过氧化氢酶基因多态性在原发性高血压中的作用与分子机制研究
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摘要
原发性高血压病(Essential Hypertension,EH)是由多个基因和环境因素共同影响所致的常见的循环系统疾病。EH遗传学研究的主要任务是寻找和确认易感基因,并阐明其在EH发生和发展中的重要机制和作用。
随着对许多疾病的深入研究,越来越多的证据表明体内的氧化还原状态与一些常见的疾病发生有着紧密的联系,例如高血压、动脉粥样硬化和其他心血管疾病的发生。而过氧化氢酶由于其抗氧化的生理功能成为原发性高血压的候选基因。我们首先在隔离群体发现CATSNP-844 A/G多态和原发性高血压相关性;随后在上海汉族开放人群发现了catalase单倍型CATH1(G-A-T)和CATH2(A-T-C)与原发性高血压的相关性(568病例:654对照),SPSS统计分析结果显示CATH1/CATH1,CATH1/CATH2和CATH2/CATH2在高血压疾病组和对照组中频率分布存在极显著差异(P=0.0028),其中CATH1/CATH2(279 out of559 or 49.9%),CATH2纯合子(63 out of 119 or 52.9%)与CATH1纯合子患病概率(226 out of 554 or 40.79%)相比较高,其比数比(odds ratio,OR)分别是1.472(95%置信区间,1.162～1.870)和1.652(95%置信区间,1.108～2.464)。而CATH1和CATH2单倍型频率在高血压疾病组和对照组中分布同样存在显著差异P=0.000778。
荧光素酶报告基因表达结果揭示CAT 5'UTR具有转录增强作用,包含Promoter和UTR的转录活性是只有Promoter报告载体的活性的2.1-4.7倍,同时CATH1转录起始活性低于CATH2,转录起始后者活性是前者的1.49-2.1倍。而基于Pyrosequencing(焦磷酸测序)系统,对体内的5'UTR(-20T/C)多态进行表达差异检测,同样证实了CATH1单倍型转录活性显著低于CATH2单倍型(P＜0.01)。Western Blot结果显示随着单倍型由CATH2/CATH2向CATH2/CATH1和CATH1/CATH1的改变,CAT蛋白的表达量有不断的升高的趋势。Western结果与转录结果的矛盾提示我们,可能由于5'-UTR多态的存在,导致二级结构出现极大变化,除了影响转录起始,对转录后翻译可能起到了更大的影响。
由于非编码区被认为对基因的表达调控有重要作用,因此该区域所受的选择作用有时对基因的进化同样是至关重要的,我们利用PGA中的多态数据对CAT进行中性检验,结果发现:在非洲人群中Fu & Li's D~*=1.99399,P＜0.02;Fu &Li's F~*=1.567890,0.1＞P＞0.05;在欧洲人群中Fu & Li's D~*=2.02971,P＜0.02,Fu & Li's F~*=2.02527,P＜0.02。CAT可能存在平衡选择。
综上所述,CAT基因与原发性高血压相关,是一个很重要的功能基因。CAT在原发性高血压发生中具体作用和机制还有待研究。随着时间和更多的数据的产生最终可以回答CAT在原发性高血压、甚至于整个心血管系统疾病的作用是否和我们预期一样。
Essential Hypertension is a common circulatory disorder of multifactorial origin caused by a combination of genetic and environmental factors.The interactions of these susceptibility genes contribute to the susceptibility of EH.The major assignment for genetic study of EH is to identify the susceptibility genes and furtherly to reveal the important role in the pathogenesis and development of EH.
