002,70:425-34.
[21] Lake SL, Lyon H, Tantisira K, et al. Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered, 2003,55:56-65.
[22]Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the llbeta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[23]Mulatero P, Williams TA, Milan A, et al. Blood pressure in patients with primary aldosteronism is influenced by bradykinin B(2) receptor and alpha-adducin gene polymorphisms. J Clin Endocrinol Metab, 2002,87:3337-43.
[24]Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab, 2005,90:1220-5.
[25] Rossi GP, Bolognesi M, Rizzoni D, et al. Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients.Hypertension, 2008,51:1366-71.
[26] Connell JM, Fraser R, MacKenzie SM, et al. The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation. Mol Cell Endocrinol, 2004,217:243-7.
[1] Conn JW. Part I. Painting background. Part II. Primary aldosteronism, a new clinical syndrome, 1954. J Lab Clin Med 1990,116:253-267.
[2] CONN JW. Presidential address. Ⅰ. Painting background. Ⅱ. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med, 1955,45:3-17.
[3] Ganguly A. Primary aldosteronism. N Engl J Med, 1998,339:1828-34.
[4] Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism,including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab, 2004,89:1045-50.
[5] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[6] Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab, 2000,85:2854-9.
[7] Mosso L, Carvajal C, Gonzalez A, et al. Primary aldosteronism and hypertensive disease. Hypertension, 2003,42:161-5.
[8] Kaplan NM. Cautions over the current epidemic of primary aldosteronism. Lancet 2000; 357:953-954.
[9] Jeschke K, Janetschek G, Peschel R, et al. Laparoscopic partial adrenalectomy in patients with aldosteroneproducing adenomas: indications, technique, and results.Urology 2003, 61:69-72.
[10] Lim PO, Young WF, MacDonald TM. A review of the medical treatment of primary aldosteronism. J Hypertens 2001,19:353-361.
[11] Curnow KM, Tusie-Luna MT, Pascoe L, et al. The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. Mol Endocrinol 1991; 5:1513-1522.
[12] Kawamoto T, Mitsuuchi Y, Toda K, et al. Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans. Proc Natl Acad Sci USA 1992, 89:1458-1462.
[13] Kojima I, Ogata E, Inano H, et al. Oxygenation of 18-hydroxycorticosterone as the final reaction for aldosterone biosynthesis. Acta Endocrinol 1984, 107:395-400.
[14] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension 1998, 32:198-204.
[15] Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab 1998, 83:1033-1036.
[16] Cover CM, Wang JM, St LE, et al. Molecular variants in the P450c11AS gene as determinants of aldosterone synthase activity in the Dahl rat model of hypertension. J Biol Chem, 1995,270:16555-60.
[17] Fardella CE, Rodriguez H, Hum DW, et al. Artificial mutations in P450c11AS(aldosterone synthase) can increase enzymatic activity: a model for low-renin hypertension. J Clin Endocrinol Metab, 1995,80:1040-3.
[18] Curnow KM, Mulatero P, Emeric-Blanchouin N, et al. The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme. Nature Struct Biol 1997, 4:32-35.
[19] Ulick S, Chu MD. Hypersecretion of a new corticosteroid, 18-hydroxycortisol in two types of adrenocortical hypertension. Clin Exp Hypertens 1982, A4:1771-1777.
[20] Shibata H, Ogishima T, Mitani F, et al. Regulation of aldosterone synthase cytochrome P-450 in rat adrenals by angiotensin Ⅱand potassium. Endocrinology 1991,128:2534-2539.
[21] Lehoux JG, Fleury A, Ducharme L. The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. Endocrinology 1998, 139:3913-3922.
[22] Takeda Y, Yoneda T, Demura M, et al. Sodium-induced cardiac aldosterone synthesis causes cardiac hypertrophy. Endocrinology 2000, 141:1901-1904.
[23] Fisher A, Fraser R, Me Connell J, et al. Amino acid residue 147 of human aldosterone synthase and llbeta-hydroxylase plays a key role in llbeta-hydroxylation. J Clin Endocrinol Metab 2000, 85:1261-1266.
[24] Fardella CE, Rodriguez H, Hum DW, et al. Artificial mutations in P450c11AS(aldosterone synthase) can increase enzymatic activity: a model for low-renin hypertension? J Clin Endocrinol Metab 1995, 80:1040-1043.
[25] Mulatero P, Glorioso N, Fallo F, et al. Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production. Eur J Endocrinol 2001,144:397-400.
[26] Sutherland DJA, Ruse JC, Laidlaw JC. Hypertension increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. J Can Med Assoc 1966,95:1109-1119.
[27] Litchfield WR, Coolidge C, Silva P, et al. Impaired potassium-stimulated aldosterone production: a possible explanation for normokalemic glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 1997, 82:1507-1510.
[28] Litchfield WR, Anderson BF, Weiss RJ, et al. Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension 1998; 31:445-450.
[29] Pascoe L, Jeunemaitre X, Lebrethon MC, et al. Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree. J Clin Invest 1995, 96:2236-2246.
[30] Lifton RP, Dluhy RG, Powers M, et al. Achimaeric 11 β-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992, 355:262-265.
[31] Pascoe L, Curnow KM, Slutsker L, et al. Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA 1992, 89:8327-8331.
[32] Lifton RP, Dluhy RG, Powers M, et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase Nature Genet 1992,2:66-74.
[33] Mulatero P, Curnow KM, Aupetit-Faisant B, et al. Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol,18-hydroxycortisol, and 18-oxocortisol. J Clin Endocrinol Metab 1998; 83:3996-4001.
[34] Pascoe L, Curnow KM. Genetic recombination as a cause of inherited disorders of aldosterone and cortisol biosynthesis and a contributor to genetic variation in blood pressure. Steroids. 1995, 60:22-27.
[35] Portrat S, Mulatero P, Curnow KM, Chaussain JL, Morel Y, Pascoe L. Deletion hybrid genes, due to unequal crossing over between CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) cause steroid 11beta-hydroxylase deficiency and congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001, 86:3197-3201.
[36] Ganguly A, Grim CE, Weinberger MH. Anomalous postural aldosterone response in glucocorticoid-suppressible hyperaldosteronism. N Engl J Med 1981, 305:991-993.
[37] Stowasser M, Tunny TJ, Gartside M, et al. In familial hyperaldosteronism type Ⅰ,hybrid gene-induced aldosterone production dominates that induced by wild type genes.J Clin Endocrinol Metab 1997, 82:3670-3676.
[38] Jamieson A, Ingram MC, Inglis GC, Davies E, et al. Altered 11 β -hydroxylase activity in glucocorticoid-suppressible hyperaldosteronism. J Clin Endocrinol Metab 1996,81:2298-2302.
[39] Fallo F, Pilon C, Williams TA, et al. Coexistence of different phenotypes in a family with glucocorticoidremediable aldosteronism. J Hum Hypertens 2004,18:47-51.
[40] Dluhy RG, Anderson B, Harlin B, et al. Glucocorticoidremediable aldosteronism is associated with severe hypertension in early childhood. J Pediatr 2001; 138:715-720.
