新疆哈萨克族和维吾尔族人群原发性高血压与αENaC和β_2-AR基因多态性的关联研究
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摘要
目的:
原发性高血压(Essential hypertension;EH)是最常见的危害人类健康的心血管疾病,能引起一系列严重后果。其发病是多种遗传因素和环境因素共同作用的结果,其中遗传因素在高血压的发病机制中起重要作用。随着人类基因组测序的完成,研究与疾病表型相关的基因序列变异已成为医学遗传学的一个主要课题。单核苷酸多态性(single-nucleotide polymorphism;SNP)作为第三代遗传标记,具有数量大、分布广的特点,系统地在群体水平上筛查、鉴定SNP,特别是基因编码区和调控区的SNP,通过病例组与对照组间的比较和统计学分析,就有可能获得与疾病相关联的SNP位点或单体型,这对于阐明某些复杂多基因疾病的遗传机制具有重要意义。本课题对新疆巴里坤地区哈萨克族牧民和吐鲁番地区维吾尔族农民进行了高血压流行病学调查,了解高血压病流行现状并分析其高发因素;同时基于HapMap计划中国人群的数据,采用病例-对照研究和标签SNP(tSNP)方法在新疆地区哈萨克族和维吾尔族人群中分别对上皮细胞钠通道α亚单位基因(Epithelium Natrium Channelgeneαsubunit;αENaC)和β_2-肾上腺素受体基因(β_2-adrenergic receptor;β_2-AR)多态进行分析。首先系统筛查两人群中αENaC和β_2-AR基因SNP的存在和频率,阐明连锁不平衡模式和单体型分布,同时选择两候选基因的tSNP,进而在病例—对照中探讨这些tSNP及其所构成单体型与高血压的关联:并比较各SNP基因型、等位基因和单体型频率在两民族群体中的分布情况,以期阐明这些候选基因与原发性高血压的关系及其在原发性高血压发病机制中的作用,从遗传学角度剖析两群体高血压患病的原因,进一步明确其对更广泛人群高血压疾病发生所起的作用。
方法:
(1)采用整群抽取随机抽样的方法对新疆巴里坤县5个乡哈萨克族牧民和吐鲁番地区3个乡维吾族农民进行了三次流行病学调查,共采集哈族血液标本1141例,其中高血压组703例,正常对照组438例;维族血液标本894例,其中高血压组424人,正常对照组470例。
(2)随机选取40例无血缘关系的哈萨克族样本,利用PCR产物直接测序的方法筛查αENaC基因调控区、启动子区、外显子以及部分内含子区域的全部序列变异。计算常见SNP(少见等位基因频率Minor Allele Frequency;MAF＞5%)的连锁不平衡系数D~1和γ~2;利用Haploview软件选择其中3个SNPs作为tSNPs,采用TaqMan技术和聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restrictedfragment long polymorphism;PCR-RFLP)技术分别对入选样本进行αENaC基因扩增和基因分型。
(3)基于本实验室前期工作基础,选择目前公认研究较多的β_2-AR基因编码区Arg16Gly和Gln27Glu两个高频多态位点,应用TaqMan技术进行高通量基因分型。
(4)以新疆地区哈萨克族和维吾尔族人群作为研究对象进行群体病例-对照分析研究,分别探讨单个SNP位点及其构成的单体型与原发性高血压的相关性,并了解αENaC和β_2-AR基因多态在新疆两民族群体中的分布情况。
(5)借助spss13.0软件进行统计学处理。x~2检验用于计数资料的关联分析和Hardy—Weinberg平衡检验,t检验用于临床指标的差异性判定,协方差分析用于均数的调整,Logistic回归分析用于多因素资料中筛查独立患病危险因素及计算优势比(Odds ratio,OR);同时运用SHEsis软件在线分析多个位点之间的连锁不平衡(linkage disequilibrium;LD)关系,Haploview软件用于单体型模块判定和tSNP的选取,应用phase软件进行多态位点单体型的构建和分析。
结果:
(1)流行病学调查结果显示:巴里坤地区哈萨克族高血压的检出率为61.6%:吐鲁番地区维吾尔族高血压的检出率为47.4%,哈萨克族人群的平均收缩压和舒张压均显著高于维吾尔族;两民族人群高血压的患病率随着年龄的增高而明显增加,且超重者和肥胖者血压增高明显多于体重正常者;血浆总胆固醇(TC)和甘油三酯(TG)的水平在高血压组和正常对照组间的差异有统计学意义(P＜0.05);高血压组男性吸烟率亦明显多于正常对照组。
(2)小样本测序在αENaC基因7kb范围内共检出9个高频SNPs位点,分别命名为G(-947)A、G(-321)A、A(+6)G、G(+49)C、C(+866)T、A334T、C(+20844)T、A(+26622)G和T663A,全部与NCBI dbSNP公共数据库中报道一致。
(3)从测序检出的9个多态位点中选择3个SNPs作为tSNPs,可以很好的预测常见单体型和剩余常见SNP,它们分别是位于启动子区的G(-947)A、外显子6的A334T和外显子13的T663A:并对这3个tSNPs进行高通量的扩增与基因分型。
(4)αENaC基因3个SNPs的基因型频率在两群体中分布均符合Hardy-Weinberg平衡;单个位点SNP关联分析显示:αENaC基因3个tSNPs基因型及等位基因频率分布在哈萨克族及维吾尔族群体高血压组和正常对照组中差异无统计学意义(P＞0.05)。
(5)分别对9个多态位点做配对连锁不平衡分析,其中只有G(-947)A和G(+49)C、A(+26622)G和T663A位点在哈萨克族群体中均存在着强连锁不平衡,多数位点存在较弱或无连锁不平衡;单体型关联分析结果显示:3个tSNPs共构成8种单体型(H1～8),单体型总体分布频率在哈萨克族病例组和对照组中的差异有统计学意义(P＜0.05),进一步的关联分析表明哈萨克族群体中,H2、H3、H6和H7单体型频率在高血压组和正常对照组的差异有统计学意义(P＜0.05):在维吾尔族群体中,除了H1和H3单体型频率在高血压组和正常对照组的差异未达到统计学意义,其余单体型频率在两组中的差异均有统计学意义(P＜0.05)。
(6)比较αENaC基因单体型频率在新疆两个不同民族中的分布,结果发现其分布在哈萨克族与维吾尔族群体中的差异有统计学意义(P＜0.05)。
(7)应用TaqMan技术对β_2-AR基因进行大样本分型后发现:Arg16Gly多态和Gln27Glu多态的基因型频率在两群体中分布均符合Hardy-Weinberg平衡;单个位点关联分析显示:基因型频率及等位基因频率分布在两民族高血压组和正常对照组中差异均无统计学意义(P＞0.05)。
(8)对β_2-AR基因两个多态位点做配对连锁不平衡分析,强度D~1值在哈萨克族和维吾尔族人群中分别为0.8和0.7,存在着连锁不平衡;进一步做单体型分析后,两位点所构成的4种单体型频率分布在两民族高血压组和正常对照组的差异均无统计学意义(P＞0.05)。
结论:
(1)新疆哈萨克族高血压患病率明显高于维吾尔族,平均收缩压和舒张压在两群体中差异有统计学意义;哈、维两民族高血压的患病率随着年龄的增加而升高,并且高血压的发生均与吸烟、高体重指数、血脂紊乱等心血管病的危险因素密切相关。
(2)研究未发现αENaC基因单个位点与新疆地区哈萨克族和维吾尔族人群的高血压相关联;而多位点单体型分析结果提示αENaC基因单体型结构分布在两民族病例组和对照组中差异均有统计学意义。由于多个位点分析的检验效能更强,因此我们推断在两民族群体中可能有民族特异性疾病易感的单体型或保护性单体型存在,本研究结果支持αENaC基因的基因剂量效应可能存在于单体型中,而不与单个位点直接关联。
(3)αENaC基因单体型频率在新疆两民族人群中的分布差异有统计学意义,推断该基因多态的分布具有民族特异性,可能与两民族不同发病特点有关。
(4)β_2-AR基因Arg16Gly和Gln27Glu多态及其它们所构成的单体型与新疆地区哈萨克族和维吾尔族人群的高血压患病无直接关联。
Objective:
Essential hypertension is the most common cardiovascular diseases that threaten human health and may lead to a series severe results such as cardiac and renal failure and shock.Hypertension is a complex disease resulted from the interaction of the cumulative effect of multiple genetic and environmental factors and genetic factors play an important role.Along with the completion of human genome project,it has been a key aim to study the sequence variations that correlate with certain diseases.As the third generation of genetic markers,Single Nucleotide Polymorphism(SNP)is characterized as large number and wide distribution.SNP or haplotype that are related to diseases may be obtained through systematically identifying SNPs especially those in coding and regulating region and the case-control study.This will play an essential role in searching the genetic mechanisms of some complex polygenic diseases.We investigated three epidemiology research in the pastoral area of balikun county and the rural area of Tuluafan to report the epidemiological characteristics of hypertension and assessment of the risk factors relevant to the high prevalence of hypertension.And we referring to the Chinese data in HapMap project and study SNPs of Epithelium Natrium Channel geneαsubunit(αENaC)andβ_2-adrenergic receptor gene(β_2-AR)that are important candidate genes of essential hypertension in Kazak and Uygur populations in Xinjiang province, Systematically screen for and examine SNPs in two ethnic groups and the pattern of intragenic linkage disequilibrium and the haplotype structure were estimated,Then investigate the relation between these polymorphisms and haplotypes and hypertension; Compare with every SNP genotype and allele gene frequency and distribution in two ethnic groups,we sought to demonstrate effect of candidate genes in hypertension pathogenesis from genetic ways and further search the mechanisms in more polulations.
Methods:
(1)Three epidemiology research was carried out in a natural population by cluster sampling and collected blood samples of 1141 kazak subjects who come from the pastoral area of balikun county,including 703 patients and 438 controls subjects,894 Uygur subjects who come from the rural area of Tuluafan,including 424 patients and 470 controls subjects.
(2)All the sequence variants located promoter,exon,intron regions ofαENaC gene were identified by directly sequencing of PCR product derived from 40 randomly selected samples.The pattern of pairwise LD between the common(minor allele frequency＞5%)SNPs was measured by D~1 andγ~2,and the tSNP were selected according to Haploview software and the papers;All tSNPs ofαENaC gene were futher genotyped in all subjects by TaqMan system and polymerase chain reaction -restriction fragment length polymorphism(PCR-RFLP).
(3)On the basic of previous research,We chose theβ_2-AR gene to study the two high frequency polymorphisms Arg16Gly and Gln27Glu located encode region,then the TaqMan assay is used for the detectionβ_2-AR genotype.
(4)The case-control study in a large group was carried out separately for each of the tSNP and followed up by haplotype analyses to determine the relation between SNPs and hypertension in two ethnic groups in Xinjiang and investigate the distribution of candidate genes polymorphisms in two ethnic groups.
(5)Spss software version 13.0 for windows was used to analyze the statistics data, association for dichotomous variables and the Hardy-Weinberg equilibrium for the polymorphisms were tested by chi-square analysis.Association for 2 groups was tested by Student' s t test for continuous variables,Analysis of covariance(ANCOVA)was used to ajuSted mean;Ajusted Odds ratios(ORs)with 95%confidence intervals from logistic regression analysis was used to estimate the relative risk of hypertension associated with genotype:linkage disequilibrium(LD)analysis was carried out in a pair-wise fashion by SHESsis software online,haplotype block was determined by haploview software and haplotypes for HT and NT were inferred by the statistical software package PHASE version 2.0.
Results:
(1)Epidemiology research indicate:The prevalence of hypertension is 61.6%and 47.4%respectively in Kazak and Uygur polulations,the average levels of systolic blood pressure and diastolic blood pressure in Kazak is significantly higher than those in Uygur and the prevalence of hypertension increases with age increasing in both populations, body mass index(BMI),serum total cholesterol(TC),triglycerides(TG)and the rate of cigarette-smoking in the male in EH group are significantly higher than NT group.
(2)In a total length of 7 kb ofαENaC gene explored,we identified 9 SNPs named G(-947)A、G(-321)A、A(+6)G、G(+49)C、C(+866)T、A334T、C(+20844)T、A(+26622)G and T663A that located promoter,exon2,6,13 and intron 1,7,11,All 9 polymorphisms were previously reported in the dbSNP at NCBI.
(3)From 3 tSNPs selected from 9 polymorphsims we can predict common haplotype and other SNPs.They are G(-947)A that located promoter,A(334)T located exon 6 and A(663)T located exon 13,then all the genotypes of 3 SNPs were detected.
(4)The genotypes of theαENaC gene variants were found to be in Hardy-Weinberg equilibrium in two ethnic groups;Single-locus association study indicated:Frequencies of genotype and allele of 3 SNPs in EH group were not significantly different from NT group respectively in Kazak and uygur populations(P＞0.05).
(5)Pairwise LD was carried out for SNP respectively,Only G(-947)A and G(+49)C,A(+26622)G and T663A polymorphisms were in LD and most of the pairwise LD values of the polymorphisms were in weak or no disequilibrium.Hyplotype based association study in the two populations indicate:8 haplotypes(H1～8)was reconsreucted by 3 tSNPs and H2,H3,H6 and H7 haplotype frequency in EH is different from HT group in Kazak population and most haplotypes frequency except for H1 and H3 in EH is also different from HT group in uygur population.
(6)Compare with hylotype frequency distribution in two ethnic and there were significantly different in Kazak and uygur populations(P＜0.05).
(7)β_2-AR gene Arg16Gly and Gln27Glu genotype are detected by TaqMan assay in arge cohort,The genotypes of theβ_2-AR gene variants were found to be in Hardy-Weinberg equilibrium in two ethnic groups,We did not observe any prevalent genotypes of theαENaC polymorphisms between controls and hypertension patients in two ethnic groups(P＞0.05).
(8)Pairwise LD was carried out for SNP,D~1 = 0.8 and 0.7 in Kazak and uygur populations respectively and two loci were in weak disequilibrium;Four common haplotypes were inferred after haplotype reconsreuction and haplotype frequencies has no statistic significant in case and in control in the two ethnic groups(P＞0.05).
Conclusions:
(1)The prevalence of hypertension in kazak is higher than this in Uygur,the average levels of systolic blood pressure and diastolic blood pressure is significantly different between Kazak and Uygur groups,and the group of high blood pressure is associated with higher levels of serum TC,TG,BMI and rate-smoking.
(2)Our results suggest that single polymorphism of theαENaC gene might be not associated with hypertension in Kazak and Uygur populations in Xinjiang,In multilocus haplotype analysis,theαENaC gene haplotype profile is significantly different between cases and controls in both ethnic groups,because multilocus haplotype analysis has more detection power than single polymorphism locus,we speculate there is ethnic-specific disease predisposing or protecting haplotypes in the hypertensives in Kazak and Uyghur populations and our data support the presence of gene-dose effect for some haplotypes but not the single polymorphism locus.
(3)Frequecy of haplotype is significantly different in Kazak and uygur populations, we indicateαENaC gene polymorphisms have ethnic specificity and maybe association with EH trait in two populations,
(4)Both single polymorphism locus of theβ_2-AR gene and haplotype that are reconstructed by SNPs might be also not associated with hypertension in Kazak and Uygur populations in Xinjiang.