Substantial evidence implicated toxic reactive oxygen species(ROS) is a critical etiological factor in a variety of diseases such as hypertension,atherosclerosis,and other vascular diseases.Being a candidate gene susceptibility to hypertension, catalase contributes to predict against damage caused by oxidative stress and limit the deleterious effects of reactive oxygen species to vascular.We had identified a SNP in the catalase gene in isolated population,which was strongly associated with essential hypertension.Later we found there were 4 SNPs in catalase regulation regeion,3 of the 4 SNPs are predominant in Chinese Han and construct 2 major haplotypes.We found that polymouphism A-844G could be a tagging SNP,capturing the sufficient information of the halotype.Considering the genetic homogeneity of isolated population,we investigated the polymorphisms of catalase promoter region by direct sequencing 1222 individuals(568 patients with EH;654 normotensive subjects) recruited from general Shanghai Chinese Han population.The genotypes showed that the polymorphism CATH1 and CATH2 is identified in the general population and the genotype distribution was significant different between hypertensive and control subjects(P=0.0017),CATH2 allele is associated with EH at the P value of less than 0.001level(P=0.000778).In this study,those CATH1/CATH2 and CATH2/CATH2 samples showed higher susceptibility to hypertension(279out of 552 or 50.5%;63 out of 118 or 53.4%) thanCATH1/CATH1 homozygote(226 out of 552or 40.9%) with an odds ratio being 1.474 and 1.625(95%confidence interval,1.162-1.870;1.108-2.464). The result of luciferase report showed CAT 5'UTR had transcription enhancer's function.The expression of luciferase report plasmid contained CAT 5'UTRs transcription level is 2.1-4.7times of the plasmid without CAT 5'UTR.At the same time,CATH2 transcription level was 1.49-2.1times of CATH1.We get the same rusk that CATH2 transcription level is higher than CATH1 in Allele Specific Expression study based on Pyrosequencing System.The results of Western blot in whole blood demonstrated that there was an increasing trend from CATH2/CATH2 to CATH2/CATH1 to CATH1/CATH1.The inconsistent results between transcription and translation hinted that the 5'-UTR polymorphism could play roles in transcription and translation,and maybe more important in translation.With regard to role in expression regulation of uncoding region,the evolution of CAT gene could owe partly to the polymorphism in 5'-UTR.In the PGA data,we found there was a balace selection in CAT gene.In African samples,Fu & Li's D~*=1.99399,P＜0.02; Fu & Li's F~*=1.567890,0.1＞P＞0.05;In European samples,Fu & Li's D~*= 2.02971,P＜0.02;Fu & Li's F~*=2.02527,P＜0.02.
These results indicated that CAT was associated with EH,and had a potential contribution to cardiovascular disease.More evidence will be needed to examine our expectations of the relationship between CAT and Essential Hypertension.
随着对许多疾病的深入研究,越来越多的证据表明体内的氧化还原状态与一些常见的疾病发生有着紧密的联系,例如高血压、动脉粥样硬化和其他心血管疾病的发生。而过氧化氢酶由于其抗氧化的生理功能成为原发性高血压的候选基因。我们首先在隔离群体发现CATSNP-844 A/G多态和原发性高血压相关性;随后在上海汉族开放人群发现了catalase单倍型CATH1(G-A-T)和CATH2(A-T-C)与原发性高血压的相关性(568病例:654对照),SPSS统计分析结果显示CATH1/CATH1,CATH1/CATH2和CATH2/CATH2在高血压疾病组和对照组中频率分布存在极显著差异(P=0.0028),其中CATH1/CATH2(279 out of559 or 49.9%),CATH2纯合子(63 out of 119 or 52.9%)与CATH1纯合子患病概率(226 out of 554 or 40.79%)相比较高,其比数比(odds ratio,OR)分别是1.472(95%置信区间,1.162～1.870)和1.652(95%置信区间,1.108～2.464)。而CATH1和CATH2单倍型频率在高血压疾病组和对照组中分布同样存在显著差异P=0.000778。
荧光素酶报告基因表达结果揭示CAT 5'UTR具有转录增强作用,包含Promoter和UTR的转录活性是只有Promoter报告载体的活性的2.1-4.7倍,同时CATH1转录起始活性低于CATH2,转录起始后者活性是前者的1.49-2.1倍。而基于Pyrosequencing(焦磷酸测序)系统,对体内的5'UTR(-20T/C)多态进行表达差异检测,同样证实了CATH1单倍型转录活性显著低于CATH2单倍型(P＜0.01)。Western Blot结果显示随着单倍型由CATH2/CATH2向CATH2/CATH1和CATH1/CATH1的改变,CAT蛋白的表达量有不断的升高的趋势。Western结果与转录结果的矛盾提示我们,可能由于5'-UTR多态的存在,导致二级结构出现极大变化,除了影响转录起始,对转录后翻译可能起到了更大的影响。
由于非编码区被认为对基因的表达调控有重要作用,因此该区域所受的选择作用有时对基因的进化同样是至关重要的,我们利用PGA中的多态数据对CAT进行中性检验,结果发现:在非洲人群中Fu & Li's D~*=1.99399,P＜0.02;Fu &Li's F~*=1.567890,0.1＞P＞0.05;在欧洲人群中Fu & Li's D~*=2.02971,P＜0.02,Fu & Li's F~*=2.02527,P＜0.02。CAT可能存在平衡选择。
综上所述,CAT基因与原发性高血压相关,是一个很重要的功能基因。CAT在原发性高血压发生中具体作用和机制还有待研究。随着时间和更多的数据的产生最终可以回答CAT在原发性高血压、甚至于整个心血管系统疾病的作用是否和我们预期一样。
Essential Hypertension is a common circulatory disorder of multifactorial origin caused by a combination of genetic and environmental factors.The interactions of these susceptibility genes contribute to the susceptibility of EH.The major assignment for genetic study of EH is to identify the susceptibility genes and furtherly to reveal the important role in the pathogenesis and development of EH.
Substantial evidence implicated toxic reactive oxygen species(ROS) is a critical etiological factor in a variety of diseases such as hypertension,atherosclerosis,and other vascular diseases.Being a candidate gene susceptibility to hypertension, catalase contributes to predict against damage caused by oxidative stress and limit the deleterious effects of reactive oxygen species to vascular.We had identified a SNP in the catalase gene in isolated population,which was strongly associated with essential hypertension.Later we found there were 4 SNPs in catalase regulation regeion,3 of the 4 SNPs are predominant in Chinese Han and construct 2 major haplotypes.We found that polymouphism A-844G could be a tagging SNP,capturing the sufficient information of the halotype.Considering the genetic homogeneity of isolated population,we investigated the polymorphisms of catalase promoter region by direct sequencing 1222 individuals(568 patients with EH;654 normotensive subjects) recruited from general Shanghai Chinese Han population.The genotypes showed that the polymorphism CATH1 and CATH2 is identified in the general population and the genotype distribution was significant different between hypertensive and control subjects(P=0.0017),CATH2 allele is associated with EH at the P value of less than 0.001level(P=0.000778).In this study,those CATH1/CATH2 and CATH2/CATH2 samples showed higher susceptibility to hypertension(279out of 552 or 50.5%;63 out of 118 or 53.4%) thanCATH1/CATH1 homozygote(226 out of 552or 40.9%) with an odds ratio being 1.474 and 1.625(95%confidence interval,1.162-1.870;1.108-2.464). The result of luciferase report showed CAT 5'UTR had transcription enhancer's function.The expression of luciferase report plasmid contained CAT 5'UTRs transcription level is 2.1-4.7times of the plasmid without CAT 5'UTR.At the same time,CATH2 transcription level was 1.49-2.1times of CATH1.We get the same rusk that CATH2 transcription level is higher than CATH1 in Allele Specific Expression study based on Pyrosequencing System.The results of Western blot in whole blood demonstrated that there was an increasing trend from CATH2/CATH2 to CATH2/CATH1 to CATH1/CATH1.The inconsistent results between transcription and translation hinted that the 5'-UTR polymorphism could play roles in transcription and translation,and maybe more important in translation.With regard to role in expression regulation of uncoding region,the evolution of CAT gene could owe partly to the polymorphism in 5'-UTR.In the PGA data,we found there was a balace selection in CAT gene.In African samples,Fu & Li's D~*=1.99399,P＜0.02; Fu & Li's F~*=1.567890,0.1＞P＞0.05;In European samples,Fu & Li's D~*= 2.02971,P＜0.02;Fu & Li's F~*=2.02527,P＜0.02.
These results indicated that CAT was associated with EH,and had a potential contribution to cardiovascular disease.More evidence will be needed to examine our expectations of the relationship between CAT and Essential Hypertension.
引文
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2.Perrotti D,Melotti P,Skorski T,Casella I et al.,Overexpression of the zinc finger protein MZF1 inhibits hematopoietic development from embryonic stem cells:correlation with negative regulation of CD34 and c-myb promoter activity.Mol Cell Biol 15:6075-6087(1995).
3.Mitchell PJ,Timmons PM,Hebert JM,Rigby PW,Tjian R,Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis.Genes Dev 5:105-119(1991).
4.Hahm K,Ernst P,Lo K,Kim GS,Turck C,Smale ST.The lymphoid transcription factor LyF-1 is encoded by specific,alternatively spliced mRNAs derived from the Ikaros gene.Mol Cell Biol.1994 Nov;14(11):7111-23.
5. Molnar A, Georgopoulos K The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol 14:8292-8303 (1994).
6. Risch NJ.. Searching for genetic determinants in the new millennium. Nature. 2000 Jun 15;405(6788):847-56.
7. Devlin B, Roeder K, Wasserman L. Genomic control, a new approach to genetic-based association studies. Theor Popul Biol. 2001 Nov; 60(3): 155-66.
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1.Groskreutz D,Schenborn ET.Reporter systems.Methods Mol Biol.1997;63:11-30
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