[41] Wyckoff JA, Seely EW, Hurwitz S,et al.Glucocorticoid-remediable aldosteronism and pregnancy. Hypertension 2000, 35:668-672.
[42] Mulatero P, Morra di Cella S, Williams TA, et al. Glucocorticoid remediable aldosteronism: low morbidity and mortality in a four-generation italian pedigree. J Clin Endocrinol Metab 2002, 87:3187-91.
[43] Stowasser M, Bachmann AW, Huggard PR, et al. Severity of hypertension in familial hyperaldosteronism type Ⅰ: relationship to gender and degree of biochemical disturbance. J Clin Endocrinol Metab 2000, 85:2160-2166.
[44] Dluhy RG, Lifton RP. Glucocorticoid-remediable aldosteronism (GRA): diagnosis,variability of phenotype and regulation of potassium homeostasis. Steroids 1995;60:48-51.
[45] Stowasser M, Gordon RD. Familial hyperaldosteronism. J Steroid Biochem Mol Biol 2001, 78:215-229.
[46] Liddle GW. Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 1960, 20:1539-1561.
[47] Mulatero P, Veglio F, Pilon C, et al. Diagnosis of glucocorticoid- remediable aldosteronism in primary aldosteronism:aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab 1998,83:2573-2575.
[48] Jonsson JR, Klemm SA, Tunny TJ, Stowasser M, Gordon RD. A new genetic test for familial hyperaldosteronism type Ⅰ aids in the detection of curable hypertension.Biochem Biophys Res Commun 1995, 207: 565-571.
[49] Stowasser M, Bachmann AW, Huggard PR, et al. Treatment of familial hyperaldosteronism type I: only partial suppression of adrenocorticotropin required to correct hypertension.J Clin Endocrinol Metab 2000, 85:3313-3318.
[50] Gordon RD, Stowasser M, Tunny TJ, et al. Clinical and pathological diversity of primary aldosteronism including a new familial variety. Clin Exp Pharmacol Physiol 1991,18:283-286.
[51] Stowasser M, Gunasekera TG, Gordon RD. Familial varieties of primary aldosteronism.Clin Exp Pharmacol Physiol 2001, 28:1087-1090.
[52] Lafferty AR, Torpy DJ, Stowasser M, et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type Ⅱ maps to chromosome 7 (7p22). J Med Genet 2000, 37:831-835.
[53] Jackson RV, Lafferty A, Torpy DJ, et al. New genetic insights in familial hyperaldosteronism. Ann NY Acad Sci 2002, 970:77-88.
[54] Mulatero P. A new form of hereditary primary aldosteronism: familial hyperaldosteronism type Ⅲ. J Clin Endocrinol Metab. 2008. 93: 2972-4.
[55] Gordon RD, Klemm SA, Tunny TJ, et al. Genetics of primary aldosteronism. Clin Exp Pharmacol Physiol, 1994, 21:915-8.
[56] Mulatero P, Morello F, Veglio F. Genetics of primary aldosteronism. J Hypertens, 2004,22:663-70.
[57] Jonsson JR, Klemm SA, Tunny TJ, et al. A new genetic test for familial hyperaldosteronism type Ⅰ aids in the detection of curable hypertension Biochem Biophys Res Commun 1995, 207: 565-571.
[58] Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[59] Mulatero P, Glorioso N, Fallo F, et al. Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production. Eur J Endocrinol, 2001,144:397-400.
[60] Nicod J, Dick B, Frey FJ, et al. Mutation analysis of CYP11B1 and CYP11B2 in patients with increased 18-hydroxycortisol production. Mol Cell Endocrinol,2004,214:167-74.
[61] Pilon C, Mulatero P, Barzon L, et al. Mutations in CYP11B1 gene converting 11beta-hydroxylase into an aldosterone-producing enzyme are not present in aldosterone-producing adenomas. J Clin Endocrinol Metab 1999, 84:4228-4231.
[62] Higaki J, Miya A, Mild T, et al. Contribution of the activation of the ras oncogene to the evolution of aldosterone- and renin-secreting tumors. J Hypertens 1991; 9:135-137.
[63] Gordon RD. Primary aldosteronism: a new understanding. Clin Exp Hypertens 1997,19:857-870.
[64] Zwermann O, Beuschlein F, Mora P, et al. Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol 2000,142:689-695.
[65] Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors.J Clin Endocrinol Metab 1998, 83:2585-2588.
[66] Fallo F, Pezzi V, Barzon L, et al. Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas. Eur J Endocrinol 2002; 147: 795-802.
[67] Miyamori I, Inaba S, Hatakeyama H, Taniguchi N, Takeda Y. Idiopathic hyperaldosteronism: analysis of aldosterone synthase gene. Biomed Pharmacother 2000, 54 (suppl 1):77S-79S.
[68] Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[69] Davies E, Holloway CD, Ingram MC, et al. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension, 1999,33:703-7.
[70] Bassett MH, Zhang Y, Clyne C, et al. Differential regulation of aldosterone synthase and 11beta-hydroxylase transcription by steroidogenic factor-1. J Mol Endocrinol 2002,28:125-135.
[71] Nicod J, Bruhin D, Auer L, et al. A biallelic gene polymorphism of CYP11B2 predicts increased aldosterone to renin ratio in selected hypertensive patients. J Clin Endocrinol Metab 2003,88:2495-500.
[72] Portrat-Doyen S, Tourniaire J, Richard O, et al. Isolated aldosterone synthase deficiency caused by simultaneous E198D and V386A mutations in the CYP11B2 gene.J Clin Endocrinol Metab 1998, 83:4156-4161.
[73] Tanahashi H, Mune T, Takahashi Y, et al. Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab 2005,90:6226-31.
[74] Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the llbeta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab 2006,91:5051-6.
[75] Mulatero P, Schiavone D, Fallo F, et al. CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism. Hypertension 2000, 35:694-698.
[76] Davies E, Kenyon CJ. CYP11B2 polymorphisms and cardiovascular risk factors. J Hypertens 2003, 21:1249-1253.
[77] Keavney B, Mayosi B, Gaukrodger N, et al. Genetic variation at the locus encompassing 11-beta hydroxylase and aldosterone synthase accounts for heritability in cortisol precursor (11-deoxycortisol) urinary metabolite excretion. J Clin Endocrinol Metab 2005, 90:1072-7.
[78] Barr M, MacKenzie SM, Friel EC, et al. Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency.Hypertension 2007,49:113-9.
[79] Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab 2005,90:1220-5.
[80] Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension? Hypertension 2003, 41:993-999.
[81] Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone.J Am Soc Nephrol, 2004,15:1993-2001.
[82] Mulatero P, Williams TA, Milan A, et al. Blood pressure in patients with primary aldosteronism is influenced by bradykinin B(2) receptor and alpha-adducin gene polymorphisms. J Clin Endocrinol Metab 2002, 87:3337-3343.
[83] Lim PO, Macdonald TM, Holloway C, et al. Variation at the aldosterone synthase(CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio. J Clin Endocrinol Metab 2002, 87:4398-4402.
1.Smith CD, Weber CJ and Amerson JR: Laparoscopic adrenalectomy: new gold standard.World J Surg. 1999; 23: 389-396.