原发性高血压(Essential hypertension;EH)是最常见的危害人类健康的心血管疾病,能引起一系列严重后果。其发病是多种遗传因素和环境因素共同作用的结果,其中遗传因素在高血压的发病机制中起重要作用。随着人类基因组测序的完成,研究与疾病表型相关的基因序列变异已成为医学遗传学的一个主要课题。单核苷酸多态性(single-nucleotide polymorphism;SNP)作为第三代遗传标记,具有数量大、分布广的特点,系统地在群体水平上筛查、鉴定SNP,特别是基因编码区和调控区的SNP,通过病例组与对照组间的比较和统计学分析,就有可能获得与疾病相关联的SNP位点或单体型,这对于阐明某些复杂多基因疾病的遗传机制具有重要意义。本课题对新疆巴里坤地区哈萨克族牧民和吐鲁番地区维吾尔族农民进行了高血压流行病学调查,了解高血压病流行现状并分析其高发因素;同时基于HapMap计划中国人群的数据,采用病例-对照研究和标签SNP(tSNP)方法在新疆地区哈萨克族和维吾尔族人群中分别对上皮细胞钠通道α亚单位基因(Epithelium Natrium Channelgeneαsubunit;αENaC)和β_2-肾上腺素受体基因(β_2-adrenergic receptor;β_2-AR)多态进行分析。首先系统筛查两人群中αENaC和β_2-AR基因SNP的存在和频率,阐明连锁不平衡模式和单体型分布,同时选择两候选基因的tSNP,进而在病例—对照中探讨这些tSNP及其所构成单体型与高血压的关联:并比较各SNP基因型、等位基因和单体型频率在两民族群体中的分布情况,以期阐明这些候选基因与原发性高血压的关系及其在原发性高血压发病机制中的作用,从遗传学角度剖析两群体高血压患病的原因,进一步明确其对更广泛人群高血压疾病发生所起的作用。
方法:
(1)采用整群抽取随机抽样的方法对新疆巴里坤县5个乡哈萨克族牧民和吐鲁番地区3个乡维吾族农民进行了三次流行病学调查,共采集哈族血液标本1141例,其中高血压组703例,正常对照组438例;维族血液标本894例,其中高血压组424人,正常对照组470例。
(2)随机选取40例无血缘关系的哈萨克族样本,利用PCR产物直接测序的方法筛查αENaC基因调控区、启动子区、外显子以及部分内含子区域的全部序列变异。计算常见SNP(少见等位基因频率Minor Allele Frequency;MAF＞5%)的连锁不平衡系数D~1和γ~2;利用Haploview软件选择其中3个SNPs作为tSNPs,采用TaqMan技术和聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restrictedfragment long polymorphism;PCR-RFLP)技术分别对入选样本进行αENaC基因扩增和基因分型。
(3)基于本实验室前期工作基础,选择目前公认研究较多的β_2-AR基因编码区Arg16Gly和Gln27Glu两个高频多态位点,应用TaqMan技术进行高通量基因分型。
(4)以新疆地区哈萨克族和维吾尔族人群作为研究对象进行群体病例-对照分析研究,分别探讨单个SNP位点及其构成的单体型与原发性高血压的相关性,并了解αENaC和β_2-AR基因多态在新疆两民族群体中的分布情况。
(5)借助spss13.0软件进行统计学处理。x~2检验用于计数资料的关联分析和Hardy—Weinberg平衡检验,t检验用于临床指标的差异性判定,协方差分析用于均数的调整,Logistic回归分析用于多因素资料中筛查独立患病危险因素及计算优势比(Odds ratio,OR);同时运用SHEsis软件在线分析多个位点之间的连锁不平衡(linkage disequilibrium;LD)关系,Haploview软件用于单体型模块判定和tSNP的选取,应用phase软件进行多态位点单体型的构建和分析。
结果:
(1)流行病学调查结果显示:巴里坤地区哈萨克族高血压的检出率为61.6%:吐鲁番地区维吾尔族高血压的检出率为47.4%,哈萨克族人群的平均收缩压和舒张压均显著高于维吾尔族;两民族人群高血压的患病率随着年龄的增高而明显增加,且超重者和肥胖者血压增高明显多于体重正常者;血浆总胆固醇(TC)和甘油三酯(TG)的水平在高血压组和正常对照组间的差异有统计学意义(P＜0.05);高血压组男性吸烟率亦明显多于正常对照组。
(2)小样本测序在αENaC基因7kb范围内共检出9个高频SNPs位点,分别命名为G(-947)A、G(-321)A、A(+6)G、G(+49)C、C(+866)T、A334T、C(+20844)T、A(+26622)G和T663A,全部与NCBI dbSNP公共数据库中报道一致。
(3)从测序检出的9个多态位点中选择3个SNPs作为tSNPs,可以很好的预测常见单体型和剩余常见SNP,它们分别是位于启动子区的G(-947)A、外显子6的A334T和外显子13的T663A:并对这3个tSNPs进行高通量的扩增与基因分型。
(4)αENaC基因3个SNPs的基因型频率在两群体中分布均符合Hardy-Weinberg平衡;单个位点SNP关联分析显示:αENaC基因3个tSNPs基因型及等位基因频率分布在哈萨克族及维吾尔族群体高血压组和正常对照组中差异无统计学意义(P＞0.05)。
(5)分别对9个多态位点做配对连锁不平衡分析,其中只有G(-947)A和G(+49)C、A(+26622)G和T663A位点在哈萨克族群体中均存在着强连锁不平衡,多数位点存在较弱或无连锁不平衡;单体型关联分析结果显示:3个tSNPs共构成8种单体型(H1～8),单体型总体分布频率在哈萨克族病例组和对照组中的差异有统计学意义(P＜0.05),进一步的关联分析表明哈萨克族群体中,H2、H3、H6和H7单体型频率在高血压组和正常对照组的差异有统计学意义(P＜0.05):在维吾尔族群体中,除了H1和H3单体型频率在高血压组和正常对照组的差异未达到统计学意义,其余单体型频率在两组中的差异均有统计学意义(P＜0.05)。
(6)比较αENaC基因单体型频率在新疆两个不同民族中的分布,结果发现其分布在哈萨克族与维吾尔族群体中的差异有统计学意义(P＜0.05)。
(7)应用TaqMan技术对β_2-AR基因进行大样本分型后发现:Arg16Gly多态和Gln27Glu多态的基因型频率在两群体中分布均符合Hardy-Weinberg平衡;单个位点关联分析显示:基因型频率及等位基因频率分布在两民族高血压组和正常对照组中差异均无统计学意义(P＞0.05)。
(8)对β_2-AR基因两个多态位点做配对连锁不平衡分析,强度D~1值在哈萨克族和维吾尔族人群中分别为0.8和0.7,存在着连锁不平衡;进一步做单体型分析后,两位点所构成的4种单体型频率分布在两民族高血压组和正常对照组的差异均无统计学意义(P＞0.05)。
结论:
(1)新疆哈萨克族高血压患病率明显高于维吾尔族,平均收缩压和舒张压在两群体中差异有统计学意义;哈、维两民族高血压的患病率随着年龄的增加而升高,并且高血压的发生均与吸烟、高体重指数、血脂紊乱等心血管病的危险因素密切相关。
(2)研究未发现αENaC基因单个位点与新疆地区哈萨克族和维吾尔族人群的高血压相关联;而多位点单体型分析结果提示αENaC基因单体型结构分布在两民族病例组和对照组中差异均有统计学意义。由于多个位点分析的检验效能更强,因此我们推断在两民族群体中可能有民族特异性疾病易感的单体型或保护性单体型存在,本研究结果支持αENaC基因的基因剂量效应可能存在于单体型中,而不与单个位点直接关联。
(3)αENaC基因单体型频率在新疆两民族人群中的分布差异有统计学意义,推断该基因多态的分布具有民族特异性,可能与两民族不同发病特点有关。
(4)β_2-AR基因Arg16Gly和Gln27Glu多态及其它们所构成的单体型与新疆地区哈萨克族和维吾尔族人群的高血压患病无直接关联。
Objective:
Essential hypertension is the most common cardiovascular diseases that threaten human health and may lead to a series severe results such as cardiac and renal failure and shock.Hypertension is a complex disease resulted from the interaction of the cumulative effect of multiple genetic and environmental factors and genetic factors play an important role.Along with the completion of human genome project,it has been a key aim to study the sequence variations that correlate with certain diseases.As the third generation of genetic markers,Single Nucleotide Polymorphism(SNP)is characterized as large number and wide distribution.SNP or haplotype that are related to diseases may be obtained through systematically identifying SNPs especially those in coding and regulating region and the case-control study.This will play an essential role in searching the genetic mechanisms of some complex polygenic diseases.We investigated three epidemiology research in the pastoral area of balikun county and the rural area of Tuluafan to report the epidemiological characteristics of hypertension and assessment of the risk factors relevant to the high prevalence of hypertension.And we referring to the Chinese data in HapMap project and study SNPs of Epithelium Natrium Channel geneαsubunit(αENaC)andβ_2-adrenergic receptor gene(β_2-AR)that are important candidate genes of essential hypertension in Kazak and Uygur populations in Xinjiang province, Systematically screen for and examine SNPs in two ethnic groups and the pattern of intragenic linkage disequilibrium and the haplotype structure were estimated,Then investigate the relation between these polymorphisms and haplotypes and hypertension; Compare with every SNP genotype and allele gene frequency and distribution in two ethnic groups,we sought to demonstrate effect of candidate genes in hypertension pathogenesis from genetic ways and further search the mechanisms in more polulations.
Methods:
(1)Three epidemiology research was carried out in a natural population by cluster sampling and collected blood samples of 1141 kazak subjects who come from the pastoral area of balikun county,including 703 patients and 438 controls subjects,894 Uygur subjects who come from the rural area of Tuluafan,including 424 patients and 470 controls subjects.
(2)All the sequence variants located promoter,exon,intron regions ofαENaC gene were identified by directly sequencing of PCR product derived from 40 randomly selected samples.The pattern of pairwise LD between the common(minor allele frequency＞5%)SNPs was measured by D~1 andγ~2,and the tSNP were selected according to Haploview software and the papers;All tSNPs ofαENaC gene were futher genotyped in all subjects by TaqMan system and polymerase chain reaction -restriction fragment length polymorphism(PCR-RFLP).
(3)On the basic of previous research,We chose theβ_2-AR gene to study the two high frequency polymorphisms Arg16Gly and Gln27Glu located encode region,then the TaqMan assay is used for the detectionβ_2-AR genotype.
(4)The case-control study in a large group was carried out separately for each of the tSNP and followed up by haplotype analyses to determine the relation between SNPs and hypertension in two ethnic groups in Xinjiang and investigate the distribution of candidate genes polymorphisms in two ethnic groups.
(5)Spss software version 13.0 for windows was used to analyze the statistics data, association for dichotomous variables and the Hardy-Weinberg equilibrium for the polymorphisms were tested by chi-square analysis.Association for 2 groups was tested by Student' s t test for continuous variables,Analysis of covariance(ANCOVA)was used to ajuSted mean;Ajusted Odds ratios(ORs)with 95%confidence intervals from logistic regression analysis was used to estimate the relative risk of hypertension associated with genotype:linkage disequilibrium(LD)analysis was carried out in a pair-wise fashion by SHESsis software online,haplotype block was determined by haploview software and haplotypes for HT and NT were inferred by the statistical software package PHASE version 2.0.
Results:
(1)Epidemiology research indicate:The prevalence of hypertension is 61.6%and 47.4%respectively in Kazak and Uygur polulations,the average levels of systolic blood pressure and diastolic blood pressure in Kazak is significantly higher than those in Uygur and the prevalence of hypertension increases with age increasing in both populations, body mass index(BMI),serum total cholesterol(TC),triglycerides(TG)and the rate of cigarette-smoking in the male in EH group are significantly higher than NT group.
(2)In a total length of 7 kb ofαENaC gene explored,we identified 9 SNPs named G(-947)A、G(-321)A、A(+6)G、G(+49)C、C(+866)T、A334T、C(+20844)T、A(+26622)G and T663A that located promoter,exon2,6,13 and intron 1,7,11,All 9 polymorphisms were previously reported in the dbSNP at NCBI.
(3)From 3 tSNPs selected from 9 polymorphsims we can predict common haplotype and other SNPs.They are G(-947)A that located promoter,A(334)T located exon 6 and A(663)T located exon 13,then all the genotypes of 3 SNPs were detected.
(4)The genotypes of theαENaC gene variants were found to be in Hardy-Weinberg equilibrium in two ethnic groups;Single-locus association study indicated:Frequencies of genotype and allele of 3 SNPs in EH group were not significantly different from NT group respectively in Kazak and uygur populations(P＞0.05).
(5)Pairwise LD was carried out for SNP respectively,Only G(-947)A and G(+49)C,A(+26622)G and T663A polymorphisms were in LD and most of the pairwise LD values of the polymorphisms were in weak or no disequilibrium.Hyplotype based association study in the two populations indicate:8 haplotypes(H1～8)was reconsreucted by 3 tSNPs and H2,H3,H6 and H7 haplotype frequency in EH is different from HT group in Kazak population and most haplotypes frequency except for H1 and H3 in EH is also different from HT group in uygur population.
(6)Compare with hylotype frequency distribution in two ethnic and there were significantly different in Kazak and uygur populations(P＜0.05).
(7)β_2-AR gene Arg16Gly and Gln27Glu genotype are detected by TaqMan assay in arge cohort,The genotypes of theβ_2-AR gene variants were found to be in Hardy-Weinberg equilibrium in two ethnic groups,We did not observe any prevalent genotypes of theαENaC polymorphisms between controls and hypertension patients in two ethnic groups(P＞0.05).
(8)Pairwise LD was carried out for SNP,D~1 = 0.8 and 0.7 in Kazak and uygur populations respectively and two loci were in weak disequilibrium;Four common haplotypes were inferred after haplotype reconsreuction and haplotype frequencies has no statistic significant in case and in control in the two ethnic groups(P＞0.05).
Conclusions:
(1)The prevalence of hypertension in kazak is higher than this in Uygur,the average levels of systolic blood pressure and diastolic blood pressure is significantly different between Kazak and Uygur groups,and the group of high blood pressure is associated with higher levels of serum TC,TG,BMI and rate-smoking.
(2)Our results suggest that single polymorphism of theαENaC gene might be not associated with hypertension in Kazak and Uygur populations in Xinjiang,In multilocus haplotype analysis,theαENaC gene haplotype profile is significantly different between cases and controls in both ethnic groups,because multilocus haplotype analysis has more detection power than single polymorphism locus,we speculate there is ethnic-specific disease predisposing or protecting haplotypes in the hypertensives in Kazak and Uyghur populations and our data support the presence of gene-dose effect for some haplotypes but not the single polymorphism locus.
(3)Frequecy of haplotype is significantly different in Kazak and uygur populations, we indicateαENaC gene polymorphisms have ethnic specificity and maybe association with EH trait in two populations,
(4)Both single polymorphism locus of theβ_2-AR gene and haplotype that are reconstructed by SNPs might be also not associated with hypertension in Kazak and Uygur populations in Xinjiang.
