Gene polymorphisms of the renin-angiotensin-aldosterone system and angiotensin II type 1-receptor activating antibodies in renal rejection

Steroid refractory acute rejection (SRAR) is a major vital factor in renal transplantation recipients. The pathogenesis of SRAR may involve both immune and non-immune mechanisms. A decreased renal allograft function has also been associated with increased activity of renin-angiotensin-aldosterone system (RAS), which may be genetically determined. A total 206 renal transplant recipients, 116 males and 90 females, were included. The effects of gene polymorphisms of the four components of RAS including angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin type 1 receptor (AT1R), and aldosterone synthase (CYP11B2) were investigated in 19 cases of renal transplant patients with SRAR. The association between SRAR and the activating antibodies targeting the AT1R were also investigated. Genotyping was performed for the M235T-AGT, the I/D-ACE, the A1166C-AT1R, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction. Our results showed that renal allograft recipients with SRAR had significantly higher occurrences of the DD genotype of ACE and CC genotype of AT1R than recipients without SRAR. The other genetic polymorphisms of the RAS were not associated with SRAR. Activating antibodies targeting the AT1R were detected in the sera from 14 SRAR victims with malignant hypertension and without anti-HLA antibodies. This study provides evidence that determination before transplantation of the polymorphism of the gene encoding components of RAS may help identify patients who are at risk for SRAR. The detection of the antibodies of AT1R may contribute to the prevention of SRAR.     

AGT and AT1R gene polymorphism in hypertensive heart disease

Left ventricular hypertrophy in patients with hypertension is a main clinical prognostic entity The aim of this study was to evaluate the association between mutations at genes of the renin-angiotensin system (RAS) and the development of left ventricular hypertrophy. Genetic polymorphism in angiotensinogen (AGT) and angiotensin Il-type 1 receptor (AT1R) genes was examined in a group of well-selected essential hypertensive caucasians with left ventricular involvement (n = 40) and a group of healthy unrelated caucasians (n = 150). Cardiac morphology and function were assessed by M-mode echocardiography. Molecular variants were analysed by amplified fragment length polymorphism. We observed a statistically significant difference both for AGT and AT1R genotype distribution in patients with left ventricular hypertrophy compared with controls (p<0.05). A 0.49 and 0.225 frequency was detected among cases for T and C mutant alleles at AGT and AT1R genes. Mutations in RAS genes are involved in the pathophysiology of target-organ damage in essential hypertension. Evaluation of molecular factors conferring a risk of developing heart involvement may lead to better identification of patient subgroups and more effective control of the clinical course.     

Association of the C-344T polymorphism of CYP11B2 gene with essential hypertension in Hani and Yi minorities of China

BACKGROUND: Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, a C-344T polymorphism in the promoter region of the CYP11B2 gene has been reported to be in association with high blood pressure. We investigated the association between this polymorphism and essential hypertension in Hani (n=305 individuals) and Yi (n=233 individuals) minorities of China. METHODS: CYP11B2 genotyping with polymerase chain reaction-restriction fragment length polymorphism was performed in 267 normotensive subjects and 271 essential hypertensive subjects. At the same time, the T(-344)C polymorphism detection in 33 subjects was also performed by sequencing. RESULT: The frequency of CYP11B2 C-344T genotype in normotensive controls and essential hypertensive cohort in Hani population were TT: 0.729 vs. 0.610; CT + CC: 0.271 vs. 0.390, respectively. The frequency of CYP11B2 C-344T genotype in normotensive controls and essential hypertensive cohort in Yi population were TT: 0.612 vs. 0.475; CT + CC: 0.388 vs. 0.525, respectively. The frequency of CC + CT genotype in the essential hypertensive group was significantly higher than that in the normotensive controls in both Hani and Yi populations (P<0.05). CONCLUSION: The -344C allele of the CYP11B2 may play a role in genetic predisposition to developing essential hypertension in Hani and Yi minorities of China.     