2.Suzuki K. Laparoscopic adrenalectomy: retroperitoneal approach. Urol Clin North Am.2001; 28: 85-95.
3.Zhang X, Fu B, Lang B, et al. Technique of Anatomical Retroperitoneoscopic Adrenalectomy With Report of 800 Cases. J Urol. 2007; 177:1254-1257.
4.Goitein D, Mintz Y, Gross D, et al. Laparoscopic adrenalectomy: Ascending the learning curve. Surg Endosc. 2004; 18: 771-773.
5.Maccabee DL, Jones A, Domreis J, et al. Transition from open to laparoscopic adrenalectomy: the need for advanced training. Surg Endosc. 2003; 17:1566-1569.
6.Frede T, Erdogru T, Zukosky D, et al. Comparison of training modalities for performing laparoscopic radical prostatectomy: experience with 1000 patients. J Urol. 2005;174:673-678.
7.Stolzenburg JU, Truss MC, Rabenalt R, et al. Training in Laparoscopy. Eau-ebu update series. 2007; 5:53-62.
8.Fu B, Zhang X, Lang B, et al. New Model for Training in Laparoscopic Dismembered Pyeloureteroplasty. J Endourol. 2007; 21:1381-1385.
9.Zhang X, Lang B, Ouyang JZ, et al. Retroperitoneoscopic Adrenalectomy Without Previous Control of Adrenal Vein Is Feasible and Safe for Pheochromocytoma. Urology.2007;69: 849-853.
10.Chandrasekera SK, Donohue JF, Orley D, et al. Basic Laparoscopic Surgical Training:Examination of a Low-Cost Alternative. Eur Urol. 2006;50: 1285-1291.
11.Katz R, Hoznek A, Salomon L, et al. Skill assessment of urological laparoscopic surgeons: can criterion levels of surgical performance be determined using the pelvic box trainer? Eur Urol. 2005;47: 482-487.
12.Teber D, Dekel Y, Frede T, et al. The Heilbronn Laparoscopic Training Program for Laparoscopic Suturing: Concept and Validation. J Endourol. 2005;19: 230-238.
13.LinksKeeley FX Jr, Eden CG, Tolley DA, et al. The British Association of Urological Surgeons: guidelines for training in laparoscopy. BJU Int. 2007; 100:379-381.
14.Ramacciato G, Paolo M, Pietromaria A, et al. Ten years of laparoscopic adrenalectomy:lesson learned from 104 procedures. Am Surg. 2005;71: 321-325.
15.Gumbs AA, Gagner M. Laparoscopic adrenalectomy. Best Pract Res Clin Endocrinol Metab 2006; 20:483-499.
16.Stolzenburg JU, Rabenalt R, Do M, et al. Modular Training for Residents with no Prior Experience with Open Pelvic Surgery in Endoscopic Extraperitoneal Radical Prostatectomy. Eur Urol. 2006;49: 491-499.
17.Lehmann KS, Ritz JP, Maass H, et al. A prospective randomized study to test the transfer of basic psychomotor skills from virtual reality to physical reality in a comparable training setting. Ann Surg. 2005;241: 442-449.
18.Gill IS. The case for laparoscopic adrenalectomy. J Urol. 2001;116: 429-436.
19.Le CQ, Lightner DJ, VanderLei L, et al. The Current Role of Medical Simulation in American Urological Residency Training Programs: An Assessment by Program Directors. J Urol. 2007; 177: 288-291.
20.Fabrizio MD, Tuerk I, Schellhammer PF. Laparoscopic radical prostatectomy:decreasing the learning curve using a mentor initiated approach. J Urol. 2003;196:2063-2065.
21.Skrekas T, Mochtar CA, Lagerveld BW, et al. Mentor-Initiated Approach in Laparoscopic Radical Prostatectomy. J Endourol. 2006;20: 831-835.
22.Sugiono M, Teber D, Anghel G, et al. Assessing the predictive validity and efficacy of a multimodal training programme for laparoscopic radical prostatectomy (LRP). Eur Urol.2007;51: 1332-1340.
23.Rassweiler J, Seemann O, Hatzinger M, et al. Technical evolution of laparoscopic radical prostatectomy after 450 cases. J Endourol. 2003;17: 143-154.
[2] Conn JW. Part Ⅰ. Painting background. Part Ⅱ. Primary aldosteronism, a new clinical syndrome, 1954. J Lab Clin Med, 1990,116:253-67.
[3] Ganguly A. Primary aldosteronism. N Engl J Med, 1998,339:1828-34.
[4] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[5] Mosso L, Carvajal C, Gonzalez A, et al. Primary aldosteronism and hypertensive disease. Hypertension, 2003,42:161-5.
[6] Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab, 2000,85:2854-9.
[7] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[8] Mulatero P, Dluhy RG, Giacchetti G, et al. Diagnosis of primary aldosteronism: from screening to subtype differentiation. Trends Endocrinol Metab, 2005,16:114-9.
[9] Plouin PF, Amar L, Chatellier G Trends in the prevalence of primary aldosteronism,aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant, 2004,19:774-7.
[10] Suzuki J, Otsuka F, Inagaki K, et al. Primary aldosteronism caused by a unilateral adrenal adenoma accompanied by autonomous cortisol secretion. Hypertens Res,2007,30:367-73.
[11] Omura M, Saito T, Sasano H, et al. [Primary aldosteronism due to unilateral adrenal hyperplasia]. Nippon Rinsho, 2006,Suppl 1:635-7.
[12] Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med, 2001,135:258-61.
[13] Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg, 2005,29:155-9.
[14] Celen O, O'Brien MJ, Melby JC, et al. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg, 1996,131:646-50.
[15] Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas: multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg, 2005,71:864-9.
[16] Harris DA, Au-Yong I, Basnyat PS, et al. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. Eur J Surg Oncol, 2003,29:467-74.
[17] Rossi GP, Bolognesi M, Rizzoni D, et al. Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients.Hypertension, 2008,51:1366-71.
[18] Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism,including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab, 2004,89:1045-50.
[19] Mattsson C, Young WF Jr. Primary aldosteronism: diagnostic and treatment strategies.Nat Clin Pract Nephrol, 2006,2:198-208; quiz, 1 p following 230.
[20] Inglis GC, Plouin PF, Friel EC, et al. Polymorphic differences from normal in the aldosterone synthase gene (CYP11B2) in patients with primary hyperaldosteronism and adrenal tumour (Conn's syndrome). Clin Endocrinol (Oxf), 2001,54:725-30.
[21] Mulatero P, Schiavone D, Fallo F, et al. CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism. Hypertension, 2000,35:694-8.
[22] Tanahashi H, Mune T, Takahashi Y, et al. Association of Lysl73Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab, 2005,90:6226-31.
[23] Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension. Hypertension, 2003,41:993-9.
[24] Kloppenborg PW, Drayer JI, Van Haelst AJ, et al. Primary aldosteronism, idiopathic aldosteronism and "low-renin" benign essential hypertension. A retrospective study.Neth J Med, 1974,17:239-47.
[25] Gordon RD, Jackson RV. Idiopathic aldosteronism: diagnostic artifact. Lancet, 1980,1:1422.