引文
铩颷1]Lander ES,Schork NG.Genetic dissection of complex traits[J].Science.1994,265:2037-2048
[2]Lifton RP.Molecular genetics of human blood pressure variation[J].Science.1996,27:2676-2680
[3]Neison MR,Mamellous G;Kammerer S,et al.Large-scale validation of singlenucletoetide polymorphisms in pene regions[J].Genome Research.2004,14:1664-1668
[4]Collins FS,Brooks LD,Chakravarti A.A DNA polymorphism discovery resourcefor research on human genetic variation[J].Genome Res.1998.8(12):1229-31
[5]Cargill M,Altshuler D,Ireland J,et al.Characterization of single-nucleotidepolymorphisms in coding regions of human genes[J].Nat Genet.1999,22(3):231-8
[6]张思仲.人类基因组的单核苷酸多态性及其医学应用[J].中华医学遗传学杂志.1999,16(1):29-31
[7]Chasman D,Adams RM.Predicting the functional consequences ofnon-synonymous single nucleotide polymorphisms:structure-based assessment ofamino acid variation[J].J Mol Biol.2001,307(2):683-706
[8]Kruglyak L.The use of a genetic map of biallelic markers in linkage studies[J].Nat Genet.1997.17(1):21-24
[9]Cabriel SB,Schaffner SF,Nguyen H,et al.The structure of haplotype blocksin the human genome[J].Science.2002,296(5576):2225-2229
[10]朱鼎良.我国高血压基因研究十年回顾和几点建议[J].中华心血管病杂志.2005,33(7):585-587
[11]Rich DE,Lander ES.On the alMic spectrum of human disease[J].Trend Genet.2001,17:502-510
[12]Botstein D,Risch N.Discovering genotypes underlying human phenotypes:pastsuccesses for mendelian disease,future approaches for complex disease[J].NatGenet.2003,33 Suppl:228-37
铩颷13]Abbott A.With your genes? Take one of these,three times a day[J].Nature.2003Oct 23;425(6960):760-762
[14]王颖,褚迅,黄薇.单核苷酸多态性研究及其对人类医学的影响[J].基础医学与临床.2004,24(6):615-618
[15]The international HapMap consortium.The international HapMap project[J].Nature.2003,426:789-796
[16]Wu X,Duan X,Gu D,et al.Prevalence of hypertension and its trends inChinese populations[J].Int J Cardiol.1995,52:39-44
[17]国家卫生部,中国高血压联盟.《中国高血压防治指南》.1999年10月
[18]吴天一,汪师贞.我国部分民族及高原地区高血压调查的综合报告[J].中华心血管病杂志.1984,12(1):1-4
[19]Hsieh K,Lalouschek W,Schillinger ME,et al.Impact of alphaENaCpolymorphisms on the risk of ischemic cerebrovascular events:a multicentercase-control study[J].Clin Chem.2005,51(6):952-956
[20]汪师贞,张月明,程祖亨.新疆维吾尔族自治区不同民族高血压流行病学因素[J].中国心血管病杂志.1984,179(3):188-191
[21]汪师贞,马依彤,程祖亨,等.限制哈萨克族高血压患者盐摄入量的降压效应观察[J].中国慢性病预防与控制.1994,2(4):167-170
[22]王娜.β2-肾上腺素能受体基因多态与高血压[J].国际心血管病杂志,2006,33(3):179-181
[23]Svetkey LP,Timmons PZ,Emovon O,et al.Association of hypertension withbeta2- and alpha2c10-adrenergic receptor genotype[J].Hypertension.199627(6):1210-1215
[24]Meirhaeghe A,Luan J,Selberg-Franks P,et al.The effect of the Gly16Argpolymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acidlevels is modulated by physical activity[J].J Clin Endocrinol Metab.2001,86(12):5881-5887
[25]Chang TJ,Tsai MH,Jiang YD,et al.The Arg16Gly polymorphism of humanbeta2-adrenoreceptor is associated with type 2 diabetes in Taiwanese people[J].Clin Endocrinol(Oxf).2002,57(5):685-690
铩颷26]Castellano M,Rossi F,Giacche M,et al.Beta(2)-adrenergic receptor genepolymorphism,age,and cardiovascular phenotypes[J].Hypertension.2003,41(2):361-367
[27]Ranade K,Shue WH,Hung YJ,et al.The glycine allele of a glycine/argininepolymorphism in the beta2-adrenergic receptor gene is associated with essentialhypertension in a population of Chinese origin[J].Am J Hypertens.2001,14(12):1196-1200
[28]梁宇,赵彦艳.β2肾上腺素能受体基因家族在中国东北高血压病高发人群中的基因型分析[J].中华医学遗传学杂志.2004,21(2):124-127
[29]黄帼,吴涤,张学军等.β2-肾上腺素能受体基因多态性与岳西地区高血压患者血压的关系[J].中华心血管病杂志.2005,33(8):713-716
[30]Horan MJ,Lenfant C.Epidemiology of blood pressure and predictors ofhypertension[J].Hypertension.1990,15(2 Suppl):120-124
[31]全国高血压抽样调查协作组.中国人群高血压患病率及其变化趋势[J].高血压杂志.1995,(3)增刊:7-13
[32]耿贯一主编.流行病学(第三卷)第二版:人民卫生出版社.北京1996,15-23
[33]卫生部科技部国家统计局.《中国居民营养与健康现状》.中华人民共和国卫生部新闻发布.2004年10月12日(http://www.moh.gov.cn/public/open.aspx?n_id=8646&seq=0)
[34]Burt VL,Whelton P,Roccella EJ,et al.Prevalence of hypertension in theUS adult population.Results from the Third National Health and NutritionExamination Survey,1988-1991[J].Hypertension.1995,25:305-313
[35]中国高血压病防治小组.《中国高血压防治指南》高血压杂志.2000,8:94-112
[36]Ward PH.Familial aggregation and genetic epidemiology of blood pressurehypertension:Pathophysiology,Diagnosis and Management[J].New York,NY:Raven Press.1990:81-100
[37]Willams RR.Are there interaction and relations between genetic andenvironmental factors predisposing to a high blood pressure?[J].J Hypertens. 1991,18(Suppl1):1-29
铩颷38]Hamet P,Pauova Z,Adarichev V,et al.Genes and environment[J].Hypertens.1998,16:397-418
[39]Fuentes RM,Notkolaa JL,Shemeikka S,et al.Familial aggregation of bloodpressure[J].J Hum Hypertens.2000,14:441-445
[40]Oshaughnessy KM.The Genetics of Essential Hypertension[J].Br J ClinPharmaco.2001,151:5-11
[41]Tanira MOM,Balushi KA Al.Genetic variations related to hypertension:areview[J].Journal of Human Hypertension.2005,19:7-19
[42]Dominiczak AF,Negrin DC,Clark JS,et al.Genes and Hypertension[J].Hypertension.2000,35:164-172
[43]余振球,马长生,赵连友,等.实用高血压学.科学出版社,北京.1996:13
[44]董承琅,陶寿淇,陈灏珠.实用心脏病学(第三版).上海科学技术出版社,上海.1996:851
[45]La Vignera S,Calogero AE,Cannizzaro MA,et al.Erectile vascular dysfunctionand analysis of the risk factors related to it Clinical experience[J].MinervaEndocrinol.2007 Mar;32(1):17-21
[46]Nakladalova M,Sovova E,Ivanova K,Kaletova M,Lukl J,Fialova J.Riskfactors for cardiovascular diseases in physicians[J].Biomed Pap Med Fac UnivPalacky Olomouc Czech Repub.2005 Dec;149(2):293-5.
[47]John U,Meyer C,Hanke M,et al.Relation between awareness of circulatorydisorders and smoking in a general population health examination[J].BMCPublic Health.2006 Feb 27;6:48
[48]Istvan JA,Lee WW,Buist AS,et al.Relation of salivaru continine to bloodpressure in middle-aged cigarette smokers[J].Am Heart.1999,137:928-931
[49]张永红,赵玉泉,佟伟军等.蒙古族居民吸烟、饮酒与高血压的关系研究[J].高血压杂志.2001,9(2):154-156
[50]Pedro MV,Arveiler D,Evans A,et al.Different alchol drinking and bloodpressure relationships in France and Northerm Ireland.The PRIME Study[J].Hypertension.2001,38:1361-1366
铩颷51]Beulens JW,Rimm EB,Ascherio A,et al.Alcohol consumption and risk forcoronary heart disease among men with hypertension[J].Ann Intem Med.2007,146(1):10-9
[52]Abuissa H,Lavie C,Spertus J,et al.Personal health habits of Americancardiologists[J].2006,97(7):1093-6
[53]Soubassi LP,Papadakis ED,Yheodoropoulos IK,Poulos GD,et al.Incidence andrisk factors of coronary artery disease in patients on chronic hemodialysis[J].Int JArtif Organs.2007 Mar;30(3):253-257
[54]Bodnar LM,Catov JM,Klebanoff MA,et al.Prepregnancy body mass index andthe occurrence of severe hypertensive disorders of pregnancy[J].Epidemiology.2007 Mar;18(2):234-9
[55]Aoyagi K,Kusano Y,Yakamura N,et al.Obesity and cardiovascular risk factorsamong men and women aged 40 years and older in a rural area of Japan[J].JPhysiol Anthropol.2006,25(6):371-5
[56]Jafar TH,Chaturvedi N,Pappas G,et al.Prevalence of overweight andobesity and their association with hypertension and diabetes mellitus in anIndo-Asian population[J].CMAJ.2006,175(9):1071-7
[57]Fuiano N,Luciano A,Pilotto L,Pietrobelli A,et al.Overweight andhypertension:longitudinal study in school-aged children[J].Minerva Pediatr.2006,58(5):451-9
[58]Schiel R,Beltschikow W,Kramer G,et al.Overweight,obesity and elevatedblood pressure in children and adolescents[J].Eur J Med Res.2006,11(3):97-101
[59]王文娟,王克安,李天麟,等.体重指数、腰围和臀围比预测高血压、高血糖的使用价值及其建议值探讨[J].中华流行病学杂志.2002,23:16-19
[60]中国肥胖问题工作组数据汇总分析协作组.我国成人体重指数和腰围对相关疾病危险因素异常的预测价值:适宜体重指数和腰围界值的研究[J].中华流行病学杂志.2002,23(1):5-10
[61]罗雷,栾荣生,袁萍.中国居民高血压病主要危险因素的meta分析[J].中 华流行病学杂志.2003,24(1):50-53
铩颷62]Iwanicka Z,Glab E,Barg E,et al.Carbohydrate and lipid metabolism disordersin obese children and adolescents[J].Med Wieku Rozwoj.2004,8(3):815-24
[63]Matos AC,Ladeia AM,et al.Assessment of cardiovascular risk factors in a ruralcommunity in the Brazilian state of Bahia[J].Arq Bras Cardiol.2003,81(3):291-302
[64]Kalichman L,Livshits G,Kobyliansky E.Indices of body composition andchronic morbidity:a cross-sectional study of a rural population in central Russia[J].Am J Hum Biol.2006,18(3):350-8
[65]Doll S,Paccaud F,Bovet P,et al.Body mass index,abdominal adiposity andblood pressure:consistency of their association across developing and developedcountries[J].Int J Obes Relat Metab Disord.2002,26(1):48-57
[66]Collins FS,McKusick VM.Implications of the Human Genome Project formedical science[J].JAMA.2001,258:540-4
[67]何秉贤 朱徐,黄定,等.新疆汉、维吾尔、哈萨克三民族高血压流行病学调查[J].新疆医学.1992,22(4):194-201
[68]Hirosbi K,Meclet T,HiromiM,et al.24-hour,blood pressure in Uygur,Kazakb and ban elderly subjects in China[J].Hypertensions Res.2000,23(2):177-185
[69]Jeunemaitre X,Soubrier F,Kotelevtsev YV,et al.Molecular basis of humanhypertension:role of angiotensinogen[J].Cell.1992,71:169-180
[70]Rieder MJ,Taylor SL,Clark AG,et al.Sequence variation in the humanangiotensin converting enzyme gene[J].Nat Genet.1999,22:59-62
[71]Levy D,DeStefano AL,Larson MG,et al.Evidence for a gene influencingblood pressure on chromosome 17 Genome scan linkage results for longitudinalblood pressure phenotypes in subjects from the framingham heart study[J].Hypertension.2000,36:477-483
[72]Persu A,Barbry P,Bassilana F,et al.Genetic analysis of the beta subunit of theepithelial Na~+ channel inessential hypertension[J].Hypertension.1998,32:129-137
铩颷73]Baker E H,Dong Y B,et al.Association of hypertension with T594M mutationin β subunit of epithelial sodium channels in black people resident in London[J].The lancet.1998,351:1388-1392
[74]Wong ZYH,Stebbing M,Ellis JA,et al.Genetic linkage of the β-and γ-subunits of the epithelial sodium channel with systolic blood pressure in thegeneral population[J].Lancet.1999,353:1222-1225
[75]贾宏钧,王钟林,杨期东.离子通道与心脑血管疾病.人民卫生出版社.2001,429-516.
[76]McDonald FJ,Price MP,Snyder PM,Welsh MJ.Cloning and expression of the[beta]- and[gamma]-subunits of the human epithelial sodium channel[J].Am JPhysiol.1995,268:C1157-C1163
[77]Iwai N,Baba S,Mannami T,et al.Association of a sodium channel alphasubunit promoter variant with blood pressure[J].J Am Soc Nephrol.2002,13:80-85
[78]Kruglyak L,Nickerson DA.Variarion is the spice of the life[J].Nat Genet.2001,27:234-236
[79]Ambrosius WT,Bloem LJ,Zhou L,Rebhun JF,et al.Genetic variants in theepithelial sodium channel in relation to aldosterone and potassium excretion andrisk for Hypertension[J].hypertension.1999,34:631-637
[80]Takao Sugiyama,Norihrio Koto,Yuji Ishinaga,et al.Evaluation of selectedpolymorphisms of the Mendelian Hypersive Disease Genes in the Japanesepopulation[J].Hypertens Res.2001,24:515-521
[81]Samaha FF,Rubenstein RC,Yan W,et al.Functional polymorphism in thecarboxyl terminus of the alpha - subunit of the human epithelial sodiumchannel[J].J Biol Chem.2004,279:2390-7
[82]Shi YY,He L.SHEsis,a powerful software platform for analyses of linkagedisequilibrium,haplotype construction,and genetic association at polymorphismloci[J].Cell Res.2005,15(2):97-8
[83]Keyue Ding,Kaixin Zhou,Fuchu He,et al.LDA- A java-based linkagedisequilibrium analyzer[J].Bioinformatics.2003,19:2147-2148
铩颷84]International HapMap Project.http://www.hapmap.org/downloads/index.html.en
[85]Stephens M,Smirth NJ,Donnelly P.A new statisticalmethod for haplotypereconstruction from population data[J].Am J Hum Genet.2001,68:978-989
[86]Wang X,Wang S,Lin R,et al.GNB3 gene C825T and ACE gene I/Dpolymorphisms in essential hypertension in a Kazakh genetic isolate[J].JHypertens.2004,18:663-668
[87]Ludwig M,Bolkenius U,Wickert L,et al.Structural organization of the geneencoding the a-subunit of the human amiloride-sensitive epithelial sodiumchannel.Hum Genet.1998,102:576-581
[88]Shodimu E,Peter M,Kathleen L,et al.Polymorphic Variants alter Function ofthe Human Epithelial Sodium Channel α-subunit:Evidence for a Role inhypertension[J].Hypertension.1998,31:1118-1124
[89]赵仲堂等.流行病学研究方法与应用.科学出版社,2000
[90]孔祥东,杨宇霞,张思仲.AGT基因单倍型与原发性高血压[J].遗传.2004,26(6):797-802
[91]方福德.基因多态性与疾病相关性的遗传分析中某些值得注意的问题[J].中华医学杂志.2004,84:796-798
[92]张怡,朱鼎良.原发性高血压遗传学研究的策略和方法[J].高血压志.2004,12(1):4-8
[93]Bray MS,Boerwinkle E.The role of beta(2)-adrenergic receptor variation inhuman hypertension[J].Curr Hypertens Reports.2000,2:39-43
[94]Wallerstedt SM,Eriksson AL,Ohlsson C,et al.Haplotype association analysisof the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor ina Swedish hypertensive population[J].J Hum Hypertens.2005,19(9):705-8
[95]Iaccarino G,Lanni F,Cipolletta E,et al.The Glu27 allele of the beta2 adrenergicreceptor increases the risk of cardiac hypertrophy in hypertension[J].Hypertens.2004,22(11):2117-22
[96]Huang G,Wu D,Zhang XJ,et al.Association between the beta 2 adrenergicreceptor polymorphism and blood pressure in YueXi population[J].Zhonghua XinXue Guan Bing Za Zhi.2005,33(8):713-6
[97] Masuo K, Katsuya T, Fu Y, et al. Beta2- and beta3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years[J]. Circulation. 2005,111(25): 3429-34
[98] Huang G, Xing H, Hao K, et al. Beta2 adrenergic receptor gene Argl6Gly polymorphism is associated with therapeutic efficacy of benazepril on essential hypertension in Chinese[J]. Clin Exp Hypertens. 2004,26(6): 581-92
[99] Kirby RF, Woodworth CH, Woodworth GG, et al. Beta-2 adrenoceptor mediated vasodilation: role in cardiovascular responses to acute stressors in spontaneously hypertensive rats [J]. Clin Exp Hypertens A. 1991,13(5): 1059-68
[100] Lentes KU, Berrettini WH, Hoehe MR, et al. A biallelic DNA polymorphism of the human beta-2-adrenergic receptor detected by Ban I-Adrbr-2[J]. Nucleic Acids Res. 1988, 16(5): 2359
[101] Kato N, Sugiyama T, Morita H, et al. Association analysis of beta(2)-adrenergic receptor polymorphisms with hypertension in Japanese [J]. Hypertension. 2001,37(2): 286-292
[102] Munakata M. Beta2 Adrenergic receptor gene polymorphisms [J]. Nippon Rinsho. 2001, 59(10): 1889-1893.
