血管紧张素原基因核心启动子区A-6G多态性与白族原发性高血压的关联分析
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摘要
[目的]研究血管紧张素原(angiotensinogen, AGT)基因核心启动子区A-6G多态性与大理地区白族人群原发性高血压之间的关系。
[方法]以大理地区67例白族原发性高血压患者(高血压组)和54例健康体检者(对照组)为对象进行研究。从所有研究受试者外周静脉抗凝血中提取DNA,采用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)方法进行基因分型,随机选取部分标本用双向荧光测序进行基因分型验证；用SAS 9.13软件进行统计分析,研究AGT基因核心启动子区A-6G多态性与白族人群原发性高血压之间的关系。
[结果](1)研究发现白族人AGT基因核心启动子区-6位点存在A/G多态性。
(2)高血压组与对照组相比,性别、年龄、身高、体重指数、血糖、血尿素氮、血肌酐、血尿酸、高血压家族史阳性率有统计学差异(P<0.05)。按不同基因型分组后,AA型、AG型、GG型三组比较,年龄、体重指数、收缩压、舒张压、总胆固醇、甘油三酯、高密度脂蛋白胆固醇(high density lipoprotein cholesterol, HDL-C)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)、血糖、血尿素氮、血肌酐、血尿酸无统计学差异(P>0.05)。
(3)高血压组AA型、AG型、GG型频率分别为49.25%、46.27%、4.48%；对照组分别为55.56%、38.89%、5.55%,两组基因型频率分布无统计学差异(P>0.05)。同时,高血压组A等位基因频率为72.4%,G等位基因频率为27.6%,对照组分别为75.0%和25.0%,两组等位基因频率分布也无统计学差异(P>0.05)。
(4)多元逐步回归分析发现,收缩压的独立影响因素包括：年龄(P<0.0001)、体重指数(P=0.0014)、高密度脂蛋白胆固醇(P=0.0974)；舒张压的独立影响因素是：体重指数(P<0.0001)、血肌酐(P=0.0107)、总胆固醇(P=0.1103)；而脉压的独立影响因素为：年龄(P<0.0001)、基因型(P=0.1299)、体重指数(P=0.0864)、高密度脂蛋白胆固醇(P=0.0654)。多元逐步回归分析进入和剔除标准均为0.15。
(5)调整年龄、性别、体重指数和降压治疗后,AA型、AG型和GG型三种基因型之间收缩压、舒张压及脉压差别无统计学意义(P>0.05)。在调整年龄、性别、体重指数和降压治疗,同时合并AG型与GG型后,G等位基因携带者和AA型之间收缩压、舒张压及脉压差别也无统计学意义(P>0.05)。
[结论](1)大理白族高血压患者AA型、AG型、GG型频率分别为49.25%、46.27%、4.48%,A等位基因频率和G等位基因频率分别为72.4%和27.6%；健康人员AA型、AG型、GG型频率为55.56%、38.89%、5.55%,A等位基因频率和G等位基因频率分别为75.0%和25.0%。
(2)AGT基因A-6G多态性与白族人群原发性高血压无关,可能对白族人群原发性高血压的发病影响不大。
(3)年龄、体重指数、高密度脂蛋白胆固醇是收缩压的独立影响因素；体重指数、血肌酐、总胆固醇是舒张压的独立影响因素；年龄、基因型、体重指数、高密度脂蛋白胆固醇是脉压的独立影响因素。
Objective:To evaluate the relationship between the A-6G polymorphism of the promoter region of angiotensinogen (AGT) gene and essential hypertension in Bai nation of Dali.
Methods:The study is consisting of 67 hypertensive subjects (hypertensive group) and 54 normotensive controls (control group) from Dali district, and all subjects are Bai nation. The DNA is extracted from anticoagulant of peripheral vein, and the A-6G polymorphism is determined in by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). And some samples are chosen randomly for validating genotype by double-way sequencing fluorescence. The relationship between A-6G polymorphism of the promoter region of AGT gene and essential hypertension of the Bai nation are analyzed by SAS 9.13.
Results:(1) There is a nucleotide substitution of promoter region of the AGT gene in the Bai nation. The nucleotide substitution is A-→G at -6 locus.
(2) There is significant difference in sex, age, body height, body mass index, fasting blood glucose, serum urea nitrogen, creatinine, uric acid, and the family history of hypertension between hypertensive group and control group (P<0.05). However, there is no significant difference in age, body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting blood glucose, serum urea nitrogen, creatinine, and uric acid between AA, AG and GG genotypes (P>0.05).