[26] Giacchetti G, Mulatero P, Mantero F, et al. Primary aldosteronism, a major form of low renin hypertension: from screening to diagnosis. Trends Endocrinol Metab,2008,19:104-8.
[27] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[28] Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[29] Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab,2005,90:1220-5.
[30] Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the llbeta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[31] Mulatero P, Morello F, Veglio F. Genetics of primary aldosteronism. J Hypertens,2004,22:663-70.
[32] Higaki J, Miya A, Miki T, et al. Contribution of the activation of the ras oncogene to the evolution of aldosterone- and renin-secreting tumors. J Hypertens, 1991,9:135-7.
[33] Gordon RD. Primary aldosteronism: a new understanding. Clin Exp Hypertens,1997,19:857-70.
[34] Zwermann O, Beuschlein F, Mora P, et al. Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol,2000,142:689-95.
[35] Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors.J Clin Endocrinol Metab, 1998,83:2585-8.
[36]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001,25:402-8.
[1] Conn JW. Part Ⅰ. Painting background. Part Ⅱ. Primary aldosteronism, a new clinical syndrome, 1954. J Lab Clin Med, 1990,116:253-67.
[2] Ganguly A. Primary aldosteronism. N Engl J Med, 1998,339:1828-34.
[3] Gordon RD, Klemm SA, Tunny TJ, et al. Genetics of primary aldosteronism. Clin Exp Pharmacol Physiol, 1994,21:915-8.
[4] Mulatero P, Morello F, Veglio F. Genetics of primary aldosteronism. J Hypertens,2004,22:663-70.
[5] Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature, 1992,355:262-5.
[6] Lafferty AR, Torpy DJ, Stowasser M, et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J Med Genet, 2000,37:831-5.
[7] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[8] Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[9] Curnow KM, Mulatero P, Emeric-Blanchouin N, et al. The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme. Nat Struct Biol, 1997,4:32-5.
[10]Higaki J, Miya A, Miki T, et al. Contribution of the activation of the ras oncogene to the evolution of aldosterone- and renin-secreting tumors. J Hypertens, 1991,9:135-7.
[11] Gordon RD. Primary aldosteronism: a new understanding. Clin Exp Hypertens,1997,19:857-70.
[12] Zwermann O, Beuschlein F, Mora P, et al. Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol, 2000,142:689-95.
[13] Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors. J Clin Endocrinol Metab, 1998,83:2585-8.
[14]Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab,2005,90:1220-5.
[15]Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the llbeta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[16] Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone.J Am Soc Nephrol, 2004,15:1993-2001.
[17] Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension. Hypertension, 2003,41:993-9.
[18]Lim PO, Macdonald TM, Holloway C, et al. Variation at the aldosterone synthase(CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio. J Clin Endocrinol Metab, 2002,87:4398-402.
[19]White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med,1994,331:250-8.
[20]Inglis GC, Plouin PF, Friel EC, et al. Polymorphic differences from normal in the aldosterone synthase gene (CYP11B2) in patients with primary hyperaldosteronism and adrenal tumour (Conn's syndrome). Clin Endocrinol (Oxf), 2001,54:725-30.
[21]Mulatero P, Schiavone D, Fallo F, et al. CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism. Hypertension, 2000,35:694-8.
[22]Tanahashi H, Mune T, Takahashi Y, et al. Association of Lysl73Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab, 2005,90:6226-31.
[23]Tsukada K, Ishimitsu T, Teranishi M, et al. Positive association of CYP11B2 gene polymorphism with genetic predisposition to essential hypertension. J Hum Hypertens,2002,16:789-93.
[24]Nicod J, Bruhin D, Auer L, et al. A biallelic gene polymorphism of CYP11B2 predicts increased aldosterone to renin ratio in selected hypertensive patients. J Clin Endocrinol Metab, 2003, 88:2495-2500.
[1] Conn JW. Part Ⅰ. Painting background. Part Ⅱ. Primary aldosteronism, a new clinical syndrome, 1954. J Lab Clin Med, 1990,116:253-67.
[2] CONN JW. Presidential address. Ⅰ. Painting background.Ⅱ. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med, 1955,45:3-17.
[3] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[4] Mosso L, Carvajal C, Gonzalez A, et al. Primary aldosteronism and hypertensive disease. Hypertension, 2003,42:161-5.
[5] Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab, 2000,85:2854-9.
[6] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[7] Mulatero P, Dluhy RG, Giacchetti G, et al. Diagnosis of primary aldosteronism: from screening to subtype differentiation. Trends Endocrinol Metab, 2005,16:114-9.
[8] Plouin PF, Amar L, Chatellier G Trends in the prevalence of primary aldosteronism,aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant, 2004,19:774-7.
[9] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[10]Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[11]Curnow KM, Tusie-Luna MT, Pascoe L, et al. The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. Mol Endocrinol,1991,5:1513-22.
[12]Sasano H, Okamoto M, Sasano N. Immunohistochemical study of cytochrome P-450 11 beta-hydroxylase in human adrenal cortex with mineralo-and glucocorticoid excess. Virchows Arch A Pathol Anat Histopathol, 1988,413:313-8.
[13]Takasaki H, Miyamori I, Nagai K, et al. Mitochondrial P-450 activities in aldosteronoma tissues. J Steroid Biochem Mol Biol, 1991,38:533-5.
[14]Ogishima T, Shibata H, Shimada H, et al. Aldosterone synthase cytochrome P-450 expressed in the adrenals of patients with primary aldosteronism. J Biol Chem,1991,266:10731-4.
[15] Suzuki H, Shibata H, Maruyama T, et al. Significance of steroidogenic enzymes in the pathogenesis of hyperfunctioning and non-hyperfunctioning adrenal tumor. Steroids,1995,60:42-7.
[16]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001,25:402-8.
[17]Fallo F, Pezzi V, Barzon L, et al. Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas. Eur J Endocrinol, 2002,147:795-802.
[18]Tanahashi H, Mune T, Takahashi Y, et al. Association of Lysl73Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab, 2005,90:6226-31.
[19]Cover CM, Wang JM, St LE, et al. Molecular variants in the P450c11AS gene as determinants of aldosterone synthase activity in the Dahl rat model of hypertension. J Biol Chem, 1995,270:16555-60.
[20]Fardella CE, Rodriguez H, Hum DW, et al. Artificial mutations in P450c11AS(aldosterone synthase) can increase enzymatic activity: a model for low-renin hypertension. J Clin Endocrinol Metab, 1995,80:1040-3.
[21]Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[22]Mulatero P, Glorioso N, Fallo F, et al. Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production. Eur J Endocrinol, 2001,144:397-400.
[23]Nicod J, Dick B, Frey FJ, et al. Mutation analysis of CYP11B1 and CYP11B2 in patients with increased 18-hydroxycortisol production. Mol Cell Endocrinol, 2004,214:167-74.
[24] Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension. Hypertension, 2003,41:993-9.
[25]Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone.J Am Soc Nephrol, 2004,15:1993-2001.
[26]Kem DC, Gomez-Sanchez C, Kramer NJ, et al. Plasma aldosterone and renin activity response to ACTH infusion in dexamethasone-suppressed normal and sodium-depleted man. J Clin Endocrinol Metab, 1975,40:116-24.