[103] Kobilka BK, Dixon RAF, Frielle T, et al. cDNA for the humanβ2-adrenergic receptor[J]. Proc Natl Acad Sci USA. 1987, 84: 46-50
[104] Giacobino JP. β3-adrenoceptor an. update[J]. Eur Endocrinol. 1995, 132: 377
[105] Reishaus E, Innis M, Macintyre N, et al. Mutations in the gene encoding for thep2-adrenergic receptor in normal and as thematic subjects [J]. Am J Respir Cell MolBiol. 1993,8:334-339
[106] Leineweber K, Buscher R, Bruck H, et al. The Gln27Glu beta(2)-adrenocetor polymorphism slows the onset of desensitization of cardiac functional response in vivo[J].Pharmacogenetic S.2003,13 (2):59-66.
[107] Meirhaeghe A, Luan J, Selberg-Franks P, et al. The effect of the Glyl6Arg polymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acid levels is modulated by physical activity[J]. J Clin Endocrinol Metab.2001,86(12): 5881-5887
铩颷108]Chang TJ,Tsai MH,Jiang YD,et al.The Arg16Gly polymorphism of humanbeta2-adrenoreceptor is associated with type 2 diabetes in Taiwanese people[J].Clin Endocrinol(Oxf).2002,57(5):685-690
[109]Castellano M,Rossi F,Giacche M,et al.Beta(2)-adrenergic receptor genepolymorphism,age,and cardiovascular phenotypes[J].Hypertension.2003,41(2):361-367
[110]Ranade K,Shue WH,Hung YJ,et al.The glycine allele of aglycine/argininepolymorp hism in the beta 2- adrenergic receptor gene isassociated with essential hypertension in a population of Chinese origin[J].Am J Hypertens.2001,14(12):1196-1200
[111]梁宇,赵彦艳.β2肾上腺素能受体基因家族在中国东北高血压病高发人群中的基因型分析[J].中华医学遗传学杂志.2004,21(2):124-127
[112]黄帼,吴涤,张学军等.β2-肾上腺素能受体基因多态性与岳西地区高血压患者血压的关系[J].中华心血管病杂志.2005,33(8):713-716
[113]Timmermann B,Mo R,Luft FC,et al.β2-adrenoceptor genetic variation isassociated with genetic predisposition to essential hypertension:The Bergenblood Pressure Study[J].Kidney Int.1998,53:1455
[114]Kotanko P,Binder A,Tasker J,et al.Essential Hypertension in AfricanCaribbeans Associates With a Variant of the β2-Adreno- ceptor[J].Hypertension.1997,30:773-776
[115]Tonolo G,Melis MG,Secchi G,et al.Association of Trp64Arg beta3-adrenergicreceptor gene polymorphism with essential hypertension in the Sardinianpopulation[J].Hypertens.1999,17(1):33-38
[116]Hongyan Wu,Wenru Tang,Hongwei Li,et al.Association of thebets2-adrenergic receptor gene with essential hypertension in the non-HanChinese Yi minority human population[J].Hypertens.2006,24:1041-1047
[117]Green SA,Tuki J,Innis M,et al.Aminoterminal polymorphism of the humanbeta2-adrenergic receptor impart distinct agonist-ptomoted regulatoryproperties[J].Biochemistry.1994,33:9414-9419
[118]Gratze G,Fortin J,Labugger R,et al.Beta2-adrenergic receptor variants affect resting blood pressure and ag0nist-induced vasodilation in young adult
Caucasians[J].Hypertension.1999,33:1425-1430
铩颷119]Dishy V,Sofowora GG,Xie HG,et al.The effect of common polymorphisms ofthe beta2 adrenergic receptor gene is associated with essential hypertension in apopulation of Chinese origin[J].Am J Hypertens.2001,14:1196-1200
[120]窦相峰,孙凯,黄晓红等.Adducin基因和血管紧张素转换酶基因多态性与原发性高血压的关系[J].中国循环杂志.2004,19(4):286-289
[121]Yang Q,Khoury MJ.Evolving methods in genetic epidemiology Ⅲ Geneenvironment interaction in epidemiologic research[J].Epidemiol Rev.1997,19(1):33-43
[122]Thiel BA,Chakravarti A,Cooper RS,et al.A genome-wide linkage analysisinvestigating the determinants of blood pressure in whites and AfricanAmericans[J].Am J Hypertens.2003,16(2):151-3
铩颷1]李立明 主编.流行病学(第五版),人民卫生出版社,400-401
[2]Hamet P,Pauova Z,Adarichev V,et al.Genes and environment[J].Hypertens.1998,16:397-418
[3]Lander ES,Schork NG.Genetic dissection of complex traits[J].Science.1994,265:2137-2048
[4]Lifton RP.Molecular genetics of human blood pressure variation[J].Science.1996,27:2676-2680
[5]Ward RH.Familial aggregation and genetic epidemiology of blood pressurehypertension:Pathophysiology,Diagnosis and Management[J].New York,NY:Raven press.1990,81-100
[6]Risch N,Merkangas K.The future of genetic studies of complex human disease[J].Science.1996,273:1516-1517
[7]Jorde LB.Linkage disequilibrium as a gene-mapping tool[J].Am J Hum Genet.1995,56:11-14
[8]Kruglyak L.What is significant in whole-genome linkage disequilibrium studies?[J].Am J Hum Genet.1997,61:810-812
[9]Terwilliger JD,Zollner S,Laan M,et al.Mapping genes through the use of linkagedisequilibrium generated by genetic drift mapping in small populations with nodemographic expansion[J].Hum Hered.1998,48:138-154
[10]Terwilliger JD,Weiss KM.Linkage disequilibrium mapping of complex disease:fantasy or reality?[J].Curr Opin Biotechnol.1998,9:578-594
[11]Ewens WJ,Spielman RS.Locating genes by linkage and association[J].Theor PopulBiol.2001,60:135-9
[12]Pritchard JK,Przeworski M.Linkage disequilibrium in humans:models and data[J].Am J Hum Genet.2001,69:1-14
[13]Zeller R.It takes time to make a pinky:unexpected insights into how SHH patternsvertebrate digits[J].Sci STKE.2004,2004:53
[14]Murone M,Rosenthal A,Sauvage F.Sonic hedgehog signaling by thepatched-smoothened receptor complex[J].Curr Biol.1999,9:76-84
[15]Denef N,Perez L,Cohen SM.Hedge hog induces opposite changes in tuen overand subcellular localization of Patched and Smoothened[J].Cell.2000,102:521-532
[16]Drysdale CM,McGraw DW,Stack CB,et al.Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo
responsiveness.Proc Natl Acad Sci USA 97[J].2000,10483-10488
铩颷17]Ball D,Hill L,Eley TC,Chomey MJ,et al.Dopamine markers and general cognitiveability[J].Neuroreport 1998,9:347-349
[18]Clark AG.Inference of haplotypes from PCR-arnplified samples of diploidpopulations[J].Mol Biol Evol.1990,7:111-122
[19]Becker T,Knapp M.Maximum-likelihood estimation of haplotype frequencies innuclear families.Genet Epidemiol.2004,27:21-32
[20]Xie X,Ott J.Testing linkage disequilibrium between a disease gene and markerloci[J].Am J Hum Genet.1993,53:1107
[21]Zhao JH,Curtis D,Sham PC.Model-free analysis and permutation tests for allelicassociations[J].Hum Hered.2000,50:133-139
[22]Zhao JH,Sham PC.Faster haplotype frequency estimation using unrelated subjects[J].Hum Hered.2002,53:36-41
[23]Schneider S,Roessli D,Excofier L.Arlequin:A software for population geneticsdata analysis(Genetics and Biometry Lab,Dept of Anthropology University ofGeneva).2000,56:76-81
[24]Stephens M,Donnelly P.A comparison of bayesian methods for haplotypereconstruction from population genotype data[J].Am J Hum Genet 2003,73:1162-1169
[25]Wang DG.Fan J B,Siao CJ,et al.Large-Scale identification mapping and genotypingof single-nucleotide polymorphisms in the human genome[J].Science.1998,280(5366):1077-1082
[26]Sach idanandam R,Weissman D,Schrnidt SC,et al.A map of human genomesequence variation containing 1.42 million single nucleotide polymorphism[J].Nature.2001,409:928-933
[27]Lander ES.The new genomics:global views of biology[J].Science.1996,274:536-539
[28]孙树汉,杨胜利.单核苷酸多态性与复杂性状疾病[J].第二军医大学学报.2004,25:117-119
[29]赵非.单核苷酸多态性研究进展[J].国外医学儿科学分册.2002,29:297-299
[30]陈蕊雯,孙树汉.单核苷酸多态性在复杂性状疾病易感基因研究中的应用[J].第二军医大学学报.2004,25:140-142
[31]Pemeger TV.What's wrong with Bonferroni adjustments[J].BMJ.1998,316: 1236-1238
铩颷32]Storey JD,Tibshirani R.Statistical significance for genomewide studies[J].ProcNatl Acad Sci USA.2003,100:9440-9445
[33]L Jane,Gold smith,Power and Sample Size Considerations in Molecular Biology.Biostatistical Methods.Humana Press Inc,2002
[34]Cohen J.Statistical power analysis for the behavioral sciences.Hillsdle,New Jersey,Lawrence Erlbaum Association.2nd edition,1988,215-271
[35]Smithies O,Maeda N.Gene targeting approaches to complex genetic disease:atherosclerosis and essential hypertension[J].Proc Natl.Acad Sci USA.1995,92:52-66
[36]Gu L,Dene H,Deng AY,et al.Genetic mapping of two pressure quantitative trait locion rat chromosome 1[J].J Clin Invest.1996,97:777
[37]Lezin ES,Liu WZ,Wang JM,et al.Genetic isolation of a chromosome 1 regionaffecting blood pressure in the spontaneously hypertensive rat[J].Hypertension.1997,30(4):854
[38]Lander ES,et al.Initial sequencing and analysis of the human genome[J].Nature.2001,409:860-921
[39]The International SNP Working Group.A map of human genome sequencevariation containing 1.42 million single nucleotide polymorphisms[J].Nature.2001,409:928-933
[40]Syvanen A.Accessing genetic variation:genotyping single-nucleotidepolymorphisms[J].Nature Rev Genet.2001,2:930-942
[41]Ng PC,Henikoff S.Accounting for human polymorphisms predicted to affectprotein function[J].Genome Res.2002,12:436-446
[42]Sunyaev S,et al.Prediction of deleterious human alleles[J].Hum Mol Genet.2001,10:591-597
[43]Chasman D,Adams RM.Predicting the functional consequences ofnon- synonymous single nucleotide polymorphisms:structure- based assessmentof amino acid variation[J].J Mol Biol.2001,307:683-706
[44]Frossard PM,Malloy MJ,Lestringant GG,et al.Hapltype soft he human rennin geneassociated with essential hypertension and stroke[J].J Hum Hypertens.2001,1(1):49-55
[45]FuY,KatsuyaT,AsaiT,et al.Lack of correlation between MboI restriction Fragmentlength polymorphismof rennin gene and essential hypertensionin Japanese[J]. Hypertens Res.2001,24(3):295-298
铩颷46]Hasimu B,Nakayama T,Mizutani Y,et al.Haplotype analysis of the human renningene and essential hypertension[J].Hypertension.2003,41(2):308-312
[47]Hasimu B,Nakayama T,Mizutani Y,et al.Anovel variable number of tandem repeatpolymorphismof the rennin gene and essential hypertension[J].Hypertens Res.2003,26(6):473-477
[48]郑泰山,项坤三,孙多奇。肾素基因与中国人2型糖尿病及其微血管病变、冠心病和高血压的相关性[J].中华内分泌代谢杂志.1997,13(4):206-209
[49]孙琦,柳青,雷家俨等.肾素基因与重庆地区人群原发性高血压的关系[J].重庆医学.2003,32(1):3-5
[50]Jeunenmaitre X,Soubrier F,Kotelevtsev YV,et aL Molecular basis of humanhypertension:role of angiotensinogen[J].Hypertension.1992,71:169-180
[51]Hata A,Namikawa C,Sasaki M,et al.AGT as a risk factor for essential hypertensionin Japan[J].J Clin Invest.1994,93:1285-1287
[52]Nishiuma S,Kario K,Kayaba K,et al.Effect of the AGT gene Met235Thr variant onblood pressure and other cardiovascular rish factors in two Japanese populations[J].J Hypertens.1995,13:717-722
[53]Frossard PM,Hill SH,Elshahat YI,et al.Association of angiotensinogen genemutations with hypertension and myocardial infarction in a gulfpopulation[J].ClinGenet.1998,54(4):285-293
[54]Caulfield M,Lavender P,Newell M,et al.Linkage of AGT gene locus to humanessential hypertension in African Caribbeans[J].J Clin Invest.1995,95:687-692
[55]Wang WY,Glenn CL,Zhang W,et al.Exclusion of angiotensinogen gene inmolecular basis of human hypertension:sibpair linkage and association analyses inAustralian anglo-caucasians[J].Am J Med Genet.1999,87(1):53-60
[56]Pamies Andreu E,Palmero Palmero C,Garcia Lozano R,et al.The effect of theangiotensinogen M235T and the angiotensin-converting enzyme I/D polymorphismson arterial hypertension and other cardiovascular risk factors[j].Med Clin.1999,113(5):164-8
[57]Caulfield M,Lavender P,Farrall M,et al.Linkage of AGT gene to essentialhypertension[J].N Engl J Med.1994,330:1629-1633
[58]Tsai CT,Fallin D,Chiang FT,et al.Angiotensinogen gene haplotype andhypertension[J].Hypertens.2003,41:9-15
[59]Li NF,Zhou L,Wu WD,et al.The relationship between the variants in 5' up stream core promoter A(-6)G and A(-20)C of angiotensinogen gene and essential
hypertension in Kazakans of Xinjiang[J].Zhong Hua Yi Xue Yi chuan Za Zhi.2004,
21:23-28
铩颷60]Niu TH,Yang JH,Wang BY,et al.Angiotensinogen gene polymorphismsM235T/T174M:no exesstrans mission to hypertensive Chinese[J].Hypertension.1999,33:698