醛固酮合成酶CYP11B2基因多态性与中国汉族人原发性高血压关系的系统分析

目的 Meta分析中国汉族人醛固酮合成酶CYP11B2基因多态性与原发性高血压关系。方法 查阅1980年1月至2006年7月发表的有关醛固酮合成酶CYP11B2基因多态性与原发性高血压关系的病例对照试验研究文献，选择的数据库有中国生物医学文献数据库（CBMdise）、中国学术期刊全文数据库（CAJ—CD）和Medline。以原发性高血压组和健康对照组基因分布的OR值为统计量，全面检索相关文献并剔除不符合要求的文献，排除发表偏倚的影响。应用RevMan4．2软件对各研究结果进行一致性检验和数据合并。最终入选5篇随机对照试验文献。结果 5．篇文献的病例对照试验一致性较好，原发性高血压组总计高血压患者1000例，对照组967例，原发性高血压组与对照组TT/（TC＋CC）OR值（95％可信区间）0．95（0．79，1．13），显著性检验Z值为0．60，P=0．55。T等住基因频率OR值为（95％可信区间）0．92（0．80，1．06），显著性检验Z值为1．17，P=0．24。结论 中国汉族人醛固酮合成酶CYP11B2基因多态性与原发性高血压无关。     

Searching genetic risk factors for sporadic Parkinson's disease

Multiple genetic and environmental factors are thought to cause idiopathic Parkinson's disease (PD). To identify the genetic factors, we are carrying case-control association studies by genome-wide MS (microsatellite) markers and SNP (single nucleotide polymorphism) markers on the candidate genes, and sib-pair analysis. We investigated 27,000 MS markers and found 8% of them were significantly associated with PD in the first screening. In the candidate gene approach, of 267 SNPs on 122 candidate genes, 22 SNPs on 16 genes showed significant p-values (less than 0.05) by chi-square statistics. The further analysis is necessary to identify causative genes for PD.     

The molecular genetics of rheumatoid arthritis disease gene

Rheumatoid arthritis(RA) is a chronic polyarthritis of unknown etiology affecting approximately 1% of the population worldwide. Previous studies have shown that the ratio of the risk for siblings of patients with the disease versus the prevalence of that disease in the general population (lambda s) is much greater in RA, suggesting that genetic factors may be involved in familial clustering. Using microsatellite marker analysis and sib-pair linkage study, we have identified three chromosome regions D1S214/253, D8S556 and DXS1232/984 as candidate loci for RA disease genes. In this article, we review the molecular genetic findings on the RA disease genes located respectively at each of the above chromosome regions. We show that the death receptor 3(DR3) gene, a Fas family member, containing nucleotide polymorphism is the candidate disease gene located at D1S214/253. We also identify the mutant forms of angiopoietin-1(Ang-1) and Dbl proto-oncogenes respectively as the candidate genes located at D8S556 and DXS1232/984. We surmise that these mutations are responsible for the impairment of apoptosis induction, angiogenesis and leukocyte function in the patients, which may predispose to autoimmunity.     

Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree.

Glucocorticoid-suppressible hyperaldosteronism is a dominantly inherited form of hypertension believed to be caused by the presence of a hybrid CYP11B1/CYP11B2 gene which has arisen from an unequal crossing over between the two CYP11B genes in a previous meiosis. We have studied a French pedigree with seven affected individuals in which two affected individuals also have adrenal tumors and two others have micronodular adrenal hyperplasia. One of the adrenal tumors and the surrounding adrenal tissue has been removed, giving a rare opportunity to study the regulation and action of the hybrid gene causing the disease. The hybrid CYP11B gene was demonstrated to be expressed at higher levels than either CYP11B1 or CYP11B2 in the cortex of the adrenal by RT-PCR and Northern blot analysis. In situ hybridization showed that both CYP11B1 and the hybrid gene were expressed in all three zones of the cortex. In cell culture experiments hybrid gene expression was stimulated by ACTH leading to increased production of aldosterone and the hybrid steroids characteristic of glucocorticoid-suppressible hyperaldosteronism. The genetic basis of the adrenal pathologies in this family is not known but may be related to the duplication causing the hyperaldosteronism.     