[27]Lehoux JG, Fleury A, Ducharme L. The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. Endocrinology, 1998,139:3913-22.
[28]Erdmann B, Gerst H, Bulow H, et al. Zone-specific localization of cytochrome P45011B1 in human adrenal tissue by PCR-derived riboprobes. Histochem Cell Biol,1995,104:301-7.
[29]Denner K, Doehmer J, Bernhardt R. Cloning of CYP11B1 and CYP11B2 from normal human adrenal and their functional expression in COS-7 and V79 Chinese hamster cells. Endocr Res, 1995,21:443-8.
[30]Zhou M, Xue D, Foecking MF, et al. Stable expression of rat cytochrome P450 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) in MA-10 cells. J Steroid Biochem Mol Biol, 1995,52:523-8.
[1] Curnow KM, Tusie-Luna MT, Pascoe L, et al. The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. Mol Endocrinol,1991,5:1513-22.
[2] Kawamoto T, Mitsuuchi Y, Toda K, et al. Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans. Proc Natl Acad Sci USA, 1992,89:1458-62.
[3] Kojima I, Ogata E, Inano H, et al. Oxygenation of 18-hydroxycorticosterone as the final reaction for aldosterone biosynthesis. Acta Endocrinol (Copenh),1984,107:395-400.
[4] Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[5] Cover CM, Wang JM, St LE, et al. Molecular variants in the P450cllAS gene as determinants of aldosterone synthase activity in the Dahl rat model of hypertension. J Biol Chem, 1995,270:16555-60.
[6] Fardella CE, Rodriguez H, Hum DW, et al. Artificial mutations in P450c11AS(aldosterone synthase) can increase enzymatic activity: a model for low-renin hypertension. J Clin Endocrinol Metab, 1995,80:1040-3.
[7] Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[8] Mulatero P, Glorioso N, Fallo F, et al. Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production. Eur J Endocrinol, 2001,144:397-400.
[9] Nicod J, Dick B, Frey FJ, et al. Mutation analysis of CYP11B1 and CYP11B2 in patients with increased 18-hydroxycortisol production. Mol Cell Endocrinol,2004,214:167-74.
[10] Higaki J, Miya A, Miki T, et al. Contribution of the activation of the ras oncogene to the evolution of aldosterone-and renin-secreting tumors. J Hypertens, 1991,9:135-7.
[11] Gordon RD. Primary aldosteronism: a new understanding. Clin Exp Hypertens, 1997,19:857-70.
[12]Zwermann O, Beuschlein F, Mora P, et al. Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol,2000,142:689-95.
[13] Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors.J Clin Endocrinol Metab, 1998,83:2585-8.
[14]Fallo F, Pezzi V, Barzon L, et al. Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas. Eur J Endocrinol, 2002,147:795-802.
[15]Miyamori I, Inaba S, Hatakeyama H, et al. Idiopathic hyperaldosteronism: analysis of aldosterone synthase gene. Biomed Pharmacother, 2000,54 Suppl l:77s-79s.
[16]Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[17]Mulatero P, Morello F, Veglio F. Genetics of primary aldosteronism. J Hypertens,2004,22:663-70.
[18] Gordon RD, Klemm SA, Tunny TJ, et al. Genetics of primary aldosteronism. Clin Exp Pharmacol Physiol, 1994,21:915-8.
[19]Pilon C, Mulatero P, Barzon L, et al. Mutations in CYP11B1 gene converting 11beta-hydroxylase into an aldosterone-producing enzyme are not present in aldosterone-producing adenomas. J Clin Endocrinol Metab, 1999,84:4228-31.
[20]Davies E, Holloway CD, Ingram MC, et al. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension, 1999,33:703-7.
[21]Staessen JA, Wang JG, Brand E, et al. Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population. J Hypertens, 2001,19:1349-58.
[22]Hautanena A, Lankinen L, Kupari M, et al. Associations between aldosterone synthase gene polymorphism and the adrenocortical function in males. J Intern Med,1998,244:11-8.
[23]Bassett MH, Zhang Y, Clyne C, et al. Differential regulation of aldosterone synthase and 11beta-hydroxylase transcription by steroidogenic factor-1. J Mol Endocrinol,2002,28:125-35.
[24]Nicod J, Bruhin D, Auer L, et al. A biallelic gene polymorphism of CYP11B2 predicts increased aldosterone to renin ratio in selected hypertensive patients. J Clin Endocrinol Metab, 2003,88:2495-500.
[25] Portrat-Doyen S, Tourniaire J, Richard O, et al. Isolated aldosterone synthase deficiency caused by simultaneous E198D and V386A mutations in the CYP11B2 gene.J Clin Endocrinol Metab, 1998,83:4156-61.
[26]Tanahashi H, Mune T, Takahashi Y, et al. Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab, 2005,90:6226-31.
[27]Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the 11beta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[28]Keavney B, Mayosi B, Gaukrodger N, et al. Genetic variation at the locus encompassing 11-beta hydroxylase and aldosterone synthase accounts for heritability in cortisol precursor (11-deoxycortisol) urinary metabolite excretion. J Clin Endocrinol Metab, 2005,90:1072-7.
[29]Barr M, MacKenzie SM, Friel EC, et al. Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency.Hypertension, 2007,49:113-9.
[30]Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab,2005,90:1220-5.
[31]Kem DC, Gomez-Sanchez C, Kramer NJ, et al. Plasma aldosterone and renin activity response to ACTH infusion in dexamethasone-suppressed normal and sodium-depleted man. J Clin Endocrinol Metab, 1975,40:116-24.
[32]Lehoux JG, Fleury A, Ducharme L. The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. Endocrinology, 1998,139:3913-22.
[33]Tamaki S, Iwai N, Tsujita Y, et al. Genetic polymorphism of CYP11B2 gene and hypertension in Japanese. Hypertension, 1999,33:266-70.
[34]Matsubara M, Sato T, Nishimura T, et al. CYP11B2 polymorphisms and home blood pressure in a population-based cohort in Japanese: the Ohasama study. Hypertens Res,2004,27:1-6.
[35]Davies E, Holloway CD, Ingram MC, et al. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension, 1999,33:703-7.
[36] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[37] Staessen JA, Wang JG, Brand E, et al. Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population. J Hypertens, 2001,19:1349-58.
[38]Russo P, Siani A, Venezia A, et al. Interaction between the C(-344)T polymorphism of CYP11B2 and age in the regulation of blood pressure and plasma aldosterone levels:cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study. J Hypertens, 2002,20:1785-92.
[39]Barbato A, Russo P, Siani A, et al. Aldosterone synthase gene (CYP11B2) C-344T polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population. J Hypertens, 2004,22:1895-901.
[40]Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone.J Am Soc Nephrol, 2004,15:1993-2001.
[41] Mulatero P, Williams TA, Milan A, et al. Blood pressure in patients with primary aldosteronism is influenced by bradykinin B(2) receptor and alpha-adducin gene polymorphisms. J Clin Endocrinol Metab, 2002,87:3337-43.