[61]Thomas GN,Young RP,Tomlinson B,et al.Ren in- angiotensin-aldosterone systemgene polymorphisms and hypertension in HongKong Chinese[J].Clin ExpHypertension.2000,22:87-97
[62]Erdos EG.Angiotensin I converting enzyme and the changes in our concepts throughthe years[J].Hypertension.1990,16(4):363-70
[63]Hubert C,Houot AM,Corvol P,et al.Structure of the angiotensin I-convertingenzyme gene.Two alternate promoters correspond to evolutionary steps of aduplicated gene[J].J Biol Chem.1991,Aug 15;266(23):15377-15383
[64]Foy CA,Rice GI,Ossei-Geming N.Angiotensin-converting enzyme(ACE)genepolymorphisms in patients characterised by coronary angiography[J].Hum Genet.1997,Sep;100(3-4):420-5
[65]Rotimi C,Puras A,Cooper R,et al.Polymorphisms of reninangio- tensin genesamong Migerians,Jamaicans,and African Americans[J].Hypertension.1996,27(3part 2):558-563
[66]Zaman MM,Yoshiike N,Tanaka H.Dissecting the contradictory finding sofangiotens in converting enzyme genetic polymorphism with blood pressure andhypertension[J].Bangladesh Med Res Counc Bull.2001,27:90-95
[67]Pereira AC,Mota GFA,Cunha RS,et al.Angiotensinogen 235T allele "dosage" isassociated with blood pressure phenotypes[J].Hypertension.2003,41:25-30
[68]叶琼,吴可贵,曾开淇,等.血管紧张素转换酶基因多态性与原发性高血压之间的关系[J].高血压杂志.1998,6(1):11-13
[69]郑豪义,戴玉华,邱长春.血管紧张素转化酶基因多态性与原发性高血压的关系[J].高血压杂志.1997,5(3):194-196
[70]孔祥东,杨宇霞.血管紧张素转化酶1基因单倍型与原发性高血压[J].临床心血管病杂志.2005,12:724-726
[71]Giver V,Poch E,Bragulat E.Renin-angiotensin system genetic polymorphism sandsalt sensitivityin essential hypertension[J].Hypertension.2000,35(1Pt2):512-517
[72]Bonnardeax A,Davies E,Jeunemaitre X.AngiotensinⅡtype-Ⅰ receptor gene polymerphisms in human essential hypertension[J].Hypertens.1994,24:63-69
铩颷73]Wang WY,Zee RY,Morris BJ.Association of angiotens in typeI receptor genepolymorphism with essential hypertension[J].Clin Genet.1997,51(1):31
[74]Ashavaid TF,Shalia KK,Nair KG,et al.ACE and AT1R gene polymor-phismsandhypertension in Indian population[J].J Clin Lab Anal.2000,14(5):230
[75]Tiret L,Blanc H,Ruidavets JB,et al.Gene polymorphisms of the renin-angiotensinsystem in relation to hypertension and parental history of myocardial infarction andstroke:the PEGASE study Projetd'Etudedes Genesdel'Hypertension Arterielle Severeamoderee Essentielle[J].J Hypertens.1998,16(1):37
[76]Zhang X,Erdmann J,Regitz-ZagrosekV,et al.Evaluation of three polymorphisms inthe promoter region of the angiotens in ⅡTypel receptor gene[J].J Hypertension.2000,18(3):267
[77]Takahashi N,Murakami H,Kodama K,et al.Association of a polymorphism at the5'-region of the angiotens in Ⅱ Type1 receptor with hypertension[J].Am Hum Gene.2000,64(Pt3):197
[78]Henderson SO,Haiman CA,Mack W,et al.Multiple Polymorphisms in therenin-angiotens in-aldosterone system(ACE,CYP11B2,AGTR1)and theircontribution to hypertension in African Americans and Latinos in the multi ethniccohort[J].Am J Med Sci.2004,328(5):266
[79]Sugimoto K,Katsuya T,Ohkubo T,et al.Associationbetween angiotens in Ⅱ typelreceptor gene polymorphis man dessential hypertension:the Ohasama Study[J].Hypertens Res,2004,27:551-556
[80]KobashiG,HataA,OhtaK,et al.A1166C variant of angiotensin Ⅱ typel receptor geneis associated with severe hypertension in pregnancy independently of T235 variant ofangiotensinogen gene[J].J Hum Genet,2004,49:182-186
[81]LiuY,Shan GL,Cui CY,et al.A1166Cpolymorphism of the angiotens in Ⅱtypelreceptor gene an dessential hypertension in Han Tibetan and Yi populations[J].Zhong hua Yi Xue Yi Chuan Xue Za Zhi.2003,20:220-224
[82]乔卫卫,张奎星,刘同宝,等.血管紧张素Ⅱ2型受体基因多态性与男性高血压病的相关研究[J].中华心血管病杂志.2005,32:668-672
[83]Kobilka BK,Dixon RAF,Frielle T,et al.cDNA for the human β2- adrenergicreCeptor[J].Proe Natl Acad Sci USA.1987,84:46-50
[84]Munakata M.Beta2 Adrenergic receptor gene polymorphisms[J].Nippon Rinsho.2001,59(10):1889-1893
铩颷85]Svetkey LP,Timmons PZ,Emovon O,et al.Association of hypertension with beta2-and alpha2c 10-adrenergic receptor genotype[J].Hypertension.1996 27(6):1210-1215
[86]Kotanko P,Binder A,Tasker J,et al.Essential Hypertension in African CaribbeansAssociates With a Variant of the β2-Adreno-ceptor[J].Hypertension.1997,30:773-776
[87]Timmermann B,Mo R,Luft FC,et al.β2-adrenoceptor genetic variation is associatedwith genetic predisposition to essential hypertension:The Bergen Blood PressureStudy[J].Kidney Int.1998,53:1455
[88]Bray MS,Krushkal J,Li L,et al.Positional genomic analysis identifies the beta(2)adrenergic receptor gene as a susceptibility locus for human hypertension[J].Circulation.2000,101(25):2877-2882
[89]梁宇,赵彦艳.β肾上腺素能受体基因家族在中国东北高血压病高发人群中的基因型分析[J].中华医学遗传学杂志.2004,21(2):124-127
[90]黄帼,吴涤,张学军,等.β2-肾上腺素能受体基因多态性与岳西地区高血压患者血压的关系[J].中华心血管病杂志.2005,33(8):713-716
[91]何鑫,初少莉,金力,等.;α-内收蛋白基因Gly460Trp多态性与原发性高血压相关关系研究[J].高血压杂志.1999,4:288-290
[92]Cusi D,Barlassina C,Azzani T,et al.Polymorphisms of α-adducing and saltsensitivity in patients with essential hypertension[J].Lancet.1997,349(9062):1353-1357
[93]Kamitani A,Zilla YH,Fraster R,et al.Human alpha adducing gene blood pressureand sodium metabolism[J].Hypertension.2001,23(7):579-589
[94]Glorioso N,Manunta P,Filigheddu F,et al.Therole of α-adducing polymorphism inblood pressure and handling regulation maynotbeex cluded by anegative associationstudy[J].Hypertension.1994,34(4):649-654
[95]JuZ,ZhangH,SunK,et al.Alpha adducing gene polymorphismis associated withessential hypertension in Chinese:a case control and family basedstudy[J].JHypertens.2003,21:1861-1868
[96]董会奕,李秋荣,王勤,罗振国.ADD-1基因和GNB3基因多态性与原发性高血压的相关性研究[J].岭南心血管病杂志.2006,4:314-317
[97]李南方,李红建,周玲,等.α-adducin基因变异与新疆哈萨克族人原发性高血压的相关性研究[J].科学技术与工程.2004,(07)
[98]许骥,华琦,李东宝.α-内收蛋白基因Gly460Trp多态性与北京汉族人群原发性高血压的关系[J].医学研究生学报.2005,11:999-1004
铩颷99]Stiffert W,Rosskopf D,siffert G,et al.Association of a human G protein subunitvariant with hypertension[J].Nature Genetics.1998,18:45-48
[100]Beige J,Hohenbleicher H,Distler A,et al.G protein β_3 subunit C825T variant andambulatory blood pressure in essential hyperten sion[J].Hypertens.1999,33:1049-1051
[101]Jacobi J,Hilgers KF,SchlaichMP,etal.825Tallele of the G-protein β3subunitgene(GNB3)is associated with impaired left ventricul ardiastolic filling in essentialhypertension[J].Hypertens.1999,17(10):1457-146
[102]戴书萍,时景璞,赵彦艳,等.中国东北高血压病高发地区人群中G蛋白p3亚单位825C/T多态分析[J].遗传学报.2002,4:294-298
[103]张明华,刘国树,石岩,等.G蛋白β3亚单位基因C825T多态性与原发性高血压[J].高血压杂志.2001,4:288-291
[104]Huang X,Ju Z,Song Y,et al.Lack of association between the G protein beta(3)subunit gene and essential hypertension in Chinese:a case control and a familybased study[J].J Mol Med.2003,81(11):729-735
[105]Kato N,Sugiyama T,Morita H,et al.Genetic analysis of theatrical natriureticpeptide gene in essential hypertension[J].Clin Sci(Lond).2000,98(3):251-258
[106]Michel Burnier.Sodium balance and hypertension:rare genetic disorder sex posepath ogenicme chamisms[J].Exp Nephrol.1998,6:496-501
[107]Bulut D,Potthast R,Hanefeld C,et al.Impaired vasodilator responses to atrialnatriuretic peptide in essential hypertension[J].Eur J Clin Invest.2003,33(7):567-573
[108]Nkeh B,Tiago A,Candy GP,etal.Association between an atrialnatriuretic peptidegene polymorphism and normal blood pressure in subjects of African ancestry[j].Cardiovasc J S Afr.2002,13(3):97-101
[109]Melander O,Frandsen E,GroopL.Plasmapro ANP1-30 reflects salt sensitivity insubjects with here dity for hypertension[J].Hypertension.2002,39(5):996-999
[110]Garty H,et al.Epithelial sodium channels:Function,structure,and regulation[J].Physiol Rev.1997,77:359-396
[111]Rossier BC,et al.1996 Homer Smith Award Lecture.Cum grano salis:Theepithelial sodium channel and the control of blood pressure[J].J Am Soc Nephrol.1997,8:980-992.
[112]Scheinman S J,Guay-Woodford LM,Thakker RV,et al.Genetic disorders of renalelectrolyte transport[J].Nengl J Med.1999,340:1177
铩颷113]Shimkets RA,Warnock DG,Bositis CM,et al.Liddles syndrome:Heritablehuman hypertension caused by mutations in the β subunit of the ep-ithelialsodiumchannel[J].Cell.1994,79:407
[114]Abriel H,Lofting J,Robhun JF,et al.Defective regulation of the epithelial Na~+channel by Nedd4 in Liddles syndroms[J].J Clin Invest.1999,103:667
[115]马晓伟,田亚男,高妍,等.对一个Liddle综合征家系临床和上皮细胞钠通道基因突变的研究[J].中华内科杂志.2001,40(6):6
[116]Pradervand S,Wang Q,Bumier M,et al.A mousemodel for Liddles syn-drome[J].JAm Soc Nephrol.1999,10:25-27
[117]Persu A,Barbry P,Bassilana F,et al.Genetic analysis of the beta sub 2 unit ofthe epithelial Na~+ channel in essential hypertension[J].Hypertension.1998,32(7):129-137
[118]Dong YB,Zhu HD,Baker EH,et al.T594 Mand G442V polymorphismsof the sodium channel beta subunit and hypertension in a black population[J].JHum Hypertens.2001,15(6):425-430
[119]Iwai Y,et al.Association of a Sodium Channel[alpha]Subunit Promoter Variantwith Blood Pressure[J].J Am Soc Nephrol.2002,13:80-85
[120]Jachymova M,Horky K,Bultas J,et al.Association of the Glu298Asppolymorphism in the endothelial nitricoxide synthase gene with essentialhypertension resistant tocon ventional therapy[J].Biochem Biophys Res Commun.2001,284:426-430
[121]Tsujita Y,BabaS,Yamauchi R,et al.Association analyses between geneticpolymorphisms of endothelial nitricoxide synthase gene and hypertension inJapanese:the suita study[J].J Hypertens.2001,19:1941-1948
[122]Shoji M,Tsutaya S,Saito R,et al.Positive association of endothelial nitricoxidesynthase gene polymorphism with hypertension in northernJ apan[J].Life Sci.2000,66:2557-2562
[123]Hingorani AD.Endothelial nitricoxid esynthase polymorphisms and hypertension[J].Curr Hypertens Rep.2003,5:19-25
[124]谭建聪,祝之明,祝善俊,等.高血压病患者G蛋白β3亚单位基因C825T和eNOS基因G894T多态性研究[J].中华心血管病杂志.2003,31:173-176
[125]Veldman BA,Spiering W,Doevendans PA,et al.The Glu 298Asp polymorphism ofthe NOS gene as adeterminant of the base line production of nitricoxide[J].Journalof hypertension.2002,20(10):2023-2027
铩颷126]Jin JJ,Nakura J,Wu ZH,et al.Association of Endo the lin-lgene variant withhypertension[J].Hypertension.2003,41:163-167
[127]Iwai N,KatsuyaT,IshikawaK,et al.Human prostacyclinsynthase gene andhypertension:the Suita Study[J].Circulation.1999,100:2231-2236
[128]Nakayama T,Soma M,Haketa A,et al.Haplotype an alysis of the prosta cyclinsynthase gene and essential hypertension[J].Hypertens Res,2003,26:553-557
[129]仝其广,赵水平,胡大一,等.脂蛋白脂酶Ser447Ter基因变异对血压影响[J].中华心血管病杂志.2004,32:474
[130]Wu DA,Bu X,Warden CH,et al.Quantitative trait locus mapping ofhuman blood pressure to a genetic region at or near the lipoprotein lipase genelocus on chromosome 8p22[J].J Clin Invest.1996,97(5):2111-2118
[131]李毅夫,赵水平.载脂蛋白E基因多态性与高血压[J].高血压杂志.2000,8(1):9-11
[132]张怀勤.载脂蛋白E基因多态性与高血压病、冠心病的相关性研究[J].基础研究.2002,2(2):20-22
[133]WanT ai Seet.Apolipo protein Egene typing in th eMalay,Chinese and Indian ethnicgroups in Malaysia a study on the distribution of the different apoE callele sandgenotypes[J].Clinica Chimica Acta.2004,340:201-205
[134]Katsuya T.Epsilon4 allele of apolipo protein E gene associates lower blood pressurein young Japanese subjects:the Suite Study[J].J Hypertens.2002,20(10):1941-1942
[135]崔国方.中国汉族载脂蛋白E基因多态性与高血压的关系[J].中国临床康复.2003,7:(18)2545-2546
[136]LiX.Association of apoli protein E gene polymorphism with essenti hypertensionand it scomp lications[J].Clin Exp Med.2003,2(4):171-179
[137]Vazquez Vigoa A,Vazquez Cruz A,Calderin RO,et al.Metabolic syndrome inpatients with essential hypertension[J].Nefrologia.2003,23(5):423-431.
[138]Schrader AP,Zee RY,Morris BJ.Association analysis of Nsil RFLP ofhuman insulin receptor gene in hypertensives[J].Clin Genet.1996,49(2):74-78
[139]Wu KG,Lin CR,Xie LD,et al.The relationship between insulin receptorgene exon8 polymorphism and Essential hypertension[J].Chinese Journalof hypertension.1999,7(3):314-317
[140]Rich DE,Lander ES.On the allelic spectrun of human disease[J].Trend Genet.2001,17:502-510
[141]朱鼎良.我国高血压基因研究十年回顾和几点建议[J].中华心血管病杂志.2005,33(7):585-587
[2]Lifton RP.Molecular genetics of human blood pressure variation[J].Science.1996,27:2676-2680
[3]Neison MR,Mamellous G;Kammerer S,et al.Large-scale validation of singlenucletoetide polymorphisms in pene regions[J].Genome Research.2004,14:1664-1668
[4]Collins FS,Brooks LD,Chakravarti A.A DNA polymorphism discovery resourcefor research on human genetic variation[J].Genome Res.1998.8(12):1229-31
[5]Cargill M,Altshuler D,Ireland J,et al.Characterization of single-nucleotidepolymorphisms in coding regions of human genes[J].Nat Genet.1999,22(3):231-8
[6]张思仲.人类基因组的单核苷酸多态性及其医学应用[J].中华医学遗传学杂志.1999,16(1):29-31
[7]Chasman D,Adams RM.Predicting the functional consequences ofnon-synonymous single nucleotide polymorphisms:structure-based assessment ofamino acid variation[J].J Mol Biol.2001,307(2):683-706
[8]Kruglyak L.The use of a genetic map of biallelic markers in linkage studies[J].Nat Genet.1997.17(1):21-24
[9]Cabriel SB,Schaffner SF,Nguyen H,et al.The structure of haplotype blocksin the human genome[J].Science.2002,296(5576):2225-2229
[10]朱鼎良.我国高血压基因研究十年回顾和几点建议[J].中华心血管病杂志.2005,33(7):585-587
[11]Rich DE,Lander ES.On the alMic spectrum of human disease[J].Trend Genet.2001,17:502-510
[12]Botstein D,Risch N.Discovering genotypes underlying human phenotypes:pastsuccesses for mendelian disease,future approaches for complex disease[J].NatGenet.2003,33 Suppl:228-37
铩颷13]Abbott A.With your genes? Take one of these,three times a day[J].Nature.2003Oct 23;425(6960):760-762
[14]王颖,褚迅,黄薇.单核苷酸多态性研究及其对人类医学的影响[J].基础医学与临床.2004,24(6):615-618
[15]The international HapMap consortium.The international HapMap project[J].Nature.2003,426:789-796
[16]Wu X,Duan X,Gu D,et al.Prevalence of hypertension and its trends inChinese populations[J].Int J Cardiol.1995,52:39-44
[17]国家卫生部,中国高血压联盟.《中国高血压防治指南》.1999年10月
[18]吴天一,汪师贞.我国部分民族及高原地区高血压调查的综合报告[J].中华心血管病杂志.1984,12(1):1-4
[19]Hsieh K,Lalouschek W,Schillinger ME,et al.Impact of alphaENaCpolymorphisms on the risk of ischemic cerebrovascular events:a multicentercase-control study[J].Clin Chem.2005,51(6):952-956
[20]汪师贞,张月明,程祖亨.新疆维吾尔族自治区不同民族高血压流行病学因素[J].中国心血管病杂志.1984,179(3):188-191
[21]汪师贞,马依彤,程祖亨,等.限制哈萨克族高血压患者盐摄入量的降压效应观察[J].中国慢性病预防与控制.1994,2(4):167-170
[22]王娜.β2-肾上腺素能受体基因多态与高血压[J].国际心血管病杂志,2006,33(3):179-181
[23]Svetkey LP,Timmons PZ,Emovon O,et al.Association of hypertension withbeta2- and alpha2c10-adrenergic receptor genotype[J].Hypertension.199627(6):1210-1215
[24]Meirhaeghe A,Luan J,Selberg-Franks P,et al.The effect of the Gly16Argpolymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acidlevels is modulated by physical activity[J].J Clin Endocrinol Metab.2001,86(12):5881-5887
[25]Chang TJ,Tsai MH,Jiang YD,et al.The Arg16Gly polymorphism of humanbeta2-adrenoreceptor is associated with type 2 diabetes in Taiwanese people[J].Clin Endocrinol(Oxf).2002,57(5):685-690
铩颷26]Castellano M,Rossi F,Giacche M,et al.Beta(2)-adrenergic receptor genepolymorphism,age,and cardiovascular phenotypes[J].Hypertension.2003,41(2):361-367
[27]Ranade K,Shue WH,Hung YJ,et al.The glycine allele of a glycine/argininepolymorphism in the beta2-adrenergic receptor gene is associated with essentialhypertension in a population of Chinese origin[J].Am J Hypertens.2001,14(12):1196-1200
[28]梁宇,赵彦艳.β2肾上腺素能受体基因家族在中国东北高血压病高发人群中的基因型分析[J].中华医学遗传学杂志.2004,21(2):124-127
[29]黄帼,吴涤,张学军等.β2-肾上腺素能受体基因多态性与岳西地区高血压患者血压的关系[J].中华心血管病杂志.2005,33(8):713-716
[30]Horan MJ,Lenfant C.Epidemiology of blood pressure and predictors ofhypertension[J].Hypertension.1990,15(2 Suppl):120-124
[31]全国高血压抽样调查协作组.中国人群高血压患病率及其变化趋势[J].高血压杂志.1995,(3)增刊:7-13
[32]耿贯一主编.流行病学(第三卷)第二版:人民卫生出版社.北京1996,15-23
[33]卫生部科技部国家统计局.《中国居民营养与健康现状》.中华人民共和国卫生部新闻发布.2004年10月12日(http://www.moh.gov.cn/public/open.aspx?n_id=8646&seq=0)
[34]Burt VL,Whelton P,Roccella EJ,et al.Prevalence of hypertension in theUS adult population.Results from the Third National Health and NutritionExamination Survey,1988-1991[J].Hypertension.1995,25:305-313
[35]中国高血压病防治小组.《中国高血压防治指南》高血压杂志.2000,8:94-112
[36]Ward PH.Familial aggregation and genetic epidemiology of blood pressurehypertension:Pathophysiology,Diagnosis and Management[J].New York,NY:Raven Press.1990:81-100
[37]Willams RR.Are there interaction and relations between genetic andenvironmental factors predisposing to a high blood pressure?[J].J Hypertens. 1991,18(Suppl1):1-29
铩颷38]Hamet P,Pauova Z,Adarichev V,et al.Genes and environment[J].Hypertens.1998,16:397-418
[39]Fuentes RM,Notkolaa JL,Shemeikka S,et al.Familial aggregation of bloodpressure[J].J Hum Hypertens.2000,14:441-445
[40]Oshaughnessy KM.The Genetics of Essential Hypertension[J].Br J ClinPharmaco.2001,151:5-11
[41]Tanira MOM,Balushi KA Al.Genetic variations related to hypertension:areview[J].Journal of Human Hypertension.2005,19:7-19
[42]Dominiczak AF,Negrin DC,Clark JS,et al.Genes and Hypertension[J].Hypertension.2000,35:164-172
[43]余振球,马长生,赵连友,等.实用高血压学.科学出版社,北京.1996:13
[44]董承琅,陶寿淇,陈灏珠.实用心脏病学(第三版).上海科学技术出版社,上海.1996:851
[45]La Vignera S,Calogero AE,Cannizzaro MA,et al.Erectile vascular dysfunctionand analysis of the risk factors related to it Clinical experience[J].MinervaEndocrinol.2007 Mar;32(1):17-21
[46]Nakladalova M,Sovova E,Ivanova K,Kaletova M,Lukl J,Fialova J.Riskfactors for cardiovascular diseases in physicians[J].Biomed Pap Med Fac UnivPalacky Olomouc Czech Repub.2005 Dec;149(2):293-5.
[47]John U,Meyer C,Hanke M,et al.Relation between awareness of circulatorydisorders and smoking in a general population health examination[J].BMCPublic Health.2006 Feb 27;6:48
[48]Istvan JA,Lee WW,Buist AS,et al.Relation of salivaru continine to bloodpressure in middle-aged cigarette smokers[J].Am Heart.1999,137:928-931
[49]张永红,赵玉泉,佟伟军等.蒙古族居民吸烟、饮酒与高血压的关系研究[J].高血压杂志.2001,9(2):154-156
[50]Pedro MV,Arveiler D,Evans A,et al.Different alchol drinking and bloodpressure relationships in France and Northerm Ireland.The PRIME Study[J].Hypertension.2001,38:1361-1366
铩颷51]Beulens JW,Rimm EB,Ascherio A,et al.Alcohol consumption and risk forcoronary heart disease among men with hypertension[J].Ann Intem Med.2007,146(1):10-9
[52]Abuissa H,Lavie C,Spertus J,et al.Personal health habits of Americancardiologists[J].2006,97(7):1093-6
[53]Soubassi LP,Papadakis ED,Yheodoropoulos IK,Poulos GD,et al.Incidence andrisk factors of coronary artery disease in patients on chronic hemodialysis[J].Int JArtif Organs.2007 Mar;30(3):253-257
[54]Bodnar LM,Catov JM,Klebanoff MA,et al.Prepregnancy body mass index andthe occurrence of severe hypertensive disorders of pregnancy[J].Epidemiology.2007 Mar;18(2):234-9
[55]Aoyagi K,Kusano Y,Yakamura N,et al.Obesity and cardiovascular risk factorsamong men and women aged 40 years and older in a rural area of Japan[J].JPhysiol Anthropol.2006,25(6):371-5
[56]Jafar TH,Chaturvedi N,Pappas G,et al.Prevalence of overweight andobesity and their association with hypertension and diabetes mellitus in anIndo-Asian population[J].CMAJ.2006,175(9):1071-7
[57]Fuiano N,Luciano A,Pilotto L,Pietrobelli A,et al.Overweight andhypertension:longitudinal study in school-aged children[J].Minerva Pediatr.2006,58(5):451-9
[58]Schiel R,Beltschikow W,Kramer G,et al.Overweight,obesity and elevatedblood pressure in children and adolescents[J].Eur J Med Res.2006,11(3):97-101
[59]王文娟,王克安,李天麟,等.体重指数、腰围和臀围比预测高血压、高血糖的使用价值及其建议值探讨[J].中华流行病学杂志.2002,23:16-19
[60]中国肥胖问题工作组数据汇总分析协作组.我国成人体重指数和腰围对相关疾病危险因素异常的预测价值:适宜体重指数和腰围界值的研究[J].中华流行病学杂志.2002,23(1):5-10
[61]罗雷,栾荣生,袁萍.中国居民高血压病主要危险因素的meta分析[J].中 华流行病学杂志.2003,24(1):50-53
铩颷62]Iwanicka Z,Glab E,Barg E,et al.Carbohydrate and lipid metabolism disordersin obese children and adolescents[J].Med Wieku Rozwoj.2004,8(3):815-24
[63]Matos AC,Ladeia AM,et al.Assessment of cardiovascular risk factors in a ruralcommunity in the Brazilian state of Bahia[J].Arq Bras Cardiol.2003,81(3):291-302
[64]Kalichman L,Livshits G,Kobyliansky E.Indices of body composition andchronic morbidity:a cross-sectional study of a rural population in central Russia[J].Am J Hum Biol.2006,18(3):350-8
[65]Doll S,Paccaud F,Bovet P,et al.Body mass index,abdominal adiposity andblood pressure:consistency of their association across developing and developedcountries[J].Int J Obes Relat Metab Disord.2002,26(1):48-57
[66]Collins FS,McKusick VM.Implications of the Human Genome Project formedical science[J].JAMA.2001,258:540-4
[67]何秉贤 朱徐,黄定,等.新疆汉、维吾尔、哈萨克三民族高血压流行病学调查[J].新疆医学.1992,22(4):194-201
[68]Hirosbi K,Meclet T,HiromiM,et al.24-hour,blood pressure in Uygur,Kazakb and ban elderly subjects in China[J].Hypertensions Res.2000,23(2):177-185
[69]Jeunemaitre X,Soubrier F,Kotelevtsev YV,et al.Molecular basis of humanhypertension:role of angiotensinogen[J].Cell.1992,71:169-180
[70]Rieder MJ,Taylor SL,Clark AG,et al.Sequence variation in the humanangiotensin converting enzyme gene[J].Nat Genet.1999,22:59-62
[71]Levy D,DeStefano AL,Larson MG,et al.Evidence for a gene influencingblood pressure on chromosome 17 Genome scan linkage results for longitudinalblood pressure phenotypes in subjects from the framingham heart study[J].Hypertension.2000,36:477-483
[72]Persu A,Barbry P,Bassilana F,et al.Genetic analysis of the beta subunit of theepithelial Na~+ channel inessential hypertension[J].Hypertension.1998,32:129-137
铩颷73]Baker E H,Dong Y B,et al.Association of hypertension with T594M mutationin β subunit of epithelial sodium channels in black people resident in London[J].The lancet.1998,351:1388-1392
[74]Wong ZYH,Stebbing M,Ellis JA,et al.Genetic linkage of the β-and γ-subunits of the epithelial sodium channel with systolic blood pressure in thegeneral population[J].Lancet.1999,353:1222-1225
[75]贾宏钧,王钟林,杨期东.离子通道与心脑血管疾病.人民卫生出版社.2001,429-516.
[76]McDonald FJ,Price MP,Snyder PM,Welsh MJ.Cloning and expression of the[beta]- and[gamma]-subunits of the human epithelial sodium channel[J].Am JPhysiol.1995,268:C1157-C1163
[77]Iwai N,Baba S,Mannami T,et al.Association of a sodium channel alphasubunit promoter variant with blood pressure[J].J Am Soc Nephrol.2002,13:80-85
[78]Kruglyak L,Nickerson DA.Variarion is the spice of the life[J].Nat Genet.2001,27:234-236
[79]Ambrosius WT,Bloem LJ,Zhou L,Rebhun JF,et al.Genetic variants in theepithelial sodium channel in relation to aldosterone and potassium excretion andrisk for Hypertension[J].hypertension.1999,34:631-637
[80]Takao Sugiyama,Norihrio Koto,Yuji Ishinaga,et al.Evaluation of selectedpolymorphisms of the Mendelian Hypersive Disease Genes in the Japanesepopulation[J].Hypertens Res.2001,24:515-521
[81]Samaha FF,Rubenstein RC,Yan W,et al.Functional polymorphism in thecarboxyl terminus of the alpha - subunit of the human epithelial sodiumchannel[J].J Biol Chem.2004,279:2390-7
[82]Shi YY,He L.SHEsis,a powerful software platform for analyses of linkagedisequilibrium,haplotype construction,and genetic association at polymorphismloci[J].Cell Res.2005,15(2):97-8
[83]Keyue Ding,Kaixin Zhou,Fuchu He,et al.LDA- A java-based linkagedisequilibrium analyzer[J].Bioinformatics.2003,19:2147-2148
铩颷84]International HapMap Project.http://www.hapmap.org/downloads/index.html.en
[85]Stephens M,Smirth NJ,Donnelly P.A new statisticalmethod for haplotypereconstruction from population data[J].Am J Hum Genet.2001,68:978-989
[86]Wang X,Wang S,Lin R,et al.GNB3 gene C825T and ACE gene I/Dpolymorphisms in essential hypertension in a Kazakh genetic isolate[J].JHypertens.2004,18:663-668
[87]Ludwig M,Bolkenius U,Wickert L,et al.Structural organization of the geneencoding the a-subunit of the human amiloride-sensitive epithelial sodiumchannel.Hum Genet.1998,102:576-581
[88]Shodimu E,Peter M,Kathleen L,et al.Polymorphic Variants alter Function ofthe Human Epithelial Sodium Channel α-subunit:Evidence for a Role inhypertension[J].Hypertension.1998,31:1118-1124
[89]赵仲堂等.流行病学研究方法与应用.科学出版社,2000
[90]孔祥东,杨宇霞,张思仲.AGT基因单倍型与原发性高血压[J].遗传.2004,26(6):797-802
[91]方福德.基因多态性与疾病相关性的遗传分析中某些值得注意的问题[J].中华医学杂志.2004,84:796-798
[92]张怡,朱鼎良.原发性高血压遗传学研究的策略和方法[J].高血压志.2004,12(1):4-8
[93]Bray MS,Boerwinkle E.The role of beta(2)-adrenergic receptor variation inhuman hypertension[J].Curr Hypertens Reports.2000,2:39-43
[94]Wallerstedt SM,Eriksson AL,Ohlsson C,et al.Haplotype association analysisof the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor ina Swedish hypertensive population[J].J Hum Hypertens.2005,19(9):705-8
[95]Iaccarino G,Lanni F,Cipolletta E,et al.The Glu27 allele of the beta2 adrenergicreceptor increases the risk of cardiac hypertrophy in hypertension[J].Hypertens.2004,22(11):2117-22
[96]Huang G,Wu D,Zhang XJ,et al.Association between the beta 2 adrenergicreceptor polymorphism and blood pressure in YueXi population[J].Zhonghua XinXue Guan Bing Za Zhi.2005,33(8):713-6
[97] Masuo K, Katsuya T, Fu Y, et al. Beta2- and beta3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years[J]. Circulation. 2005,111(25): 3429-34
[98] Huang G, Xing H, Hao K, et al. Beta2 adrenergic receptor gene Argl6Gly polymorphism is associated with therapeutic efficacy of benazepril on essential hypertension in Chinese[J]. Clin Exp Hypertens. 2004,26(6): 581-92
[99] Kirby RF, Woodworth CH, Woodworth GG, et al. Beta-2 adrenoceptor mediated vasodilation: role in cardiovascular responses to acute stressors in spontaneously hypertensive rats [J]. Clin Exp Hypertens A. 1991,13(5): 1059-68
[100] Lentes KU, Berrettini WH, Hoehe MR, et al. A biallelic DNA polymorphism of the human beta-2-adrenergic receptor detected by Ban I-Adrbr-2[J]. Nucleic Acids Res. 1988, 16(5): 2359
[101] Kato N, Sugiyama T, Morita H, et al. Association analysis of beta(2)-adrenergic receptor polymorphisms with hypertension in Japanese [J]. Hypertension. 2001,37(2): 286-292
[102] Munakata M. Beta2 Adrenergic receptor gene polymorphisms [J]. Nippon Rinsho. 2001, 59(10): 1889-1893.