EMILIN1 CYP11B2基因多态性与原发性高血压相关性研究

目的 研究 EMILIN1、CYP11B2基因多态性与原发性高血压的相关性。方法 回顾性分析该院2010年3月至2012年3月期间收治的100例原发性高血压患者,将其作为临床研究对象（患者组）,另选取血压正常的健康自愿者100例作为健康对照组,进行基因多态性的对比研究。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法 分别检测两组EMILIN1基因SNP位点和CYP11B2基因SNP位点的等位基因及基因型分布情况。结果 患者组患者EMILIN1基因rs2304682位点上的基因型与等位基因频率与健康对照组比较,差异有统计学意义（P＜0．05）,患者组CG基因型、G等位基因频率明显高于健康对照组,而CC基因型、C等位基因频率则比健康对照组低;CYP11B2基因多态性基因型及等位基因频率发现,患者组（CYP11B2）-344 T/C基因多态性中TT基因型、T基因频率明显高于健康对照组,而CT 基因型、C基因频率则低于健康对照组,差异均有统计学意义（P＜0．05）。结论 EMILIN1基因多态性可能与原发性高血压有一定的相关性,（CYP11B2）-344T/C位点上等位基因T的频率较高。     

Immunoregulatory genes in autoimmune thyroid disease]

Autoimmune thyroid diseases (AITD) has a strong genetic basis. Although several candidate genes have been studied, the AITD causing genes are still unknown. Major candidate immune regulatory genes include human leukocyte antigen (HLA) gene, Ig heavy chain genes, T cell receptor genes, IL-1 receptor antagonist gene, IL-1 alpha gene and cytotoxic T lymphocyte antigen-4 (CTLA-4) gene. The relation between HLA and AITD has extensively been studied. In addition, polymorphism of the 3'-untranslated region and codon 17 of the CTLA-4 gene has been reported to associate positively with AITD. However, no linkage analyses have showed positive relation between AITD and these candidate genes except for HLA.     

Genes in rennin-angiotensin system

A large number of association studies revealed the importance of gene polymorphisms in renin-angiotensin system(RAS) in the pathogenesis of hypertension. Among these many polymorphisms of RAS genes, M235T or G-6A polymorphism of angiotensinogen gene increases the risk for salt sensitivity, lacunar infarction, non-dipper type of blood pressure variation, etc. and plasma angiotensinogen level. On the other hand, homozygous deletion polymorphism of angiotensin converting enzyme gene(ACE DD) increases the risk for male hypertension, ischemic heart disease and renal disease via increase of plasma and tissue ACE levels, and shows poor response to medication. Gene targeting experiments in mice enable us to examine whether quantitative changes in gene expression in RAS affect blood pressure, resulted that a simple computer simulation concerning RAS and the kallikrein-kinin system(KKS) emphasize the importance of interaction between RAS and KKS. This mini-review also describes the effect of renin or AT1 receptor gene polymorphisms, and the role of RAS genes in the correlation between inflammation and atherosclerosis.     

丹参酮ⅡA抑制醛固酮生物合成的作用

背景醛固酮是左心室肥厚重要的致病因子,有证据提示中药丹参提取物能够干预醛固酮的生物合成. 目的探讨丹参酮ⅡA对心肌醛固酮合成相关基因表达的作用. 设计随机对照观察. 单位华中科技大学同济医学院附属同济医院. 材料实验于2002-11/2004-03在华中科技大学同济医学院附属同济医院急诊科实验室完成,选用12周龄雄性自发性高血压SHR大鼠20只,随机分为高血压组、丹参酮ⅡA组,每组10只. 方法丹参酮ⅡA组经尾静脉注射丹参酮ⅡA溶液1.5 mg/(kg·d),高血压组给予相当容积的蒸馏水.给药12周后断头处死大鼠,留取心肌标本,通过反转录-聚合酶链反应,以GAPDH基因扩增引物表为内参照,分别测定心肌醛固酮合成相关基因CYP11B1及CYP11B2 mRNA表达. 主要观察指标心肌醛固酮合成相关基因CYP11B1及CYP11B2 mRNA表达水平. 结果20只大鼠被纳入实验,并全部进入结果分析,无脱失值.①两组大鼠心肌CYP11B1及CYP11B2基因表达的定性分析以100bp Plus Lad-der为Marker,分别在440 bp,461 bp及336 bp处可见清晰的扩增条带,DNA测序证实为CYP11B1,YP11B2及GAPDH的编码基因片段.②两组大鼠心肌CYP11B1及CYP11B2基因表达的定量分析丹参酮ⅡA组CYP11B1及CYP11B2的mRNA表达水平明显低于高血压组(0.924±0.121,1.343±0.132,P＜0.05;1.017±0.119,1.675±0.126,P＜0.01). 结论丹参酮ⅡA可能通过直接下调心脏局部醛固酮合成相关基因CYP11B1及CYP11B2 mRNA表达,抑制心脏局部醛固酮的生物合成,从而发挥抗高血压左室肥厚的效应.     

Polygenetic regression model of renin-angiotensin system genes and the risk of coronary artery disease in a large angiographic population

BackgroundPolygenetic effect has rarely been addressed in the genetic studies of coronary artery disease (CAD). We used the largest and ethnically homogeneous angiographic cohort to analyze multilocus data in renin-angiotensin system genes, and provide an explicit demonstration of gene–gene interactions.MethodsA total of 1254 consecutive patients who underwent cardiac catheterization (735 with coronary artery disease and 519 without) were recruited. Angiotensin converting enzyme(ACE) gene I/D polymorphism; T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen (AGT) gene; and A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects, adjust non-genetic confounding effects and detect gene–gene interaction between ACE and AT1R genes.ResultsWe found significant differences in global AGT gene haplotype profile and individual haplotypes between cases and controls. Significant two-way and three-way gene–gene interactions between ACE I/D, AT1R A1166C polymorphisms and AGT gene haplotypes were detected. However, subjects carrying both D allele and GGCATC haplotype had an increased risk of CAD (odds ratio = 1.63 [1.16–2.29]; P = 0.004). We also used haplotype counting to directly estimate the odds ratio of each specific AGT gene haplotype, and found that the effects of haplotypes were markedly different in subgroups with different ACE or AT1R gene genotype.ConclusionsThe regression-based haplotype analyses permits simultaneous dectection of multi-locus and multi-gene effects in determining the risk of CAD. We provide the paradigm for genetic studies of complex-trait diseases using candidate genes based on biological pathways.     

Association between the eNOS (Glu298Asp) and the RAS genes polymorphisms and premature coronary artery disease in a Turkish population

BACKGROUND: The renin-angiotensin system (RAS) and endothelial nitric oxide (NO) affect the pathogenesis of atherosclerosis and prognosis of coronary artery disease (CAD). Previous epidemiologic data suggested that genetic factors are more likely to affect young rather than old people. Our objective was to investigate the association between the polymorphisms of eNOS (Glu298Asp) and the RAS genes and premature CAD in a Turkish population. METHODS: A total of 115 Turkish patients with premature CAD and 83 controls were included in the study. ACE I/D, AT1R A/C, AGT T/M and eNOS Glu298Asp gene polymorphisms were analysed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: It was found that increased premature CAD risk is associated with higher frequencies of the ACE DD [OR: 2.600 (CI 95% 1.395-4.847, p=0.002)], AGT MM [OR=2.407 (CI 95% 1.267-4.573, p=0.007)] and eNOS 894TT [OR=17.000 (CI 95% 3.952-73.125, p<0.001)] genotypes. Carriers of ACE DD+eNOS 894TT (p=0.002), AGT MM+eNOS 894TT (p=0.001), AT1R AA+eNOS 894TT and AT1R non-AA+eNOS 894TT (p=0.002) genotypes were significantly associated with the risk of premature CAD. CONCLUSIONS: This study indicates a synergistic contribution of RAS genes (ACE I/D, AGT T/M, AT1R T/C) and eNOS Glu298Asp polymorphisms to the development of the premature CAD.     

血管紧张素原基因部分多态性指标与原发性高血压的发病风险:社区病例对照

背景:血管紧张素原基因是第一个被发现的原发性高血压候选基因,T174M5和M235T多态均位于AGT基因第二外显子,且存在连锁不平衡。启动子区域A-6G和G-217A位点多态对其基因表达起重要调节作用,且血管紧张素原基因的表达产物与血压水平的维持密切相关。目的:探讨血管紧张素原基因A-6G,T174M和G-217A位点多态性与中国汉族人群原发性高血压发病风险的关系。设计:整群抽样,病例-对照分析。单位:南京医科大学第一附属医院老年医学科与心血管科,国家人类基因组南方研究中心,江苏省东台市人民医院心血管科。对象:实验于2005-09/10在江苏省东台市农村完成。①263例实验对象均来自江苏省盐城市东台县农村,其中原发性高血压组177例为未经药物治疗的原发性高血压患者,高血压的诊断参照1999年WHO/ISH高血压诊断标准(收缩压≥140mmHg和/或舒张压≥90mmHg);正常对照组86例。②纳入标准:实验对象为汉族;长期居住本地非外来人口;能清楚回答问题;经病史、临床症状、体征及辅助检查确诊;统一问卷面访调查资料完整。③排除标准:原发性高血压组排除继发性高血压,正常对照组排除高血压家族史,同时两组人群均排除肝、肾慢性疾病和糖尿病。方法:采集外周静脉血3mL,用FlexiGeneDNAKit(250)提取人外周血中DNA。应用primer3软件进行引物设计,并排除引物序列中的多态位点。多重聚合酶链反应扩增后,取3μL反应产物用琼脂糖凝胶电泳检测扩增结果,扩增成功的聚合酶链反应产物用QIAquickPCRPurifica-tionKit纯化,纯化后的产物用DNaseⅠ片段化,片段化的酶切产物以脱氧核苷酸末端转移酶进行荧光素标记。每个单核苷酸多态各设计2条等位基因特异性探针和1条错配探针,芯片用OmniGridTM100点样仪制备,每个探针重复3次,形成3个阵列。杂交液95℃变性10min后,立即置于冰上冷切,取10μL杂交液加入到芯片矩阵上,50℃杂交2h,然后洗涤,甩干。GenePix4000B共聚焦激光扫描仪进行芯片扫描,利用GenePixPro提取得到每条探针的荧光信号强度值,通过计算每个单核苷酸多态的等位基因分数判断基因型。主要观察指标:①两组血管紧张素原基因各多态位点基因型分布频率的比较。②血管紧张素原基因A-6G和T174M位点多态性与原发性高血压发病风险的相关分析。③两组血管紧张素原基因A-6G,T174M和G-217A位点多态性对血压的影响。结果:按意向处理分析,263例实验对象均进入结果分析。①血管紧张素原基因A-6G位点AA,AG,GG基因型(P=0.014)以及A,G等位基因频率(P=0.004,OR=0.44)差异明显;T174M位点CC,CT,TT基因型(P=0.031)以及C,T等位基因频率(P=0.014,OR=0.55)差异有显著性意义;未发现G-217A位点GG,AG,AA基因型(P=0.722)以及G,A等位基因频率(P=0.403,OR=0.80)有明显差异。②携带A-6G多态AA基因型和T174M多态CC基因型的个体发生原发性高血压的风险分别减少57%(95%可信区间=0.23～0.82,P=0.010)和56%(95%可信区间=0.25～0.79,P=0.006)。③两组血管紧张素原基因A-6G,T174M和G-217A位点各基因型的收缩压、舒张压和平均动脉压的差异均无显著性意义(F=0.100～2.911,P均>0.05)。结论:血管紧张素原基因A-6G位点AA基因型和T174M位点CC基因型可能会减少中国汉族人群原发性高血压发病风险,未发现G-217A多态基因型与其有显著相关性。     

Linkage between obesity and a marker near the tumor necrosis factor-alpha locus in Pima Indians.