[1] Mosso L, Carvajal C, Gonzalez A, et al. Primary aldosteronism and hypertensive disease. Hypertension, 2003,42:161-5.
[2] Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab, 2000,85:2854-9.
[3] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[4] Suzuki J, Otsuka F, Inagaki K, et al. Primary aldosteronism caused by a unilateral adrenal adenoma accompanied by autonomous cortisol secretion. Hypertens Res,2007,30:367-73.
[5] Omura M, Saito T, Sasano H, et al. [Primary aldosteronism due to unilateral adrenal hyperplasia]. Nippon Rinsho, 2006,Suppl 1:635-7.
[6] Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med, 2001,135:258-61.
[7] Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg, 2005,29:155-9.
[8] Celen O, O'Brien MJ, Melby JC, et al. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg, 1996,131:646-50.
[9] Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas: multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg, 2005,71:864-9.
[10] Harris DA, Au-Yong I, Basnyat PS, et al. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. Eur J Surg Oncol, 2003,29:467-74.
[11] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension, 1998,32:198-204.
[12]Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab, 1998,83:1033-6.
[13]Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab,2005,90:1220-5.
[14]Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the 11 beta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[15]Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension. Hypertension, 2003,41:993-9.
[16]Kloppenborg PW, Drayer JI, Van Haelst AJ, et al. Primary aldosteronism, idiopathic aldosteronism and "low-renin" benign essential hypertension. A retrospective study.Neth J Med, 1974,17:239-47.
[17] Gordon RD, Jackson RV. Idiopathic aldosteronism: diagnostic artifact. Lancet,1980,1:1422.
[18]Balkestein EJ, Wang JG, Struijker-Boudier HA, et al. Carotid and femoral intima-media thickness in relation to three candidate genes in a Caucasian population. J Hypertens,2002,20:1551-61.
[19]Kupari M, Hautanen A, Lankinen L, et al. Associations between human aldosterone synthase (CYP11B2) gene polymorphisms and left ventricular size, mass, and function.Circulation, 1998,97:569-75.
[20] Schaid DJ, Rowland CM, Tines DE, et al. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet, 2002,70:425-34.
[21] Lake SL, Lyon H, Tantisira K, et al. Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered, 2003,55:56-65.
[22]Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the llbeta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab,2006,91:5051-6.
[23]Mulatero P, Williams TA, Milan A, et al. Blood pressure in patients with primary aldosteronism is influenced by bradykinin B(2) receptor and alpha-adducin gene polymorphisms. J Clin Endocrinol Metab, 2002,87:3337-43.
[24]Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab, 2005,90:1220-5.
[25] Rossi GP, Bolognesi M, Rizzoni D, et al. Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients.Hypertension, 2008,51:1366-71.
[26] Connell JM, Fraser R, MacKenzie SM, et al. The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation. Mol Cell Endocrinol, 2004,217:243-7.
[1] Conn JW. Part I. Painting background. Part II. Primary aldosteronism, a new clinical syndrome, 1954. J Lab Clin Med 1990,116:253-267.
[2] CONN JW. Presidential address. Ⅰ. Painting background. Ⅱ. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med, 1955,45:3-17.
[3] Ganguly A. Primary aldosteronism. N Engl J Med, 1998,339:1828-34.
[4] Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism,including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab, 2004,89:1045-50.
[5] Fardella CE, Mosso L, Gomez-Sanchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab, 2000,85:1863-7.
[6] Loh KC, Koay ES, Khaw MC, et al. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab, 2000,85:2854-9.
[7] Mosso L, Carvajal C, Gonzalez A, et al. Primary aldosteronism and hypertensive disease. Hypertension, 2003,42:161-5.
[8] Kaplan NM. Cautions over the current epidemic of primary aldosteronism. Lancet 2000; 357:953-954.
[9] Jeschke K, Janetschek G, Peschel R, et al. Laparoscopic partial adrenalectomy in patients with aldosteroneproducing adenomas: indications, technique, and results.Urology 2003, 61:69-72.
[10] Lim PO, Young WF, MacDonald TM. A review of the medical treatment of primary aldosteronism. J Hypertens 2001,19:353-361.
[11] Curnow KM, Tusie-Luna MT, Pascoe L, et al. The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. Mol Endocrinol 1991; 5:1513-1522.
[12] Kawamoto T, Mitsuuchi Y, Toda K, et al. Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans. Proc Natl Acad Sci USA 1992, 89:1458-1462.
[13] Kojima I, Ogata E, Inano H, et al. Oxygenation of 18-hydroxycorticosterone as the final reaction for aldosterone biosynthesis. Acta Endocrinol 1984, 107:395-400.
[14] Brand E, Chatelain N, Mulatero P, et al. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension 1998, 32:198-204.
[15] Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab 1998, 83:1033-1036.
[16] Cover CM, Wang JM, St LE, et al. Molecular variants in the P450c11AS gene as determinants of aldosterone synthase activity in the Dahl rat model of hypertension. J Biol Chem, 1995,270:16555-60.
[17] Fardella CE, Rodriguez H, Hum DW, et al. Artificial mutations in P450c11AS(aldosterone synthase) can increase enzymatic activity: a model for low-renin hypertension. J Clin Endocrinol Metab, 1995,80:1040-3.
[18] Curnow KM, Mulatero P, Emeric-Blanchouin N, et al. The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme. Nature Struct Biol 1997, 4:32-35.
[19] Ulick S, Chu MD. Hypersecretion of a new corticosteroid, 18-hydroxycortisol in two types of adrenocortical hypertension. Clin Exp Hypertens 1982, A4:1771-1777.
[20] Shibata H, Ogishima T, Mitani F, et al. Regulation of aldosterone synthase cytochrome P-450 in rat adrenals by angiotensin Ⅱand potassium. Endocrinology 1991,128:2534-2539.
[21] Lehoux JG, Fleury A, Ducharme L. The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. Endocrinology 1998, 139:3913-3922.
[22] Takeda Y, Yoneda T, Demura M, et al. Sodium-induced cardiac aldosterone synthesis causes cardiac hypertrophy. Endocrinology 2000, 141:1901-1904.
[23] Fisher A, Fraser R, Me Connell J, et al. Amino acid residue 147 of human aldosterone synthase and llbeta-hydroxylase plays a key role in llbeta-hydroxylation. J Clin Endocrinol Metab 2000, 85:1261-1266.
[24] Fardella CE, Rodriguez H, Hum DW, et al. Artificial mutations in P450c11AS(aldosterone synthase) can increase enzymatic activity: a model for low-renin hypertension? J Clin Endocrinol Metab 1995, 80:1040-1043.
[25] Mulatero P, Glorioso N, Fallo F, et al. Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production. Eur J Endocrinol 2001,144:397-400.
[26] Sutherland DJA, Ruse JC, Laidlaw JC. Hypertension increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. J Can Med Assoc 1966,95:1109-1119.
[27] Litchfield WR, Coolidge C, Silva P, et al. Impaired potassium-stimulated aldosterone production: a possible explanation for normokalemic glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 1997, 82:1507-1510.
[28] Litchfield WR, Anderson BF, Weiss RJ, et al. Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension 1998; 31:445-450.