[103] Kobilka BK, Dixon RAF, Frielle T, et al. cDNA for the humanβ2-adrenergic receptor[J]. Proc Natl Acad Sci USA. 1987, 84: 46-50
[104] Giacobino JP. β3-adrenoceptor an. update[J]. Eur Endocrinol. 1995, 132: 377
[105] Reishaus E, Innis M, Macintyre N, et al. Mutations in the gene encoding for thep2-adrenergic receptor in normal and as thematic subjects [J]. Am J Respir Cell MolBiol. 1993,8:334-339
[106] Leineweber K, Buscher R, Bruck H, et al. The Gln27Glu beta(2)-adrenocetor polymorphism slows the onset of desensitization of cardiac functional response in vivo[J].Pharmacogenetic S.2003,13 (2):59-66.
[107] Meirhaeghe A, Luan J, Selberg-Franks P, et al. The effect of the Glyl6Arg polymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acid levels is modulated by physical activity[J]. J Clin Endocrinol Metab.2001,86(12): 5881-5887
铩颷108]Chang TJ,Tsai MH,Jiang YD,et al.The Arg16Gly polymorphism of humanbeta2-adrenoreceptor is associated with type 2 diabetes in Taiwanese people[J].Clin Endocrinol(Oxf).2002,57(5):685-690
[109]Castellano M,Rossi F,Giacche M,et al.Beta(2)-adrenergic receptor genepolymorphism,age,and cardiovascular phenotypes[J].Hypertension.2003,41(2):361-367
[110]Ranade K,Shue WH,Hung YJ,et al.The glycine allele of aglycine/argininepolymorp hism in the beta 2- adrenergic receptor gene isassociated with essential hypertension in a population of Chinese origin[J].Am J Hypertens.2001,14(12):1196-1200
[111]梁宇,赵彦艳.β2肾上腺素能受体基因家族在中国东北高血压病高发人群中的基因型分析[J].中华医学遗传学杂志.2004,21(2):124-127
[112]黄帼,吴涤,张学军等.β2-肾上腺素能受体基因多态性与岳西地区高血压患者血压的关系[J].中华心血管病杂志.2005,33(8):713-716
[113]Timmermann B,Mo R,Luft FC,et al.β2-adrenoceptor genetic variation isassociated with genetic predisposition to essential hypertension:The Bergenblood Pressure Study[J].Kidney Int.1998,53:1455
[114]Kotanko P,Binder A,Tasker J,et al.Essential Hypertension in AfricanCaribbeans Associates With a Variant of the β2-Adreno- ceptor[J].Hypertension.1997,30:773-776
[115]Tonolo G,Melis MG,Secchi G,et al.Association of Trp64Arg beta3-adrenergicreceptor gene polymorphism with essential hypertension in the Sardinianpopulation[J].Hypertens.1999,17(1):33-38
[116]Hongyan Wu,Wenru Tang,Hongwei Li,et al.Association of thebets2-adrenergic receptor gene with essential hypertension in the non-HanChinese Yi minority human population[J].Hypertens.2006,24:1041-1047
[117]Green SA,Tuki J,Innis M,et al.Aminoterminal polymorphism of the humanbeta2-adrenergic receptor impart distinct agonist-ptomoted regulatoryproperties[J].Biochemistry.1994,33:9414-9419
[118]Gratze G,Fortin J,Labugger R,et al.Beta2-adrenergic receptor variants affect resting blood pressure and ag0nist-induced vasodilation in young adult
Caucasians[J].Hypertension.1999,33:1425-1430
铩颷119]Dishy V,Sofowora GG,Xie HG,et al.The effect of common polymorphisms ofthe beta2 adrenergic receptor gene is associated with essential hypertension in apopulation of Chinese origin[J].Am J Hypertens.2001,14:1196-1200
[120]窦相峰,孙凯,黄晓红等.Adducin基因和血管紧张素转换酶基因多态性与原发性高血压的关系[J].中国循环杂志.2004,19(4):286-289
[121]Yang Q,Khoury MJ.Evolving methods in genetic epidemiology Ⅲ Geneenvironment interaction in epidemiologic research[J].Epidemiol Rev.1997,19(1):33-43
[122]Thiel BA,Chakravarti A,Cooper RS,et al.A genome-wide linkage analysisinvestigating the determinants of blood pressure in whites and AfricanAmericans[J].Am J Hypertens.2003,16(2):151-3
铩颷1]李立明 主编.流行病学(第五版),人民卫生出版社,400-401
[2]Hamet P,Pauova Z,Adarichev V,et al.Genes and environment[J].Hypertens.1998,16:397-418
[3]Lander ES,Schork NG.Genetic dissection of complex traits[J].Science.1994,265:2137-2048
[4]Lifton RP.Molecular genetics of human blood pressure variation[J].Science.1996,27:2676-2680
[5]Ward RH.Familial aggregation and genetic epidemiology of blood pressurehypertension:Pathophysiology,Diagnosis and Management[J].New York,NY:Raven press.1990,81-100
[6]Risch N,Merkangas K.The future of genetic studies of complex human disease[J].Science.1996,273:1516-1517
[7]Jorde LB.Linkage disequilibrium as a gene-mapping tool[J].Am J Hum Genet.1995,56:11-14
[8]Kruglyak L.What is significant in whole-genome linkage disequilibrium studies?[J].Am J Hum Genet.1997,61:810-812
[9]Terwilliger JD,Zollner S,Laan M,et al.Mapping genes through the use of linkagedisequilibrium generated by genetic drift mapping in small populations with nodemographic expansion[J].Hum Hered.1998,48:138-154
[10]Terwilliger JD,Weiss KM.Linkage disequilibrium mapping of complex disease:fantasy or reality?[J].Curr Opin Biotechnol.1998,9:578-594
[11]Ewens WJ,Spielman RS.Locating genes by linkage and association[J].Theor PopulBiol.2001,60:135-9
[12]Pritchard JK,Przeworski M.Linkage disequilibrium in humans:models and data[J].Am J Hum Genet.2001,69:1-14
[13]Zeller R.It takes time to make a pinky:unexpected insights into how SHH patternsvertebrate digits[J].Sci STKE.2004,2004:53
[14]Murone M,Rosenthal A,Sauvage F.Sonic hedgehog signaling by thepatched-smoothened receptor complex[J].Curr Biol.1999,9:76-84
[15]Denef N,Perez L,Cohen SM.Hedge hog induces opposite changes in tuen overand subcellular localization of Patched and Smoothened[J].Cell.2000,102:521-532
[16]Drysdale CM,McGraw DW,Stack CB,et al.Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo
responsiveness.Proc Natl Acad Sci USA 97[J].2000,10483-10488
铩颷17]Ball D,Hill L,Eley TC,Chomey MJ,et al.Dopamine markers and general cognitiveability[J].Neuroreport 1998,9:347-349
[18]Clark AG.Inference of haplotypes from PCR-arnplified samples of diploidpopulations[J].Mol Biol Evol.1990,7:111-122
[19]Becker T,Knapp M.Maximum-likelihood estimation of haplotype frequencies innuclear families.Genet Epidemiol.2004,27:21-32
[20]Xie X,Ott J.Testing linkage disequilibrium between a disease gene and markerloci[J].Am J Hum Genet.1993,53:1107
[21]Zhao JH,Curtis D,Sham PC.Model-free analysis and permutation tests for allelicassociations[J].Hum Hered.2000,50:133-139
[22]Zhao JH,Sham PC.Faster haplotype frequency estimation using unrelated subjects[J].Hum Hered.2002,53:36-41
[23]Schneider S,Roessli D,Excofier L.Arlequin:A software for population geneticsdata analysis(Genetics and Biometry Lab,Dept of Anthropology University ofGeneva).2000,56:76-81
[24]Stephens M,Donnelly P.A comparison of bayesian methods for haplotypereconstruction from population genotype data[J].Am J Hum Genet 2003,73:1162-1169
[25]Wang DG.Fan J B,Siao CJ,et al.Large-Scale identification mapping and genotypingof single-nucleotide polymorphisms in the human genome[J].Science.1998,280(5366):1077-1082
[26]Sach idanandam R,Weissman D,Schrnidt SC,et al.A map of human genomesequence variation containing 1.42 million single nucleotide polymorphism[J].Nature.2001,409:928-933
[27]Lander ES.The new genomics:global views of biology[J].Science.1996,274:536-539
[28]孙树汉,杨胜利.单核苷酸多态性与复杂性状疾病[J].第二军医大学学报.2004,25:117-119
[29]赵非.单核苷酸多态性研究进展[J].国外医学儿科学分册.2002,29:297-299
[30]陈蕊雯,孙树汉.单核苷酸多态性在复杂性状疾病易感基因研究中的应用[J].第二军医大学学报.2004,25:140-142
[31]Pemeger TV.What's wrong with Bonferroni adjustments[J].BMJ.1998,316: 1236-1238
铩颷32]Storey JD,Tibshirani R.Statistical significance for genomewide studies[J].ProcNatl Acad Sci USA.2003,100:9440-9445
[33]L Jane,Gold smith,Power and Sample Size Considerations in Molecular Biology.Biostatistical Methods.Humana Press Inc,2002
[34]Cohen J.Statistical power analysis for the behavioral sciences.Hillsdle,New Jersey,Lawrence Erlbaum Association.2nd edition,1988,215-271
[35]Smithies O,Maeda N.Gene targeting approaches to complex genetic disease:atherosclerosis and essential hypertension[J].Proc Natl.Acad Sci USA.1995,92:52-66
[36]Gu L,Dene H,Deng AY,et al.Genetic mapping of two pressure quantitative trait locion rat chromosome 1[J].J Clin Invest.1996,97:777
[37]Lezin ES,Liu WZ,Wang JM,et al.Genetic isolation of a chromosome 1 regionaffecting blood pressure in the spontaneously hypertensive rat[J].Hypertension.1997,30(4):854
[38]Lander ES,et al.Initial sequencing and analysis of the human genome[J].Nature.2001,409:860-921
[39]The International SNP Working Group.A map of human genome sequencevariation containing 1.42 million single nucleotide polymorphisms[J].Nature.2001,409:928-933
[40]Syvanen A.Accessing genetic variation:genotyping single-nucleotidepolymorphisms[J].Nature Rev Genet.2001,2:930-942
[41]Ng PC,Henikoff S.Accounting for human polymorphisms predicted to affectprotein function[J].Genome Res.2002,12:436-446
[42]Sunyaev S,et al.Prediction of deleterious human alleles[J].Hum Mol Genet.2001,10:591-597
[43]Chasman D,Adams RM.Predicting the functional consequences ofnon- synonymous single nucleotide polymorphisms:structure- based assessmentof amino acid variation[J].J Mol Biol.2001,307:683-706
[44]Frossard PM,Malloy MJ,Lestringant GG,et al.Hapltype soft he human rennin geneassociated with essential hypertension and stroke[J].J Hum Hypertens.2001,1(1):49-55
[45]FuY,KatsuyaT,AsaiT,et al.Lack of correlation between MboI restriction Fragmentlength polymorphismof rennin gene and essential hypertensionin Japanese[J]. Hypertens Res.2001,24(3):295-298
铩颷46]Hasimu B,Nakayama T,Mizutani Y,et al.Haplotype analysis of the human renningene and essential hypertension[J].Hypertension.2003,41(2):308-312
[47]Hasimu B,Nakayama T,Mizutani Y,et al.Anovel variable number of tandem repeatpolymorphismof the rennin gene and essential hypertension[J].Hypertens Res.2003,26(6):473-477
[48]郑泰山,项坤三,孙多奇。肾素基因与中国人2型糖尿病及其微血管病变、冠心病和高血压的相关性[J].中华内分泌代谢杂志.1997,13(4):206-209
[49]孙琦,柳青,雷家俨等.肾素基因与重庆地区人群原发性高血压的关系[J].重庆医学.2003,32(1):3-5
[50]Jeunenmaitre X,Soubrier F,Kotelevtsev YV,et aL Molecular basis of humanhypertension:role of angiotensinogen[J].Hypertension.1992,71:169-180
[51]Hata A,Namikawa C,Sasaki M,et al.AGT as a risk factor for essential hypertensionin Japan[J].J Clin Invest.1994,93:1285-1287
[52]Nishiuma S,Kario K,Kayaba K,et al.Effect of the AGT gene Met235Thr variant onblood pressure and other cardiovascular rish factors in two Japanese populations[J].J Hypertens.1995,13:717-722
[53]Frossard PM,Hill SH,Elshahat YI,et al.Association of angiotensinogen genemutations with hypertension and myocardial infarction in a gulfpopulation[J].ClinGenet.1998,54(4):285-293
[54]Caulfield M,Lavender P,Newell M,et al.Linkage of AGT gene locus to humanessential hypertension in African Caribbeans[J].J Clin Invest.1995,95:687-692
[55]Wang WY,Glenn CL,Zhang W,et al.Exclusion of angiotensinogen gene inmolecular basis of human hypertension:sibpair linkage and association analyses inAustralian anglo-caucasians[J].Am J Med Genet.1999,87(1):53-60
[56]Pamies Andreu E,Palmero Palmero C,Garcia Lozano R,et al.The effect of theangiotensinogen M235T and the angiotensin-converting enzyme I/D polymorphismson arterial hypertension and other cardiovascular risk factors[j].Med Clin.1999,113(5):164-8
[57]Caulfield M,Lavender P,Farrall M,et al.Linkage of AGT gene to essentialhypertension[J].N Engl J Med.1994,330:1629-1633
[58]Tsai CT,Fallin D,Chiang FT,et al.Angiotensinogen gene haplotype andhypertension[J].Hypertens.2003,41:9-15
[59]Li NF,Zhou L,Wu WD,et al.The relationship between the variants in 5' up stream core promoter A(-6)G and A(-20)C of angiotensinogen gene and essential
hypertension in Kazakans of Xinjiang[J].Zhong Hua Yi Xue Yi chuan Za Zhi.2004,
21:23-28
铩颷60]Niu TH,Yang JH,Wang BY,et al.Angiotensinogen gene polymorphismsM235T/T174M:no exesstrans mission to hypertensive Chinese[J].Hypertension.1999,33:698
[61]Thomas GN,Young RP,Tomlinson B,et al.Ren in- angiotensin-aldosterone systemgene polymorphisms and hypertension in HongKong Chinese[J].Clin ExpHypertension.2000,22:87-97
[62]Erdos EG.Angiotensin I converting enzyme and the changes in our concepts throughthe years[J].Hypertension.1990,16(4):363-70
[63]Hubert C,Houot AM,Corvol P,et al.Structure of the angiotensin I-convertingenzyme gene.Two alternate promoters correspond to evolutionary steps of aduplicated gene[J].J Biol Chem.1991,Aug 15;266(23):15377-15383
[64]Foy CA,Rice GI,Ossei-Geming N.Angiotensin-converting enzyme(ACE)genepolymorphisms in patients characterised by coronary angiography[J].Hum Genet.1997,Sep;100(3-4):420-5
[65]Rotimi C,Puras A,Cooper R,et al.Polymorphisms of reninangio- tensin genesamong Migerians,Jamaicans,and African Americans[J].Hypertension.1996,27(3part 2):558-563
[66]Zaman MM,Yoshiike N,Tanaka H.Dissecting the contradictory finding sofangiotens in converting enzyme genetic polymorphism with blood pressure andhypertension[J].Bangladesh Med Res Counc Bull.2001,27:90-95
[67]Pereira AC,Mota GFA,Cunha RS,et al.Angiotensinogen 235T allele "dosage" isassociated with blood pressure phenotypes[J].Hypertension.2003,41:25-30
[68]叶琼,吴可贵,曾开淇,等.血管紧张素转换酶基因多态性与原发性高血压之间的关系[J].高血压杂志.1998,6(1):11-13
[69]郑豪义,戴玉华,邱长春.血管紧张素转化酶基因多态性与原发性高血压的关系[J].高血压杂志.1997,5(3):194-196
[70]孔祥东,杨宇霞.血管紧张素转化酶1基因单倍型与原发性高血压[J].临床心血管病杂志.2005,12:724-726
[71]Giver V,Poch E,Bragulat E.Renin-angiotensin system genetic polymorphism sandsalt sensitivityin essential hypertension[J].Hypertension.2000,35(1Pt2):512-517
[72]Bonnardeax A,Davies E,Jeunemaitre X.AngiotensinⅡtype-Ⅰ receptor gene polymerphisms in human essential hypertension[J].Hypertens.1994,24:63-69
铩颷73]Wang WY,Zee RY,Morris BJ.Association of angiotens in typeI receptor genepolymorphism with essential hypertension[J].Clin Genet.1997,51(1):31
[74]Ashavaid TF,Shalia KK,Nair KG,et al.ACE and AT1R gene polymor-phismsandhypertension in Indian population[J].J Clin Lab Anal.2000,14(5):230
[75]Tiret L,Blanc H,Ruidavets JB,et al.Gene polymorphisms of the renin-angiotensinsystem in relation to hypertension and parental history of myocardial infarction andstroke:the PEGASE study Projetd'Etudedes Genesdel'Hypertension Arterielle Severeamoderee Essentielle[J].J Hypertens.1998,16(1):37
[76]Zhang X,Erdmann J,Regitz-ZagrosekV,et al.Evaluation of three polymorphisms inthe promoter region of the angiotens in ⅡTypel receptor gene[J].J Hypertension.2000,18(3):267
[77]Takahashi N,Murakami H,Kodama K,et al.Association of a polymorphism at the5'-region of the angiotens in Ⅱ Type1 receptor with hypertension[J].Am Hum Gene.2000,64(Pt3):197
[78]Henderson SO,Haiman CA,Mack W,et al.Multiple Polymorphisms in therenin-angiotens in-aldosterone system(ACE,CYP11B2,AGTR1)and theircontribution to hypertension in African Americans and Latinos in the multi ethniccohort[J].Am J Med Sci.2004,328(5):266
[79]Sugimoto K,Katsuya T,Ohkubo T,et al.Associationbetween angiotens in Ⅱ typelreceptor gene polymorphis man dessential hypertension:the Ohasama Study[J].Hypertens Res,2004,27:551-556
[80]KobashiG,HataA,OhtaK,et al.A1166C variant of angiotensin Ⅱ typel receptor geneis associated with severe hypertension in pregnancy independently of T235 variant ofangiotensinogen gene[J].J Hum Genet,2004,49:182-186
[81]LiuY,Shan GL,Cui CY,et al.A1166Cpolymorphism of the angiotens in Ⅱtypelreceptor gene an dessential hypertension in Han Tibetan and Yi populations[J].Zhong hua Yi Xue Yi Chuan Xue Za Zhi.2003,20:220-224
[82]乔卫卫,张奎星,刘同宝,等.血管紧张素Ⅱ2型受体基因多态性与男性高血压病的相关研究[J].中华心血管病杂志.2005,32:668-672
[83]Kobilka BK,Dixon RAF,Frielle T,et al.cDNA for the human β2- adrenergicreCeptor[J].Proe Natl Acad Sci USA.1987,84:46-50
[84]Munakata M.Beta2 Adrenergic receptor gene polymorphisms[J].Nippon Rinsho.2001,59(10):1889-1893
铩颷85]Svetkey LP,Timmons PZ,Emovon O,et al.Association of hypertension with beta2-and alpha2c 10-adrenergic receptor genotype[J].Hypertension.1996 27(6):1210-1215
[86]Kotanko P,Binder A,Tasker J,et al.Essential Hypertension in African CaribbeansAssociates With a Variant of the β2-Adreno-ceptor[J].Hypertension.1997,30:773-776
[87]Timmermann B,Mo R,Luft FC,et al.β2-adrenoceptor genetic variation is associatedwith genetic predisposition to essential hypertension:The Bergen Blood PressureStudy[J].Kidney Int.1998,53:1455
[88]Bray MS,Krushkal J,Li L,et al.Positional genomic analysis identifies the beta(2)adrenergic receptor gene as a susceptibility locus for human hypertension[J].Circulation.2000,101(25):2877-2882
[89]梁宇,赵彦艳.β肾上腺素能受体基因家族在中国东北高血压病高发人群中的基因型分析[J].中华医学遗传学杂志.2004,21(2):124-127
[90]黄帼,吴涤,张学军,等.β2-肾上腺素能受体基因多态性与岳西地区高血压患者血压的关系[J].中华心血管病杂志.2005,33(8):713-716
[91]何鑫,初少莉,金力,等.;α-内收蛋白基因Gly460Trp多态性与原发性高血压相关关系研究[J].高血压杂志.1999,4:288-290
[92]Cusi D,Barlassina C,Azzani T,et al.Polymorphisms of α-adducing and saltsensitivity in patients with essential hypertension[J].Lancet.1997,349(9062):1353-1357
[93]Kamitani A,Zilla YH,Fraster R,et al.Human alpha adducing gene blood pressureand sodium metabolism[J].Hypertension.2001,23(7):579-589
[94]Glorioso N,Manunta P,Filigheddu F,et al.Therole of α-adducing polymorphism inblood pressure and handling regulation maynotbeex cluded by anegative associationstudy[J].Hypertension.1994,34(4):649-654
[95]JuZ,ZhangH,SunK,et al.Alpha adducing gene polymorphismis associated withessential hypertension in Chinese:a case control and family basedstudy[J].JHypertens.2003,21:1861-1868
[96]董会奕,李秋荣,王勤,罗振国.ADD-1基因和GNB3基因多态性与原发性高血压的相关性研究[J].岭南心血管病杂志.2006,4:314-317
[97]李南方,李红建,周玲,等.α-adducin基因变异与新疆哈萨克族人原发性高血压的相关性研究[J].科学技术与工程.2004,(07)
[98]许骥,华琦,李东宝.α-内收蛋白基因Gly460Trp多态性与北京汉族人群原发性高血压的关系[J].医学研究生学报.2005,11:999-1004
铩颷99]Stiffert W,Rosskopf D,siffert G,et al.Association of a human G protein subunitvariant with hypertension[J].Nature Genetics.1998,18:45-48
[100]Beige J,Hohenbleicher H,Distler A,et al.G protein β_3 subunit C825T variant andambulatory blood pressure in essential hyperten sion[J].Hypertens.1999,33:1049-1051
[101]Jacobi J,Hilgers KF,SchlaichMP,etal.825Tallele of the G-protein β3subunitgene(GNB3)is associated with impaired left ventricul ardiastolic filling in essentialhypertension[J].Hypertens.1999,17(10):1457-146
[102]戴书萍,时景璞,赵彦艳,等.中国东北高血压病高发地区人群中G蛋白p3亚单位825C/T多态分析[J].遗传学报.2002,4:294-298
[103]张明华,刘国树,石岩,等.G蛋白β3亚单位基因C825T多态性与原发性高血压[J].高血压杂志.2001,4:288-291
[104]Huang X,Ju Z,Song Y,et al.Lack of association between the G protein beta(3)subunit gene and essential hypertension in Chinese:a case control and a familybased study[J].J Mol Med.2003,81(11):729-735
[105]Kato N,Sugiyama T,Morita H,et al.Genetic analysis of theatrical natriureticpeptide gene in essential hypertension[J].Clin Sci(Lond).2000,98(3):251-258
[106]Michel Burnier.Sodium balance and hypertension:rare genetic disorder sex posepath ogenicme chamisms[J].Exp Nephrol.1998,6:496-501
[107]Bulut D,Potthast R,Hanefeld C,et al.Impaired vasodilator responses to atrialnatriuretic peptide in essential hypertension[J].Eur J Clin Invest.2003,33(7):567-573
[108]Nkeh B,Tiago A,Candy GP,etal.Association between an atrialnatriuretic peptidegene polymorphism and normal blood pressure in subjects of African ancestry[j].Cardiovasc J S Afr.2002,13(3):97-101
[109]Melander O,Frandsen E,GroopL.Plasmapro ANP1-30 reflects salt sensitivity insubjects with here dity for hypertension[J].Hypertension.2002,39(5):996-999
[110]Garty H,et al.Epithelial sodium channels:Function,structure,and regulation[J].Physiol Rev.1997,77:359-396
[111]Rossier BC,et al.1996 Homer Smith Award Lecture.Cum grano salis:Theepithelial sodium channel and the control of blood pressure[J].J Am Soc Nephrol.1997,8:980-992.
[112]Scheinman S J,Guay-Woodford LM,Thakker RV,et al.Genetic disorders of renalelectrolyte transport[J].Nengl J Med.1999,340:1177
铩颷113]Shimkets RA,Warnock DG,Bositis CM,et al.Liddles syndrome:Heritablehuman hypertension caused by mutations in the β subunit of the ep-ithelialsodiumchannel[J].Cell.1994,79:407
[114]Abriel H,Lofting J,Robhun JF,et al.Defective regulation of the epithelial Na~+channel by Nedd4 in Liddles syndroms[J].J Clin Invest.1999,103:667
[115]马晓伟,田亚男,高妍,等.对一个Liddle综合征家系临床和上皮细胞钠通道基因突变的研究[J].中华内科杂志.2001,40(6):6
[116]Pradervand S,Wang Q,Bumier M,et al.A mousemodel for Liddles syn-drome[J].JAm Soc Nephrol.1999,10:25-27
[117]Persu A,Barbry P,Bassilana F,et al.Genetic analysis of the beta sub 2 unit ofthe epithelial Na~+ channel in essential hypertension[J].Hypertension.1998,32(7):129-137
[118]Dong YB,Zhu HD,Baker EH,et al.T594 Mand G442V polymorphismsof the sodium channel beta subunit and hypertension in a black population[J].JHum Hypertens.2001,15(6):425-430
[119]Iwai Y,et al.Association of a Sodium Channel[alpha]Subunit Promoter Variantwith Blood Pressure[J].J Am Soc Nephrol.2002,13:80-85
[120]Jachymova M,Horky K,Bultas J,et al.Association of the Glu298Asppolymorphism in the endothelial nitricoxide synthase gene with essentialhypertension resistant tocon ventional therapy[J].Biochem Biophys Res Commun.2001,284:426-430
[121]Tsujita Y,BabaS,Yamauchi R,et al.Association analyses between geneticpolymorphisms of endothelial nitricoxide synthase gene and hypertension inJapanese:the suita study[J].J Hypertens.2001,19:1941-1948
[122]Shoji M,Tsutaya S,Saito R,et al.Positive association of endothelial nitricoxidesynthase gene polymorphism with hypertension in northernJ apan[J].Life Sci.2000,66:2557-2562
[123]Hingorani AD.Endothelial nitricoxid esynthase polymorphisms and hypertension[J].Curr Hypertens Rep.2003,5:19-25
[124]谭建聪,祝之明,祝善俊,等.高血压病患者G蛋白β3亚单位基因C825T和eNOS基因G894T多态性研究[J].中华心血管病杂志.2003,31:173-176
[125]Veldman BA,Spiering W,Doevendans PA,et al.The Glu 298Asp polymorphism ofthe NOS gene as adeterminant of the base line production of nitricoxide[J].Journalof hypertension.2002,20(10):2023-2027
铩颷126]Jin JJ,Nakura J,Wu ZH,et al.Association of Endo the lin-lgene variant withhypertension[J].Hypertension.2003,41:163-167
[127]Iwai N,KatsuyaT,IshikawaK,et al.Human prostacyclinsynthase gene andhypertension:the Suita Study[J].Circulation.1999,100:2231-2236
[128]Nakayama T,Soma M,Haketa A,et al.Haplotype an alysis of the prosta cyclinsynthase gene and essential hypertension[J].Hypertens Res,2003,26:553-557
[129]仝其广,赵水平,胡大一,等.脂蛋白脂酶Ser447Ter基因变异对血压影响[J].中华心血管病杂志.2004,32:474
[130]Wu DA,Bu X,Warden CH,et al.Quantitative trait locus mapping ofhuman blood pressure to a genetic region at or near the lipoprotein lipase genelocus on chromosome 8p22[J].J Clin Invest.1996,97(5):2111-2118
[131]李毅夫,赵水平.载脂蛋白E基因多态性与高血压[J].高血压杂志.2000,8(1):9-11
[132]张怀勤.载脂蛋白E基因多态性与高血压病、冠心病的相关性研究[J].基础研究.2002,2(2):20-22
[133]WanT ai Seet.Apolipo protein Egene typing in th eMalay,Chinese and Indian ethnicgroups in Malaysia a study on the distribution of the different apoE callele sandgenotypes[J].Clinica Chimica Acta.2004,340:201-205
[134]Katsuya T.Epsilon4 allele of apolipo protein E gene associates lower blood pressurein young Japanese subjects:the Suite Study[J].J Hypertens.2002,20(10):1941-1942
[135]崔国方.中国汉族载脂蛋白E基因多态性与高血压的关系[J].中国临床康复.2003,7:(18)2545-2546
[136]LiX.Association of apoli protein E gene polymorphism with essenti hypertensionand it scomp lications[J].Clin Exp Med.2003,2(4):171-179
[137]Vazquez Vigoa A,Vazquez Cruz A,Calderin RO,et al.Metabolic syndrome inpatients with essential hypertension[J].Nefrologia.2003,23(5):423-431.
[138]Schrader AP,Zee RY,Morris BJ.Association analysis of Nsil RFLP ofhuman insulin receptor gene in hypertensives[J].Clin Genet.1996,49(2):74-78
[139]Wu KG,Lin CR,Xie LD,et al.The relationship between insulin receptorgene exon8 polymorphism and Essential hypertension[J].Chinese Journalof hypertension.1999,7(3):314-317
[140]Rich DE,Lander ES.On the allelic spectrun of human disease[J].Trend Genet.2001,17:502-510
[141]朱鼎良.我国高血压基因研究十年回顾和几点建议[J].中华心血管病杂志.2005,33(7):585-587