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.
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