[29] Pascoe L, Jeunemaitre X, Lebrethon MC, et al. Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree. J Clin Invest 1995, 96:2236-2246.
[30] Lifton RP, Dluhy RG, Powers M, et al. Achimaeric 11 β-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992, 355:262-265.
[31] Pascoe L, Curnow KM, Slutsker L, et al. Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA 1992, 89:8327-8331.
[32] Lifton RP, Dluhy RG, Powers M, et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase Nature Genet 1992,2:66-74.
[33] Mulatero P, Curnow KM, Aupetit-Faisant B, et al. Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol,18-hydroxycortisol, and 18-oxocortisol. J Clin Endocrinol Metab 1998; 83:3996-4001.
[34] Pascoe L, Curnow KM. Genetic recombination as a cause of inherited disorders of aldosterone and cortisol biosynthesis and a contributor to genetic variation in blood pressure. Steroids. 1995, 60:22-27.
[35] Portrat S, Mulatero P, Curnow KM, Chaussain JL, Morel Y, Pascoe L. Deletion hybrid genes, due to unequal crossing over between CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) cause steroid 11beta-hydroxylase deficiency and congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001, 86:3197-3201.
[36] Ganguly A, Grim CE, Weinberger MH. Anomalous postural aldosterone response in glucocorticoid-suppressible hyperaldosteronism. N Engl J Med 1981, 305:991-993.
[37] Stowasser M, Tunny TJ, Gartside M, et al. In familial hyperaldosteronism type Ⅰ,hybrid gene-induced aldosterone production dominates that induced by wild type genes.J Clin Endocrinol Metab 1997, 82:3670-3676.
[38] Jamieson A, Ingram MC, Inglis GC, Davies E, et al. Altered 11 β -hydroxylase activity in glucocorticoid-suppressible hyperaldosteronism. J Clin Endocrinol Metab 1996,81:2298-2302.
[39] Fallo F, Pilon C, Williams TA, et al. Coexistence of different phenotypes in a family with glucocorticoidremediable aldosteronism. J Hum Hypertens 2004,18:47-51.
[40] Dluhy RG, Anderson B, Harlin B, et al. Glucocorticoidremediable aldosteronism is associated with severe hypertension in early childhood. J Pediatr 2001; 138:715-720.
[41] Wyckoff JA, Seely EW, Hurwitz S,et al.Glucocorticoid-remediable aldosteronism and pregnancy. Hypertension 2000, 35:668-672.
[42] Mulatero P, Morra di Cella S, Williams TA, et al. Glucocorticoid remediable aldosteronism: low morbidity and mortality in a four-generation italian pedigree. J Clin Endocrinol Metab 2002, 87:3187-91.
[43] Stowasser M, Bachmann AW, Huggard PR, et al. Severity of hypertension in familial hyperaldosteronism type Ⅰ: relationship to gender and degree of biochemical disturbance. J Clin Endocrinol Metab 2000, 85:2160-2166.
[44] Dluhy RG, Lifton RP. Glucocorticoid-remediable aldosteronism (GRA): diagnosis,variability of phenotype and regulation of potassium homeostasis. Steroids 1995;60:48-51.
[45] Stowasser M, Gordon RD. Familial hyperaldosteronism. J Steroid Biochem Mol Biol 2001, 78:215-229.
[46] Liddle GW. Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 1960, 20:1539-1561.
[47] Mulatero P, Veglio F, Pilon C, et al. Diagnosis of glucocorticoid- remediable aldosteronism in primary aldosteronism:aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab 1998,83:2573-2575.
[48] Jonsson JR, Klemm SA, Tunny TJ, Stowasser M, Gordon RD. A new genetic test for familial hyperaldosteronism type Ⅰ aids in the detection of curable hypertension.Biochem Biophys Res Commun 1995, 207: 565-571.
[49] Stowasser M, Bachmann AW, Huggard PR, et al. Treatment of familial hyperaldosteronism type I: only partial suppression of adrenocorticotropin required to correct hypertension.J Clin Endocrinol Metab 2000, 85:3313-3318.
[50] Gordon RD, Stowasser M, Tunny TJ, et al. Clinical and pathological diversity of primary aldosteronism including a new familial variety. Clin Exp Pharmacol Physiol 1991,18:283-286.
[51] Stowasser M, Gunasekera TG, Gordon RD. Familial varieties of primary aldosteronism.Clin Exp Pharmacol Physiol 2001, 28:1087-1090.
[52] Lafferty AR, Torpy DJ, Stowasser M, et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type Ⅱ maps to chromosome 7 (7p22). J Med Genet 2000, 37:831-835.
[53] Jackson RV, Lafferty A, Torpy DJ, et al. New genetic insights in familial hyperaldosteronism. Ann NY Acad Sci 2002, 970:77-88.
[54] Mulatero P. A new form of hereditary primary aldosteronism: familial hyperaldosteronism type Ⅲ. J Clin Endocrinol Metab. 2008. 93: 2972-4.
[55] Gordon RD, Klemm SA, Tunny TJ, et al. Genetics of primary aldosteronism. Clin Exp Pharmacol Physiol, 1994, 21:915-8.
[56] Mulatero P, Morello F, Veglio F. Genetics of primary aldosteronism. J Hypertens, 2004,22:663-70.
[57] Jonsson JR, Klemm SA, Tunny TJ, et al. A new genetic test for familial hyperaldosteronism type Ⅰ aids in the detection of curable hypertension Biochem Biophys Res Commun 1995, 207: 565-571.
[58] Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[59] Mulatero P, Glorioso N, Fallo F, et al. Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production. Eur J Endocrinol, 2001,144:397-400.
[60] Nicod J, Dick B, Frey FJ, et al. Mutation analysis of CYP11B1 and CYP11B2 in patients with increased 18-hydroxycortisol production. Mol Cell Endocrinol,2004,214:167-74.
[61] Pilon C, Mulatero P, Barzon L, et al. Mutations in CYP11B1 gene converting 11beta-hydroxylase into an aldosterone-producing enzyme are not present in aldosterone-producing adenomas. J Clin Endocrinol Metab 1999, 84:4228-4231.
[62] Higaki J, Miya A, Mild T, et al. Contribution of the activation of the ras oncogene to the evolution of aldosterone- and renin-secreting tumors. J Hypertens 1991; 9:135-137.
[63] Gordon RD. Primary aldosteronism: a new understanding. Clin Exp Hypertens 1997,19:857-870.
[64] Zwermann O, Beuschlein F, Mora P, et al. Multiple endocrine neoplasia type 1 gene expression is normal in sporadic adrenocortical tumors. Eur J Endocrinol 2000,142:689-695.
[65] Beuschlein F, Schulze E, Mora P, et al. Steroid 21-hydroxylase mutations and 21-hydroxylase messenger ribonucleic acid expression in human adrenocortical tumors.J Clin Endocrinol Metab 1998, 83:2585-2588.
[66] Fallo F, Pezzi V, Barzon L, et al. Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas. Eur J Endocrinol 2002; 147: 795-802.
[67] Miyamori I, Inaba S, Hatakeyama H, Taniguchi N, Takeda Y. Idiopathic hyperaldosteronism: analysis of aldosterone synthase gene. Biomed Pharmacother 2000, 54 (suppl 1):77S-79S.