Because tumor necrosis factor-alpha (TNF-alpha) expression is increased in adipose tissue of both rodent models of obesity and obese humans, it has been considered as a candidate gene for obesity. Pima Indians were scored for genotypes at three polymorphic dinucleotide repeat loci (markers) near the gene TNF-alpha at 6p21.3. In a sib-pair linkage analysis, percent body fat, as measured by hydrostatic weighing, was linked (304 sib-pairs, P = 0.002) to the marker closest (10 kb) to TNF-alpha. The same marker was associated (P = 0.01) by analysis of variance with BMI. To search for possible DNA variants in TNF-alpha that contribute to obesity, single stranded conformational polymorphism analysis was performed from 20 obese and 20 lean subjects. Primer pairs were designed for the entire TNF-alpha protein coding region and part of the promoter. Only a single polymorphism located in the promoter region was detected. No association could be demonstrated between alleles at this polymorphism and percent body fat. We conclude that the linkage of TNF-alpha to obesity might be due to a sequence variant undetected in TNF-alpha or due to a variant in some other closely linked gene.     

醛固酮合酶基因多态性与原发性高血压相关性研究

目的探讨醛固酮合酶基因（CYP11B2）-344T/C多态性与原发性高血压的相关性。方法采用关联分析,收集湖南地区汉族男性原发性高血压患者100例,正常对照100名。应用聚合酶链反应-限制性片段长度多态性分析（PCR-RFLP）对2组对象的CYP11B2-344T/C多态进行分析。结果2组对象CYP11B2基因型（TT型、CT型和CC型）的频率差异无统计学意义（χ^2=0.34,P〉0.05）,等位基因的频率差异也无统计学意义（χ^2=0.28,P〉0.05）,但各组内等位基因T的频率（原发性高血压组：67.67%）高于等位基因C（32.33%）;对照组T69.67%高于C 30.33%。结论多基因联合分析显示,在男性患者中,CYP11B2-344T/C多态性与原发性高血压无明显相关,但CYP11B2-344各组内等位基因T的频率高于等位基因C。     

Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22.

Resistance to insulin-mediated glucose disposal is a common finding in patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as in nondiabetic individuals with hypertension. In an effort to identify the generic loci responsible for variations in blood pressure in individuals at increased risk of insulin resistance, we studied the distribution of blood pressure in 48 Taiwanese families with NIDDM and conducted quantitative sib-pair linkage analysis with candidate loci for insulin resistance, lipid metabolism, and blood pressure control. We found no evidence for linkage of the angiotensin converting enzyme locus on chromosome 17, nor the angiotensinogen and renin loci on chromosome 1, with either systolic or diastolic blood pressures. In contrast, we obtained significant evidence for linkage or systolic blood pressure, but not diastolic blood pressure, to a genetic region at or near the lipoprotein lipase (LPL) locus on the short arm of chromosome 8 (P = 0.002, n = 125 sib-pairs, for the haplotype generated from two simple sequence repeat markers within the LPL gene). Further strengthening this linkage observation, two flanking marker loci for LPL locus, D8S261 (9 cM telomeric to LPL locus) and D8S282 (3 cM centromeric to LPL locus), also showed evidence for linkage with systolic blood pressure (P = 0.02 and 0.0002 for D8S261 and D8S282, respectively). Two additional centromeric markers (D8S133, 5 cM from LPL locus, and NEFL, 11 cM from LPL locus) yielded significant P values of 0.01 and 0.001, respectively. Allelic variation around the LPL gene locus accounted for as much as 52-73% of the total interindividual variation in systolic blood pressure levels in this data set. Thus, we have identified a genetic locus at or near the LPL gene locus which contributes to the variation of systolic blood pressure levels in nondiabetic family members at high risk for insulin resistance and NIDDM.     

Angiotensin I-converting enzyme gene polymorphism in a Serbian population: a gender-specific association with hypertension

Human essential hypertension has a multifactorial origin and is caused by a delicate interaction between susceptibility genes and environmental factors. Candidate genes are selected from the renin-angiotensin system (RAS) and are physiologically implicated in blood pressure regulation. We investigated the association between insertion/deletion (I/D) polymorphism at the angiotensin-converting enzyme (ACE) locus and hypertension in a case-control study conducted in a population of Caucasians (175 females, 210 males). Case subjects were those with untreated borderline hypertension. A significant, moderate, male, gender-specific independent association between DD genotype and high blood pressure was found. Adjusted odds ratio (OR) was 2.0 (95% CI, 1.1 to 3.9; p=0.03) in the whole group and 2.5 (95% CI, 1.2 to 5.1; p=0.01) in the group truncated on the basis of age (< or = 50 years). Our findings support the hypothesis that ACE is a gender-specific candidate gene for hypertension.     

Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension

BACKGROUND: Salt-sensitive (SS) hypertension affects >30 million Americans and is often associated with low plasma renin activity. We tested the diagnostic validity of several candidate genes for SS and low-renin hypertension. METHODS: In Japanese patients with newly diagnosed, untreated hypertension (n = 184), we studied polymorphisms in 10 genes, including G protein-coupled receptor kinase type 4 (GRK4), some variations of which are associated with hypertension and impair D1 receptor (D1R)-inhibited renal sodium transport. We used the multifactor dimensionality reduction method to determine the genotype associated with salt sensitivity (> or =10% increase in blood pressure with high sodium intake) or low renin. To determine whether the GRK4 genotype is associated with impaired D1R function, we tested the natriuretic effect of docarpamine, a dopamine prodrug, in normotensive individuals with or without GRK4 polymorphisms (n = 18). RESULTS: A genetic model based on GRK4 R65L, GRK4 A142V, and GRK4 A486V was 94.4% predictive of SS hypertension, whereas the single-locus model with only GRK4 A142V was 78.4% predictive, and a 2-locus model of GRK4 A142V and CYP11B2 C-344T was 77.8% predictive of low-renin hypertension. Sodium excretion was inversely related to the number of GRK4 variants in hypertensive persons, and the natriuretic response to dopaminergic stimulation was impaired in normotensive persons having > or =3 GRK4 gene variants. CONCLUSIONS: GRK4 gene variants are associated with SS and low-renin hypertension. However, the genetic model predicting SS hypertension is different from the model for low renin, suggesting genetic differences in these 2 phenotypes. Like low-renin testing, screening for GRK4 variants may be a useful diagnostic adjunct for detection of SS hypertension.     

原发性高血压患者醛固酮合酶基因多态性与血浆醛固酮水平的关系研究

目的 :探索武汉地区汉族高血压人群醛固酮合酶CYP11B2基因 3 44C/T多态性与血浆醛固酮 (pAldo)水平的相关性。方法 :应用PCR RELP技术对 10 6例武汉地区汉族高血压病人的CYP11B2基因 3 44C/T多态性进行分析 ,应用放射免疫法测定 10 6例武汉地区汉族高血压病人的血浆醛固酮水平。结果 :武汉地区汉族高血压人群CYP11B2基因 3 44C/T多态性以TT和CT为主要基因型 ,C等位基因较少见 ,其频率为 0 2 5。高血压患者血浆醛固酮水平在CYP11B2基因 3 44C/T的 3个不同基因型组中差异有显著性 (P <0 0 1)。结论 :武汉地区高血压人群的血浆醛固酮水平与CYP11B2基因 3 44C/T多态性相关 ,且高醛固酮水平与C等位基因相关。