(3) The frequencies of AA, AG and GG in hypertensive group is 49.25%,46.27%, 4.48% respectively, and is 55.56%,38.89%,5.55% in control group. There is no significant difference in the distribution of genotype frequency between hypertensive group and control group (P>0.05). Meanwhile, the frequencies of A allele is 72.4% and G allele is 27.6% in hypertensive group, and in control group, the frequencies of A allele is 75.0% and G allele is 25.0%, there is also no significant difference in the distribution of frequencies of allele (P>0.05).
(4) According to the result of multiple regression analysis (a=0.15), the determinants of systolic blood pressure are age (P<0.0001), body mass index (P=0.0014), high density lipoprotein cholesterol (HDL-C) (P=0.0974); the determinants of diastolic blood pressure are body mass index (P<0.0001), creatinine (P=0.0107), total cholesterol (P=0.1103); And the determinants of pulse pressure are age (P<0.0001), genotype (P=0.1299), body mass index (P=0.0864), high density lipoprotein cholesterol (HDL-C) (P=0.0654).
(5) Before and after adjustment of age, sex, body mass index and antihypertensive treatment, there is no significant difference of systolic blood pressure, diastolic blood pressure, pulse pressure between three genotypes of AGT A-6G polymorphism (P> 0.05). Before and after adjustment of age, sex, body mass index and antihypertensive treatment, there is no significant difference of systolic blood pressure, diastolic blood pressure, pulse pressure between AA homozygote and G allele carrier (P>0.05).
Conclusion:(1) In the Bai nation population, the frequencies of AA, AG and GG in hypertensive is 49.25%,46.27%,4.48% respectively, and the frequencies of A allele is 72.4% and G allele is 27.6%. However, the frequencies of AA, AG and GG in the healthy is 55.56%,38.89%,5.55% respectively and the frequencies of A allele is 75.0% and G allele is 25.0%.
(2) There is no significant correlation between A-6G polymorphism of the promoter region of AGT gene and essential hypertension in the Bai nation, which suggests that the A-6G polymorphism of AGT may be is not involved in the pathogenesis of essential hypertension in the Bai nation.
(2) The independent determinants of systolic blood pressure are age, body mass index and high density lipoprotein cholesterol (HDL-C); the independent determinants of diastolic blood pressure are body mass index, creatinine and total cholesterol; and the independent determinants of pulse pressure are age, genotype, body mass index and high density lipoprotein cholesterol (HDL-C).
[方法]以大理地区67例白族原发性高血压患者(高血压组)和54例健康体检者(对照组)为对象进行研究。从所有研究受试者外周静脉抗凝血中提取DNA,采用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)方法进行基因分型,随机选取部分标本用双向荧光测序进行基因分型验证；用SAS 9.13软件进行统计分析,研究AGT基因核心启动子区A-6G多态性与白族人群原发性高血压之间的关系。
[结果](1)研究发现白族人AGT基因核心启动子区-6位点存在A/G多态性。
(2)高血压组与对照组相比,性别、年龄、身高、体重指数、血糖、血尿素氮、血肌酐、血尿酸、高血压家族史阳性率有统计学差异(P<0.05)。按不同基因型分组后,AA型、AG型、GG型三组比较,年龄、体重指数、收缩压、舒张压、总胆固醇、甘油三酯、高密度脂蛋白胆固醇(high density lipoprotein cholesterol, HDL-C)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)、血糖、血尿素氮、血肌酐、血尿酸无统计学差异(P>0.05)。
(3)高血压组AA型、AG型、GG型频率分别为49.25%、46.27%、4.48%；对照组分别为55.56%、38.89%、5.55%,两组基因型频率分布无统计学差异(P>0.05)。同时,高血压组A等位基因频率为72.4%,G等位基因频率为27.6%,对照组分别为75.0%和25.0%,两组等位基因频率分布也无统计学差异(P>0.05)。
(4)多元逐步回归分析发现,收缩压的独立影响因素包括：年龄(P<0.0001)、体重指数(P=0.0014)、高密度脂蛋白胆固醇(P=0.0974)；舒张压的独立影响因素是：体重指数(P<0.0001)、血肌酐(P=0.0107)、总胆固醇(P=0.1103)；而脉压的独立影响因素为：年龄(P<0.0001)、基因型(P=0.1299)、体重指数(P=0.0864)、高密度脂蛋白胆固醇(P=0.0654)。多元逐步回归分析进入和剔除标准均为0.15。
(5)调整年龄、性别、体重指数和降压治疗后,AA型、AG型和GG型三种基因型之间收缩压、舒张压及脉压差别无统计学意义(P>0.05)。在调整年龄、性别、体重指数和降压治疗,同时合并AG型与GG型后,G等位基因携带者和AA型之间收缩压、舒张压及脉压差别也无统计学意义(P>0.05)。
[结论](1)大理白族高血压患者AA型、AG型、GG型频率分别为49.25%、46.27%、4.48%,A等位基因频率和G等位基因频率分别为72.4%和27.6%；健康人员AA型、AG型、GG型频率为55.56%、38.89%、5.55%,A等位基因频率和G等位基因频率分别为75.0%和25.0%。
(2)AGT基因A-6G多态性与白族人群原发性高血压无关,可能对白族人群原发性高血压的发病影响不大。
(3)年龄、体重指数、高密度脂蛋白胆固醇是收缩压的独立影响因素；体重指数、血肌酐、总胆固醇是舒张压的独立影响因素；年龄、基因型、体重指数、高密度脂蛋白胆固醇是脉压的独立影响因素。
Objective:To evaluate the relationship between the A-6G polymorphism of the promoter region of angiotensinogen (AGT) gene and essential hypertension in Bai nation of Dali.
Methods:The study is consisting of 67 hypertensive subjects (hypertensive group) and 54 normotensive controls (control group) from Dali district, and all subjects are Bai nation. The DNA is extracted from anticoagulant of peripheral vein, and the A-6G polymorphism is determined in by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). And some samples are chosen randomly for validating genotype by double-way sequencing fluorescence. The relationship between A-6G polymorphism of the promoter region of AGT gene and essential hypertension of the Bai nation are analyzed by SAS 9.13.
Results:(1) There is a nucleotide substitution of promoter region of the AGT gene in the Bai nation. The nucleotide substitution is A-→G at -6 locus.
(2) There is significant difference in sex, age, body height, body mass index, fasting blood glucose, serum urea nitrogen, creatinine, uric acid, and the family history of hypertension between hypertensive group and control group (P<0.05). However, there is no significant difference in age, body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting blood glucose, serum urea nitrogen, creatinine, and uric acid between AA, AG and GG genotypes (P>0.05).
(3) The frequencies of AA, AG and GG in hypertensive group is 49.25%,46.27%, 4.48% respectively, and is 55.56%,38.89%,5.55% in control group. There is no significant difference in the distribution of genotype frequency between hypertensive group and control group (P>0.05). Meanwhile, the frequencies of A allele is 72.4% and G allele is 27.6% in hypertensive group, and in control group, the frequencies of A allele is 75.0% and G allele is 25.0%, there is also no significant difference in the distribution of frequencies of allele (P>0.05).
(4) According to the result of multiple regression analysis (a=0.15), the determinants of systolic blood pressure are age (P<0.0001), body mass index (P=0.0014), high density lipoprotein cholesterol (HDL-C) (P=0.0974); the determinants of diastolic blood pressure are body mass index (P<0.0001), creatinine (P=0.0107), total cholesterol (P=0.1103); And the determinants of pulse pressure are age (P<0.0001), genotype (P=0.1299), body mass index (P=0.0864), high density lipoprotein cholesterol (HDL-C) (P=0.0654).
(5) Before and after adjustment of age, sex, body mass index and antihypertensive treatment, there is no significant difference of systolic blood pressure, diastolic blood pressure, pulse pressure between three genotypes of AGT A-6G polymorphism (P> 0.05). Before and after adjustment of age, sex, body mass index and antihypertensive treatment, there is no significant difference of systolic blood pressure, diastolic blood pressure, pulse pressure between AA homozygote and G allele carrier (P>0.05).
Conclusion:(1) In the Bai nation population, the frequencies of AA, AG and GG in hypertensive is 49.25%,46.27%,4.48% respectively, and the frequencies of A allele is 72.4% and G allele is 27.6%. However, the frequencies of AA, AG and GG in the healthy is 55.56%,38.89%,5.55% respectively and the frequencies of A allele is 75.0% and G allele is 25.0%.
(2) There is no significant correlation between A-6G polymorphism of the promoter region of AGT gene and essential hypertension in the Bai nation, which suggests that the A-6G polymorphism of AGT may be is not involved in the pathogenesis of essential hypertension in the Bai nation.
(2) The independent determinants of systolic blood pressure are age, body mass index and high density lipoprotein cholesterol (HDL-C); the independent determinants of diastolic blood pressure are body mass index, creatinine and total cholesterol; and the independent determinants of pulse pressure are age, genotype, body mass index and high density lipoprotein cholesterol (HDL-C).
引文
[1]叶任高,陆再英.内科学[M].6版.北京：人民卫生出版社,2004,247-262.
[2]孙宁玲.高血压研究及治疗的新趋势[J].中华老年心脑血管病杂志,2006;8(11)：721-723.
[3]姚泰,吴博威.生理学[M].6版.北京：人民卫生出版社,2003,123-124.
[4]Nakajima T, Jorde LB, Ishigami T, et al. Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations [J]. Am J Hum Genet,2002; 70(1):108-123.
[5]何燕,钟国强.原发性高血压候选基因的研究进展[J].医学综述,2006;12(18)：1104-1106.
[6]Dickon ME, Sigmund CD, Genetic basis of hypertension:revisiting angiotensinogen [J]. Hypertension,2006; 48(1):14-20.
[7]Yanai K, Saito T, Hirota K, et al. Molecular variation of the human angiotensinogen core promoter element located between the TATA box and transcription initiation site affects its transcriptional activity [J]. J Bio Chem,1997; 272(48):30558-30562.
[8]Yanai K, Nibu Y, Murakami K, et al. A cis-acting DNA element located between TATA box and transcription in initiation site is critical in response to regulatory sequences in human angiotensinogen gene [J]. The Journal of Biological Chemistry,1996; 271(27):15981-15986.
[9]Inoue I, Nakajima T, Williams CS, et al. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro [J]. J Clin Invest,1997; 99(7):1786-1797.
[10]Sato N, Katsuya T, Nakagawa T, et al. Nine polymorphism of angiotensinogen gene in the susceptibility to essential hypertension [J]. Life Sciences,2000; 68(3): 259-272.
[11]Sehi AA, Nordestgaard BG, Agerholm-Larsen A, et al. Angiotensinogen polymorphisms and elevated blood pressure in the general population:the Copenhagen city heart study [J]. Hypertension,2001; 37(3):875-881.
[12]Cargill M, Altshuler D, Ireland J, et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes [J]. Nat Genet,1999; 22(3): 231-238.
[13]Halushka MK, Fan JB, Bentley K, et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis [J]. Nat Genet, 1999; 22(3):239-247.
[14]刘艳,金玮,姜正文,等.血管紧张素原基因的六种单核苷酸多态性与原发性高血压的相关性[J].中华医学遗传学杂志,2004;21(2)：116-119.
[15]呼日勒,赵世刚,牛广明,等.血管紧张素原基因5'端启动子区A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压的相关性[J].中国组织工程研究与临床康复,2007;11(30)：5865-5868.
[16]李南方,周玲,吴卫东,等.血管紧张素原基因5'端核心启动子区(-6) A-G和(-20) A-C变异与哈萨克族人原发性高血压相关性分析[J].中华医学遗传学杂志,2004;21(1)：23-28.
[17]曹爱华,王昆兰,夏中信,等.云南大理白族居民高血压患病情况及相关因素[J].中国慢性病预防与控制,2008;16(1)：84-85.
[18]肖义泽,陈杨,许雯,等.云南省不同民族高血压患病率及血压平均水平分布特征分析[J].心脑血管病防治,2010;10(1)：26-27.
[19]Guidelines Subcommittee.1999 World Health Organization-International Society of Hypertension guidelines for management of hypertension [J]. J Hypertens, 1999; 17(2):151-183.
[20]Jeunematire X, Soubrier F, Kotelevtsev YV, et al. Molecular basis of human hypertension:role of angiotensinogen [J]. Cell,1992; 71(1):169-180.
[21]Wu SJ, Chiang FT, Chen WJ, et al. Three single-nucleotide polymorphisms of the angiotensinogen gene and susceptibility to hypertension:single locus genotype vs. haplotype analysis [J]. Physiol Genomics,2004; 17(2):79-86.
[22]赵则祥.人类原发性高血压发生机制研究进展[J].中国优生与遗传杂志, 2003;11(4)：140-142.
[23]王琰.血管紧张素原基因与黎族原发性高血压并脑梗死相关性[D].山西：山西医科大学,2007.
[24]Liu YW, Qin WJ, Hou SQ, et al. A-6G variant of the angiotensinogen gene and essential hypertension in Han, Tibetan and Yi populations [J]. Hypertens Res, 2001; 24(2):159-163.
[25]孔祥东,杨宇霞,张思仲,等.血管紧张素原基因和血管紧张素转换酶基因多态性与高血压[J].中华心血管病杂志,2003;31(10)：735-738.
[26]Hilgers KF, Delles C, Veelken R, et al. Aniotensinogen core promoter variants and non-modulating hypertension [J]. Hypertension,2001; 38(6):1250-1254.
[27]Province MA, Boerwinkle E, Chakravarti A, et al. Lack of association of the angiotensinogen-6 polymorphism with blood pressure levels in the comprehensive NHLBI Family Blood Pressure Program [J]. J Hypertens,2000; 18(7):867-876.
[28]杨春,邱长春,卢圣栋,等.血管紧张素原基因核心启动子区域突变与藏族原发性高血压的关联分析[J].中华医学遗传学杂志,2000;17(3)：149-152.
[29]王忠,赵卉,袁红玲,等.血管紧张素原基因核心启动子(AGCEI) G-6A变异与新疆哈萨克族原发性高血压的相关性研究[J].中国心血管病研究杂志,2006;4(6)：464-466.
[30]马爱群,胡大一,牛小麟,等.心血管病学.北京：人民卫生出版社,2005,339-395.
[31]宋玉梅,骆宏杰,何嗣胜,等.血压异常的危险因素分析[J].疾病控制杂志,2003；6(1)：41-43.
[32]Ribeiro J, Guerra S, Pinto A, et al. Overweight and obesity in children and adolescents:relationship with blood pressure, and physical activity [J]. Ann Hum Biol,2003; 30(2):203-213.
[33]庞建,蔡慧敏.南源社区居民高血压与肥胖等相关因素调查分析[J].中华全科医学,2011;9(2)：254-255.
[34]Zavaroni I, Bonora E, Pagliara M, et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance [J]. N Engl J Med,1989; 320(11):702-706.
[35]Bonaa KH, Thelle DS. Association between blood pressure and serum lipids in a population: The Tromso Study [J]. Circulation,1991; 83(4):1305-1314.
[36]郝唯蔚,赵春华,武权,等.不同血压水平与血肌酐相关性的研究[J].中国临床保健杂志,2009;12(3)：238-239.
[37]Benetos A, Safar M, Rudnichi A, et al. Pulse pressure:a predictor of long-term cardiovascular mortality in a French male population [J]. Hypertension,1997; 30(6):1410-1415.
[38]Zakopulos NA, Lekakis JP, Papamichael CM, et al. Pulse pressure in normetensives:a marker of cardiovascular disease [J]. Am J Hypertens,2001; 14(3):195-199.
[39]朱理敏,王宪衍.脉压与心脑血管疾病危险因子[J].中华心血管病杂志,2001;29(9)：573-574.
[40]Pereira TV, Nunes AC, Rudnicki M, et al. Meta-analysis of the association of 4 angiotensinogen polymorphisms with essential hypertension:A role beyond M235T? [J]. Hypertension,2008; 51(3):778-783.
[1]何燕,钟国强.原发性高血压候选基因的研究进展[J]. 医学综述,2006,12(18)：1104-1106.
[2]姚泰,吴博威.生理学[M].6版. 北京：人民卫生出版社,2003：123-124.
[3]Dickson ME, Sigmund CD. Genetic basis of hypertension: revisiting angiotensinogen [J]. Hypertension,2006,48(1):14-20.
[4]Yanai K, Saito T, Hirota K, et al. Molecular variation of the human angiotensinogen core promoter element located between the TATA box and transcription initiation site affects its transcriptional activity [J]. J Bio Chem,1997, 272(48):30558-30562.
[5]Tiago AD, Samani NJ, Candy GP, et al. Angiotensinogen gene promoter region variant modifies body size-ambulatory blood pressure relations in hypertension [J]. Circulation,2002,106(12):1483-1487.
[6]李洁,哈黛文.血管紧张素原的研究进展[J]. 国外医学生理、病理科学与临床分册,2000,20(1)：79-81.
[7]Wu SJ, Chiang FT, Chen WJ, et al. Three single-nucleotide polymorphisms of the angiotensinogen gene and susceptibility to hypertension:single locus genotype vs. haplotype analysis [J]. Physiol Genomics,2004,17(2):79-86.
[8]赵则祥.人类原发性高血压发生机制研究进展[J]. 中国优生与遗传杂志,2003,11(4)：140-142.
[9]Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension [J]. Cell,2001,104(4):545-556.
[10]Nakajima T, Jorde LB, Ishigami T, et al. Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations [J]. Am J Hum Genet, 2002,70(1):108-123.
[11]Markovic D, Tang X, Guruju M, et al. Association of angiotensinogen gene polymorphisms with essential hypertension in African-Americans and Caucasians [J]. Hum Hered,2005,60(2):89-96.
[12]Brand-Herrmann SM, Kopke K, Reichenberger F, et al. Angiotensinogen promoter haplotypes are associated with blood pressure in untreated hypertensives [J]. J Hypertens,2004,22(7):1289-1297.
[13]Hilgers KF, Delles C, Veelken R, et al. Angiotensinogen core promoter variants and non-modulating hypertension [J]. Hypertension,2001,38(6):1250-1254.
[14]刘艳,金玮,姜正文,等.血管紧张素原基因的六种单核苷酸多态性与原发性高血压的相关性[J].中华医学遗传学杂志,2004,21(2)：116-119.
[15]呼日勒,赵世刚,牛广明,等.血管紧张素原基因5'端启动子区A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压的相关性[J].中国组织工程研究与临床康复,2007,11(30)：5865-5868.
[16]杨春,邱长春,卢圣栋,等.血管紧张素原基因核心启动子区域突变与藏族原发性高血压的关联分析[J].中华医学遗传学杂志,2000,17(3)：149-152.
[17]Liu YW, Qin WJ, Hou SQ, et al. A-6G variant of the angiotensinogen gene and essential hypertension in Han, Tibetan and Yi populations [J]. Hypertens Res,2001, 24(2):159-163.
[18]王忠,赵卉,袁红玲,等.血管紧张素原基因核心启动子(AGCEI)G-6A变异与新疆哈萨克族原发性高血压的相关性研究[J].中国心血管病研究杂志,2006,4(6)：464-466.
[19]孔祥东,杨宇霞,张思仲,等.血管紧张素原基因和血管紧张素转换酶基因多态性与高血压[J].中华心血管病杂志,2003,31(10)：735-738.
[20]李南方,周玲,吴卫东,等.血管紧张素原基因5'端核心启动子区(-6) A-G和(-20)A-C变异与哈萨克族人原发性高血压相关性分析[J].中华医学遗传学杂志,2004,21(1)：23-28.
[21]Province MA, Boerwinkle E, Chakravarti A, et al. Lack of association of the angiotensinogen-6 polymorphism with blood pressure levels in the comprehensive NHLBI Family Blood Pressure Program [J]. J Hypertens,2000,18(7):867-876.
[22]Pereira TV, Nunes AC, Rudnicki M, et al. Meta-Analysis of the association of 4 angiotensinogen polymorphisms with essential hypertension:A role beyond M235T? [J]. Hypertension,2008,51(3):778-783.
[2]孙宁玲.高血压研究及治疗的新趋势[J].中华老年心脑血管病杂志,2006;8(11)：721-723.
[3]姚泰,吴博威.生理学[M].6版.北京：人民卫生出版社,2003,123-124.
[4]Nakajima T, Jorde LB, Ishigami T, et al. Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations [J]. Am J Hum Genet,2002; 70(1):108-123.
[5]何燕,钟国强.原发性高血压候选基因的研究进展[J].医学综述,2006;12(18)：1104-1106.
[6]Dickon ME, Sigmund CD, Genetic basis of hypertension:revisiting angiotensinogen [J]. Hypertension,2006; 48(1):14-20.
[7]Yanai K, Saito T, Hirota K, et al. Molecular variation of the human angiotensinogen core promoter element located between the TATA box and transcription initiation site affects its transcriptional activity [J]. J Bio Chem,1997; 272(48):30558-30562.
[8]Yanai K, Nibu Y, Murakami K, et al. A cis-acting DNA element located between TATA box and transcription in initiation site is critical in response to regulatory sequences in human angiotensinogen gene [J]. The Journal of Biological Chemistry,1996; 271(27):15981-15986.
[9]Inoue I, Nakajima T, Williams CS, et al. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro [J]. J Clin Invest,1997; 99(7):1786-1797.
[10]Sato N, Katsuya T, Nakagawa T, et al. Nine polymorphism of angiotensinogen gene in the susceptibility to essential hypertension [J]. Life Sciences,2000; 68(3): 259-272.
[11]Sehi AA, Nordestgaard BG, Agerholm-Larsen A, et al. Angiotensinogen polymorphisms and elevated blood pressure in the general population:the Copenhagen city heart study [J]. Hypertension,2001; 37(3):875-881.
[12]Cargill M, Altshuler D, Ireland J, et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes [J]. Nat Genet,1999; 22(3): 231-238.
[13]Halushka MK, Fan JB, Bentley K, et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis [J]. Nat Genet, 1999; 22(3):239-247.
[14]刘艳,金玮,姜正文,等.血管紧张素原基因的六种单核苷酸多态性与原发性高血压的相关性[J].中华医学遗传学杂志,2004;21(2)：116-119.
[15]呼日勒,赵世刚,牛广明,等.血管紧张素原基因5'端启动子区A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压的相关性[J].中国组织工程研究与临床康复,2007;11(30)：5865-5868.
[16]李南方,周玲,吴卫东,等.血管紧张素原基因5'端核心启动子区(-6) A-G和(-20) A-C变异与哈萨克族人原发性高血压相关性分析[J].中华医学遗传学杂志,2004;21(1)：23-28.
[17]曹爱华,王昆兰,夏中信,等.云南大理白族居民高血压患病情况及相关因素[J].中国慢性病预防与控制,2008;16(1)：84-85.
[18]肖义泽,陈杨,许雯,等.云南省不同民族高血压患病率及血压平均水平分布特征分析[J].心脑血管病防治,2010;10(1)：26-27.
[19]Guidelines Subcommittee.1999 World Health Organization-International Society of Hypertension guidelines for management of hypertension [J]. J Hypertens, 1999; 17(2):151-183.
[20]Jeunematire X, Soubrier F, Kotelevtsev YV, et al. Molecular basis of human hypertension:role of angiotensinogen [J]. Cell,1992; 71(1):169-180.
[21]Wu SJ, Chiang FT, Chen WJ, et al. Three single-nucleotide polymorphisms of the angiotensinogen gene and susceptibility to hypertension:single locus genotype vs. haplotype analysis [J]. Physiol Genomics,2004; 17(2):79-86.
[22]赵则祥.人类原发性高血压发生机制研究进展[J].中国优生与遗传杂志, 2003;11(4)：140-142.
[23]王琰.血管紧张素原基因与黎族原发性高血压并脑梗死相关性[D].山西：山西医科大学,2007.
[24]Liu YW, Qin WJ, Hou SQ, et al. A-6G variant of the angiotensinogen gene and essential hypertension in Han, Tibetan and Yi populations [J]. Hypertens Res, 2001; 24(2):159-163.
[25]孔祥东,杨宇霞,张思仲,等.血管紧张素原基因和血管紧张素转换酶基因多态性与高血压[J].中华心血管病杂志,2003;31(10)：735-738.
[26]Hilgers KF, Delles C, Veelken R, et al. Aniotensinogen core promoter variants and non-modulating hypertension [J]. Hypertension,2001; 38(6):1250-1254.
[27]Province MA, Boerwinkle E, Chakravarti A, et al. Lack of association of the angiotensinogen-6 polymorphism with blood pressure levels in the comprehensive NHLBI Family Blood Pressure Program [J]. J Hypertens,2000; 18(7):867-876.
[28]杨春,邱长春,卢圣栋,等.血管紧张素原基因核心启动子区域突变与藏族原发性高血压的关联分析[J].中华医学遗传学杂志,2000;17(3)：149-152.
[29]王忠,赵卉,袁红玲,等.血管紧张素原基因核心启动子(AGCEI) G-6A变异与新疆哈萨克族原发性高血压的相关性研究[J].中国心血管病研究杂志,2006;4(6)：464-466.
[30]马爱群,胡大一,牛小麟,等.心血管病学.北京：人民卫生出版社,2005,339-395.
[31]宋玉梅,骆宏杰,何嗣胜,等.血压异常的危险因素分析[J].疾病控制杂志,2003；6(1)：41-43.
[32]Ribeiro J, Guerra S, Pinto A, et al. Overweight and obesity in children and adolescents:relationship with blood pressure, and physical activity [J]. Ann Hum Biol,2003; 30(2):203-213.
[33]庞建,蔡慧敏.南源社区居民高血压与肥胖等相关因素调查分析[J].中华全科医学,2011;9(2)：254-255.
[34]Zavaroni I, Bonora E, Pagliara M, et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance [J]. N Engl J Med,1989; 320(11):702-706.
[35]Bonaa KH, Thelle DS. Association between blood pressure and serum lipids in a population: The Tromso Study [J]. Circulation,1991; 83(4):1305-1314.
[36]郝唯蔚,赵春华,武权,等.不同血压水平与血肌酐相关性的研究[J].中国临床保健杂志,2009;12(3)：238-239.
[37]Benetos A, Safar M, Rudnichi A, et al. Pulse pressure:a predictor of long-term cardiovascular mortality in a French male population [J]. Hypertension,1997; 30(6):1410-1415.
[38]Zakopulos NA, Lekakis JP, Papamichael CM, et al. Pulse pressure in normetensives:a marker of cardiovascular disease [J]. Am J Hypertens,2001; 14(3):195-199.
[39]朱理敏,王宪衍.脉压与心脑血管疾病危险因子[J].中华心血管病杂志,2001;29(9)：573-574.
[40]Pereira TV, Nunes AC, Rudnicki M, et al. Meta-analysis of the association of 4 angiotensinogen polymorphisms with essential hypertension:A role beyond M235T? [J]. Hypertension,2008; 51(3):778-783.
[1]何燕,钟国强.原发性高血压候选基因的研究进展[J]. 医学综述,2006,12(18)：1104-1106.
[2]姚泰,吴博威.生理学[M].6版. 北京：人民卫生出版社,2003：123-124.
[3]Dickson ME, Sigmund CD. Genetic basis of hypertension: revisiting angiotensinogen [J]. Hypertension,2006,48(1):14-20.
[4]Yanai K, Saito T, Hirota K, et al. Molecular variation of the human angiotensinogen core promoter element located between the TATA box and transcription initiation site affects its transcriptional activity [J]. J Bio Chem,1997, 272(48):30558-30562.
[5]Tiago AD, Samani NJ, Candy GP, et al. Angiotensinogen gene promoter region variant modifies body size-ambulatory blood pressure relations in hypertension [J]. Circulation,2002,106(12):1483-1487.
[6]李洁,哈黛文.血管紧张素原的研究进展[J]. 国外医学生理、病理科学与临床分册,2000,20(1)：79-81.
[7]Wu SJ, Chiang FT, Chen WJ, et al. Three single-nucleotide polymorphisms of the angiotensinogen gene and susceptibility to hypertension:single locus genotype vs. haplotype analysis [J]. Physiol Genomics,2004,17(2):79-86.
[8]赵则祥.人类原发性高血压发生机制研究进展[J]. 中国优生与遗传杂志,2003,11(4)：140-142.
[9]Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension [J]. Cell,2001,104(4):545-556.
[10]Nakajima T, Jorde LB, Ishigami T, et al. Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations [J]. Am J Hum Genet, 2002,70(1):108-123.
[11]Markovic D, Tang X, Guruju M, et al. Association of angiotensinogen gene polymorphisms with essential hypertension in African-Americans and Caucasians [J]. Hum Hered,2005,60(2):89-96.
[12]Brand-Herrmann SM, Kopke K, Reichenberger F, et al. Angiotensinogen promoter haplotypes are associated with blood pressure in untreated hypertensives [J]. J Hypertens,2004,22(7):1289-1297.
[13]Hilgers KF, Delles C, Veelken R, et al. Angiotensinogen core promoter variants and non-modulating hypertension [J]. Hypertension,2001,38(6):1250-1254.
[14]刘艳,金玮,姜正文,等.血管紧张素原基因的六种单核苷酸多态性与原发性高血压的相关性[J].中华医学遗传学杂志,2004,21(2)：116-119.
[15]呼日勒,赵世刚,牛广明,等.血管紧张素原基因5'端启动子区A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压的相关性[J].中国组织工程研究与临床康复,2007,11(30)：5865-5868.
[16]杨春,邱长春,卢圣栋,等.血管紧张素原基因核心启动子区域突变与藏族原发性高血压的关联分析[J].中华医学遗传学杂志,2000,17(3)：149-152.
[17]Liu YW, Qin WJ, Hou SQ, et al. A-6G variant of the angiotensinogen gene and essential hypertension in Han, Tibetan and Yi populations [J]. Hypertens Res,2001, 24(2):159-163.
[18]王忠,赵卉,袁红玲,等.血管紧张素原基因核心启动子(AGCEI)G-6A变异与新疆哈萨克族原发性高血压的相关性研究[J].中国心血管病研究杂志,2006,4(6)：464-466.
[19]孔祥东,杨宇霞,张思仲,等.血管紧张素原基因和血管紧张素转换酶基因多态性与高血压[J].中华心血管病杂志,2003,31(10)：735-738.
[20]李南方,周玲,吴卫东,等.血管紧张素原基因5'端核心启动子区(-6) A-G和(-20)A-C变异与哈萨克族人原发性高血压相关性分析[J].中华医学遗传学杂志,2004,21(1)：23-28.
[21]Province MA, Boerwinkle E, Chakravarti A, et al. Lack of association of the angiotensinogen-6 polymorphism with blood pressure levels in the comprehensive NHLBI Family Blood Pressure Program [J]. J Hypertens,2000,18(7):867-876.
[22]Pereira TV, Nunes AC, Rudnicki M, et al. Meta-Analysis of the association of 4 angiotensinogen polymorphisms with essential hypertension:A role beyond M235T? [J]. Hypertension,2008,51(3):778-783.