[68] Takeda Y, Furukawa K, Inaba S, et al. Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism. J Clin Endocrinol Metab, 1999,84:1633-7.
[69] Davies E, Holloway CD, Ingram MC, et al. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension, 1999,33:703-7.
[70] Bassett MH, Zhang Y, Clyne C, et al. Differential regulation of aldosterone synthase and 11beta-hydroxylase transcription by steroidogenic factor-1. J Mol Endocrinol 2002,28:125-135.
[71] Nicod J, Bruhin D, Auer L, et al. A biallelic gene polymorphism of CYP11B2 predicts increased aldosterone to renin ratio in selected hypertensive patients. J Clin Endocrinol Metab 2003,88:2495-500.
[72] Portrat-Doyen S, Tourniaire J, Richard O, et al. Isolated aldosterone synthase deficiency caused by simultaneous E198D and V386A mutations in the CYP11B2 gene.J Clin Endocrinol Metab 1998, 83:4156-4161.
[73] Tanahashi H, Mune T, Takahashi Y, et al. Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab 2005,90:6226-31.
[74] Imrie H, Freel M, Mayosi BM, et al. Association between aldosterone production and variation in the llbeta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab 2006,91:5051-6.
[75] Mulatero P, Schiavone D, Fallo F, et al. CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism. Hypertension 2000, 35:694-698.
[76] Davies E, Kenyon CJ. CYP11B2 polymorphisms and cardiovascular risk factors. J Hypertens 2003, 21:1249-1253.
[77] Keavney B, Mayosi B, Gaukrodger N, et al. Genetic variation at the locus encompassing 11-beta hydroxylase and aldosterone synthase accounts for heritability in cortisol precursor (11-deoxycortisol) urinary metabolite excretion. J Clin Endocrinol Metab 2005, 90:1072-7.
[78] Barr M, MacKenzie SM, Friel EC, et al. Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency.Hypertension 2007,49:113-9.
[79] Ganapathipillai S, Laval G, Hoffmann IS, et al. CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. J Clin Endocrinol Metab 2005,90:1220-5.
[80] Connell JM, Fraser R, MacKenzie S, et al. Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension? Hypertension 2003, 41:993-999.
[81] Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone.J Am Soc Nephrol, 2004,15:1993-2001.
[82] Mulatero P, Williams TA, Milan A, et al. Blood pressure in patients with primary aldosteronism is influenced by bradykinin B(2) receptor and alpha-adducin gene polymorphisms. J Clin Endocrinol Metab 2002, 87:3337-3343.
[83] Lim PO, Macdonald TM, Holloway C, et al. Variation at the aldosterone synthase(CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio. J Clin Endocrinol Metab 2002, 87:4398-4402.
1.Smith CD, Weber CJ and Amerson JR: Laparoscopic adrenalectomy: new gold standard.World J Surg. 1999; 23: 389-396.
2.Suzuki K. Laparoscopic adrenalectomy: retroperitoneal approach. Urol Clin North Am.2001; 28: 85-95.
3.Zhang X, Fu B, Lang B, et al. Technique of Anatomical Retroperitoneoscopic Adrenalectomy With Report of 800 Cases. J Urol. 2007; 177:1254-1257.
4.Goitein D, Mintz Y, Gross D, et al. Laparoscopic adrenalectomy: Ascending the learning curve. Surg Endosc. 2004; 18: 771-773.
5.Maccabee DL, Jones A, Domreis J, et al. Transition from open to laparoscopic adrenalectomy: the need for advanced training. Surg Endosc. 2003; 17:1566-1569.
6.Frede T, Erdogru T, Zukosky D, et al. Comparison of training modalities for performing laparoscopic radical prostatectomy: experience with 1000 patients. J Urol. 2005;174:673-678.
7.Stolzenburg JU, Truss MC, Rabenalt R, et al. Training in Laparoscopy. Eau-ebu update series. 2007; 5:53-62.
8.Fu B, Zhang X, Lang B, et al. New Model for Training in Laparoscopic Dismembered Pyeloureteroplasty. J Endourol. 2007; 21:1381-1385.
9.Zhang X, Lang B, Ouyang JZ, et al. Retroperitoneoscopic Adrenalectomy Without Previous Control of Adrenal Vein Is Feasible and Safe for Pheochromocytoma. Urology.2007;69: 849-853.
10.Chandrasekera SK, Donohue JF, Orley D, et al. Basic Laparoscopic Surgical Training:Examination of a Low-Cost Alternative. Eur Urol. 2006;50: 1285-1291.
11.Katz R, Hoznek A, Salomon L, et al. Skill assessment of urological laparoscopic surgeons: can criterion levels of surgical performance be determined using the pelvic box trainer? Eur Urol. 2005;47: 482-487.
12.Teber D, Dekel Y, Frede T, et al. The Heilbronn Laparoscopic Training Program for Laparoscopic Suturing: Concept and Validation. J Endourol. 2005;19: 230-238.
13.LinksKeeley FX Jr, Eden CG, Tolley DA, et al. The British Association of Urological Surgeons: guidelines for training in laparoscopy. BJU Int. 2007; 100:379-381.
14.Ramacciato G, Paolo M, Pietromaria A, et al. Ten years of laparoscopic adrenalectomy:lesson learned from 104 procedures. Am Surg. 2005;71: 321-325.
15.Gumbs AA, Gagner M. Laparoscopic adrenalectomy. Best Pract Res Clin Endocrinol Metab 2006; 20:483-499.
16.Stolzenburg JU, Rabenalt R, Do M, et al. Modular Training for Residents with no Prior Experience with Open Pelvic Surgery in Endoscopic Extraperitoneal Radical Prostatectomy. Eur Urol. 2006;49: 491-499.
17.Lehmann KS, Ritz JP, Maass H, et al. A prospective randomized study to test the transfer of basic psychomotor skills from virtual reality to physical reality in a comparable training setting. Ann Surg. 2005;241: 442-449.
18.Gill IS. The case for laparoscopic adrenalectomy. J Urol. 2001;116: 429-436.
19.Le CQ, Lightner DJ, VanderLei L, et al. The Current Role of Medical Simulation in American Urological Residency Training Programs: An Assessment by Program Directors. J Urol. 2007; 177: 288-291.
20.Fabrizio MD, Tuerk I, Schellhammer PF. Laparoscopic radical prostatectomy:decreasing the learning curve using a mentor initiated approach. J Urol. 2003;196:2063-2065.
21.Skrekas T, Mochtar CA, Lagerveld BW, et al. Mentor-Initiated Approach in Laparoscopic Radical Prostatectomy. J Endourol. 2006;20: 831-835.
22.Sugiono M, Teber D, Anghel G, et al. Assessing the predictive validity and efficacy of a multimodal training programme for laparoscopic radical prostatectomy (LRP). Eur Urol.2007;51: 1332-1340.
23.Rassweiler J, Seemann O, Hatzinger M, et al. Technical evolution of laparoscopic radical prostatectomy after 450 cases. J Endourol. 2003;17: 143-154.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |