功能磁性纳米颗粒在原发性高血压易感性研究中的应用
摘要
研究复杂疾病背后的遗传作用有助于有效药物的开发。原发性高血压是最常见的心血管疾病,其发病率逐年上升,是遗传因素与环境因素综合作用的结果,原发性高血压呈家族聚集现象进一步说明遗传基因的存在。而肾素-血管紧张素系统(Renin-angitensin System,RAS)基因群中血管紧张素原(Angiotensinogen AGT)基因与原发性高血压(Essential Hypertension EH)相关性的研究成为人们关注的焦点。
为了进一步揭示AGT基因与原发性高血压的相关性,我们对AGT基因两个多态位点:M235T位点和A-6G位点与湖南地区原发性高血压的易感相关性进行了研究。
我们制备了平均粒径为30 nm的γ-Fe_2O_3颗粒,颗粒的饱和磁化强度为48.4 emu/g,具有超顺磁性,并对其进行了链霉亲和素修饰,实验证明链霉亲和素修饰的γ-Fe_2O_3磁性颗粒具有很好的生物活性,可以进一步用于生物检测。利用生物素与链霉亲和素系统的超强特异结合作用,将链霉亲和素修饰的γ-Fe_2O_3磁性颗粒应用于下一步SNP分型检测中。本文中,我们收集了湖南地区243例原发性高血压样本,247例正常对照样本,并对血管紧张素原基因中的两个最受关注的位点M235T位点和A-6G位点进行易感性研究。首先扩增生物素标记的PCR产物,将其固定于链霉亲和素标记的磁性纳米颗粒上,然后与双色荧光标记(Cy3和Cy5)的等位基因特异性探针进行杂交;最后通过扫描以获得样本的基因型。利用该方法,我们成功地对来自243个高血压及正常样本的2个位点进行了分型,对于纯合型样本,其正错配信号强度比均大于3,杂合型样本其Cy3:Cy5信号强度比介于0.64和1.7之间,分型方法经测序验证。
通过用SPSS 13.0分析软件对分型结果进行统计学分析,发现原发性高血压病例组血管紧张素原基因M235T位点CC,CT,TT基因型频率与正常对照组比较差异有显著性意义(χ2=5.532,P=0.063);C,T等位基因频率与正常对照组比较差异有显著性意义(χ2=5.745,P=0.017)。提示M235T位点中T等位基因是湖南地区人口原发性高血压的危险因素。原发性高血压病例组血管紧张素原基因A-6G位点AA,AG,GG基因型频率与正常对照组比较差异无显著性意义(χ2=1.701,P=0.427);A,G等位基因频率与正常对照组比较差异无显著性意义(χ2=1.436,P=0.231)。提示AGT基因A-6G多态不是湖南地区人口原发性高血压发生的危险因素。
The study of genetic effect of complex diseases benefits to the exploitation of effective medicines. Essential hypertension (EH) is a common kind cardiovascular disease, with growing up morbidity. EH is a result of multiple reactions of genetics and environment. The symptom of family EH certified the existence of genetic factor in a further step. The susceptibility between angiotensinogen gene of rennin-angitensin system gene group and EH has become a hot topic.
In order to show the susceptibility of AGT and EH, the relationship between EH and two loci M235T and A-6G located in angiotensinogen gene was studied.
In this work, superparamagneticγ-Fe_2O_3 magnetic nanoparticles with average size of 30 nm were prepared, with magnetic saturation of 48.4 emu/g. The particles functionalized with streptavidin were proved to be bio-active and could be used in biology test. Utilizing the super specific bonding effect of biotin-streptavidin system, streptavidin modifiedγ-Fe_2O_3 nanoparticles were used in SNP detection. 243 EH samples and 247 healthy samples in Hunan area were collected. The SNP of two loci, M235T and A-6G located in angiotensinogen gene, were detected. PCR products were modified on the streptavidin-γ-Fe_2O_3 nanoparticles, then hybridized with two probes labeled with two fluorescence colors: Cy5 and Cy3. The hybridization results were scanned with a GenePix 4100 scanner. When the sample is homozygous, the ratio of Cy3 to Cy5 is higher than 3. When the sample is heterozygous, the ratio is between 0.64 and 1.7. This SNP typying method had been proved to work well.
After statistic analysis using SPSS 13.0 software, the difference of gene type CC, CT, TT ratio on M235T locus between the sick group of EH and the healthy group was found significant (χ2=5.532,P=0.063). And so was the difference between the allele gene C, T (χ2=5.745,P=0.017). The morbidity of individuals with mutation type TT was found greater than the others. There may be some correlation of the mutation type TT with essential hypertension in people of Hunan area. The difference of gene type AA, AG, GG ratio on A-6G site between the sick group of the EH and healthy group was found not significant (χ2=1.701,P=0.427). And neither was the difference between the allele gene C, T (χ2=1.436,P=0.231). The SNP of A-6G locus may not be a dangerous factor of essential hypertension in people of Hunan area.
为了进一步揭示AGT基因与原发性高血压的相关性,我们对AGT基因两个多态位点:M235T位点和A-6G位点与湖南地区原发性高血压的易感相关性进行了研究。
我们制备了平均粒径为30 nm的γ-Fe_2O_3颗粒,颗粒的饱和磁化强度为48.4 emu/g,具有超顺磁性,并对其进行了链霉亲和素修饰,实验证明链霉亲和素修饰的γ-Fe_2O_3磁性颗粒具有很好的生物活性,可以进一步用于生物检测。利用生物素与链霉亲和素系统的超强特异结合作用,将链霉亲和素修饰的γ-Fe_2O_3磁性颗粒应用于下一步SNP分型检测中。本文中,我们收集了湖南地区243例原发性高血压样本,247例正常对照样本,并对血管紧张素原基因中的两个最受关注的位点M235T位点和A-6G位点进行易感性研究。首先扩增生物素标记的PCR产物,将其固定于链霉亲和素标记的磁性纳米颗粒上,然后与双色荧光标记(Cy3和Cy5)的等位基因特异性探针进行杂交;最后通过扫描以获得样本的基因型。利用该方法,我们成功地对来自243个高血压及正常样本的2个位点进行了分型,对于纯合型样本,其正错配信号强度比均大于3,杂合型样本其Cy3:Cy5信号强度比介于0.64和1.7之间,分型方法经测序验证。
通过用SPSS 13.0分析软件对分型结果进行统计学分析,发现原发性高血压病例组血管紧张素原基因M235T位点CC,CT,TT基因型频率与正常对照组比较差异有显著性意义(χ2=5.532,P=0.063);C,T等位基因频率与正常对照组比较差异有显著性意义(χ2=5.745,P=0.017)。提示M235T位点中T等位基因是湖南地区人口原发性高血压的危险因素。原发性高血压病例组血管紧张素原基因A-6G位点AA,AG,GG基因型频率与正常对照组比较差异无显著性意义(χ2=1.701,P=0.427);A,G等位基因频率与正常对照组比较差异无显著性意义(χ2=1.436,P=0.231)。提示AGT基因A-6G多态不是湖南地区人口原发性高血压发生的危险因素。
The study of genetic effect of complex diseases benefits to the exploitation of effective medicines. Essential hypertension (EH) is a common kind cardiovascular disease, with growing up morbidity. EH is a result of multiple reactions of genetics and environment. The symptom of family EH certified the existence of genetic factor in a further step. The susceptibility between angiotensinogen gene of rennin-angitensin system gene group and EH has become a hot topic.
In order to show the susceptibility of AGT and EH, the relationship between EH and two loci M235T and A-6G located in angiotensinogen gene was studied.
In this work, superparamagneticγ-Fe_2O_3 magnetic nanoparticles with average size of 30 nm were prepared, with magnetic saturation of 48.4 emu/g. The particles functionalized with streptavidin were proved to be bio-active and could be used in biology test. Utilizing the super specific bonding effect of biotin-streptavidin system, streptavidin modifiedγ-Fe_2O_3 nanoparticles were used in SNP detection. 243 EH samples and 247 healthy samples in Hunan area were collected. The SNP of two loci, M235T and A-6G located in angiotensinogen gene, were detected. PCR products were modified on the streptavidin-γ-Fe_2O_3 nanoparticles, then hybridized with two probes labeled with two fluorescence colors: Cy5 and Cy3. The hybridization results were scanned with a GenePix 4100 scanner. When the sample is homozygous, the ratio of Cy3 to Cy5 is higher than 3. When the sample is heterozygous, the ratio is between 0.64 and 1.7. This SNP typying method had been proved to work well.
After statistic analysis using SPSS 13.0 software, the difference of gene type CC, CT, TT ratio on M235T locus between the sick group of EH and the healthy group was found significant (χ2=5.532,P=0.063). And so was the difference between the allele gene C, T (χ2=5.745,P=0.017). The morbidity of individuals with mutation type TT was found greater than the others. There may be some correlation of the mutation type TT with essential hypertension in people of Hunan area. The difference of gene type AA, AG, GG ratio on A-6G site between the sick group of the EH and healthy group was found not significant (χ2=1.701,P=0.427). And neither was the difference between the allele gene C, T (χ2=1.436,P=0.231). The SNP of A-6G locus may not be a dangerous factor of essential hypertension in people of Hunan area.
引文
[1] Cooper D N, Smith B A, Cooke H J, et al. An estimate of unique DNA sequence heterozygosity in the human genome. Hum Genet,1985, 69: 201-205
[2] Richard A G, Mark J, Zhang H C, et a1.International HapMap Consortium.A haplotype map of the human genome.Nature, 2005, 437:1241-1242
[3] Camargo A A, Samaia H P, Diasneto E, et a1. One contribution of 700 000 ORF sequence tags to the definition of the huron transcriptome. Proc Nati Acad Sci USA, 2001, 98: 12103. 12108
[4] Hieter P, Boguski M. Fuuctionai genomies: it’s all you read it. Science, 1997, 278:601—602
[5]刘万清,贺林. SNP--为人类基因组描绘新的蓝图.遗传,1998,20:38-40
[6] Ito A, Shinkai M,Honda H, Kobayashi T,Medical application of founctionalized magnetic nanoparticals. J Biosci bioeng, 2005, 100(1): 1
[7] Wang XianXiang, Huang Shuo, Shan Zhi, Yang WanShen. Preparation of Fe3O4@Au nano-composites by self-assembly technique for immobilization of glucose oxidase. Chinese Science Bulletin 2009, 54, 1176.
[8] Lubbe A S, Alexiou C, Bergemann C.Clinical application of magnetic drug targeting. Surg Res, 2001, 95(2): 200-206.
[9] Unak, Perihan. Imaging and therapy with radionuclide labeled magnetic nanoparticles. Brazilian Archives of Biology and Technology. 2008, 51, 31.
[10] Pankhurst, Q. A. Connolly, J. Jones, S. K. Dobson, J. Applications of magnetic nanoparticles in biomedicine. J. Phys. D: Appl. Phys., 2003, 36, 167.
[11] Loots G G, Locksley R M, Blankespoor CM, et al. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science, 2000, 288:136-140
[12] Jiang X, Sheng H H, Lin G, et al, Effect of rennin-angiotensinal-dosterone system gene polymorphisms on blood pressure response to antihypertensive treatment. Chin Med J.,2007,120:782-786
[13] Gottgens B, Barton LM, Gilbert J G, et al, Analysis of vertebrate SCL loci identifies conserved enhancers, Nature Biotechnol,2000, 18:181-186
[14] Ulf L, Nilsson M, Kwok P Y. Reading Bits of Genetic Information: Methods for Single-Nucleotide Polymorphism Analysis. GenomeResearch, 1998, 8:769-776.
[15] Francis S C, Mark S G, Aravinda Chakravarti. Variations on a Theme: Cataloging Human DNA Sequence Variation. Science, 1997, 278: 1580-1581.
[16] Mullikin jc,Hunt SE,Cole CG.An SNP map of human chromosome22.Natum,2000,4O7:516
[17]陈汉奎,冯忻.温度梯度凝胶电泳技术及应用.生物化学与生物物理进展, 1999, 26 (3): 297-299.
[18]陆利华,张家洵,朱一川.变性梯度凝胶电泳装置及其在DNA突变检测中的初步应用.生物技术通讯, 2001,12(3):208-210.
[19] Cohen J B, A D Levinson. A point mutation in the last intron responsible for increased expression and transforming activity of the cHaras oncogene. Nature, 1988, 334: 119-124.
[20] Day I N M, S E Humphries. Electrophoresis for genotyping: Microtiter array diagonal gel electrophoresis on horizontal poly2acrylamide gels, hydrolink, or agarose. Anal Biochem, 1994, 222: 389-395.
[21] Holland PM, Abramson R D, Watson R, Gelfand D H. Detectionof specific polymerase chain reaction p roduct by utilizing the 5’-3’exonuclease activity of thermus aquaticus DNA polymerase. Proc. Natl. Acad. Sci. USA, 1991, 88: 7276-7280.
[22] Yagi S, Kramer F R. Molecular beacons: probes that fluoresce upon hybridization. Nat. Biotechnol, 1996, 14: 303-308.
[23] Lyamichev V, Mast A L, Hall J G, Prudent J R, KaiserM W, Takova T, Kwiatkowski R W, Sander T J, de ArrudaM, Arco DA, Neri B P, BrowM A. Polymorphism identification and quantitative detection of genomicDNA by invasive cleavage of oligonucleotide p robes. Nat. Biotechnol, 1999, 17: 292-296.
[24] Pickering J, Bamford A, Godbole V, Briggs J, Scozzafava G, RoeP, Wheeler C, Ghouze F, Cuss S. Integration of DNA ligation androlling circle amp lification for the homogeneous, end2point detection of single nucleotide polymorphisms. Nucleic Acids Res, 2002, 30: 60.
[25]晏春根. Toll样受体单核苷酸多态性与疾病易感性的关系.中华医院感染学杂志, 2006, 16(3): 358-360.
[26] Lida A, Ohnishi Y, Ozaki K, et al. High-density single-nucleotide polymorphism(SNP) map in the 96-kb region containing the entire humanDigeorge syndrome critical region 2 (DGCR2) gene at 22q11.2.Journalof Human genetics, 2001, 46: 604-608.
[27] Tsang S, Sun Z H, Luke B, et al. A comprehensive SNP-based geneticanalysis of inbred mouse strains. Mammalian Genome, 2005, 16: 476-480.
[28] Sattarzadeh A, Achenbach U, Lubeck J, et al. Single nucleotide polymorphism(SNP) genotyping as basis for developing a PCR-based markerhighly diagnostic for potato varieties with high resistance to Globoderapallida pathotype Pa2/3.Molecular Breeding,2006,18: 301-312.
[29] Kaessmann H, Zollner S, Gustasson A C, et al. Extensive linkage disequilibriumin small human populations in Eurasia.American Journal of Human Genetics, 2002,70(3): 673-685.
[30] Germano J, Klein A S. Species specific nuclear and chloroplast singlenucleotide polymorphisms to distinguish Picea glauca, P.mariana, and P.rubens.Theoretical and Applied Genetics, 1999, 99: 37-49.
[31] E.Cardinal, N.Bureau, B.Aubin, R.Chhem. Role of ultrasound in musculoskeletal infections. Radiologic Clinics of North America, 39: 191-201
[32] Caulfield M, Lavender P. Farrall M, et al. Linkange of the angiotensinogen gene to essential hypertension. N. Engl. J Med 1994, 330: 1629-1633
[33] Caillard 1, Clauser E, Corvol P. Structure of human angiotensinogen gene. DNA, 1989, 8:87-99
[34] Gu Dongfeng,eynolds K,Wu Xigui . Prevenlance,awareness,treatment,and control of hypertension in China.Hypertension,2002,40:920-927.
[35] He J,Whelton PK,Wu X,Burt VL, Tao S, Roccella EJ, Klag MJ.Comparison of secular trends in prevalence of hypertension in the People's Republic of China and the United States of America.Am J Hypertens,1996,9:74.
[36] Inoue I,Nakajima T,illiams CS,J Quackenbush, R Puryear, M Powers, T Cheng, E H Ludwig, A M Sharma, A Hata, X Jeunemaitre, and J M Lalouel.A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro.J Clin Invest, 1997, 99:1786-1797.
[37] Tamura K, Umemura S,Fukamizu A,Ishii M, Murakami K.Recent advances in the study of rennin and angiotensinogen gene;from molecules to the whole body. Hypertension Res., 1995,18:7-18.
[38] Kim HS,Krege JH,Kluckman KD,Hagaman JR, Hodgin JB, Best CF, Jennette JC, Coffman TM, Maeda N, Smithies O.Genetic control of blood pressure and the angiotensinogen Iocus.Proc Natl Acad Sci UAS,1995,92:2735-2739.
[39] Jeunermatire X,Soubraer F,Kotelvtsev YV,Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM.Molecular basis of human hypertension, role of angitensinogen.Cell,1992,71:169-180.
[40] Sun S. Murray C. B. Weller D. Folks, L. Moser, A. Monodisperse FePt Nanoparticles and Ferromagnetic FePt Nanocrystal Superlattices. Science 2000, 287:1989.
[41] Miller M. M. Prinz, G. A. Cheng S. F. Bounnak, S. Detection of a micron-sized magnetic sphere using a ring-shaped anisotropic magnetoresistance-based sensor: A model for a magnetoresistance-based biosensor, Appl. Phys. Lett. 2002, 81:2211.
[42] Jain T. K. Morales M. A. Sahoo, S. K. Leslie-Pelecky, D. L. Labhasetwar, V. Iron oxide nanoparticles for sustained delivery of anticancer agents.Mol. Pharm. 2005, 2:194.
[43] Chourpa I. Douziech-Eyrolles L. Ngaboni-Okassa L. Fouquenet J. F. Cohen-Jonathan S. Souce, M. Marchais H. Dubois P. Molecular composition of iron oxide nanoparticles, precursors for magnetic drug targeting, as characterized by confocal Raman microspectroscopy. Analyst, 2005, 130: 1395.
[44] Bulte J. W. Intracellular Endosomal Magnetic Labeling of Cells. Methods Mol. Med. 2006, 124, 419.
[45] Modo M. Bulte, J. W. Cellular MR imaging. Mol. Imaging 2005, 4: 143.
[46] Burtea C. Laurent S. Roch A. Vander Elst L. Muller R. N. CMALISA (cellular magnetic-linked immunosorbent assay), a new application of cellular ELISA for MRI. J. Inorg. Biochem., 2005, 99: 1135.
[47] Boutry S. Laurent S. Vander Elst L. Muller, R. N. Specific Eselectin targeting with a superparamagnetic MRI contrast agent. Contrast Med. Mol. Imaging, 2006, 1: 15.
[48] Babes L. Denizot B. Tanguy G. Le Jeune J. J. Jallet P., Synthesis of Iron Oxide Nanoparticles Used as MRI Contrast Agents: A Parametric Study. J. Colloid Interface Sci., 1999, 212 (2), 474-482.
[49] Sonvico F. Dubernet C. Colombo P. Couvreur P., Metallic Colloid Nanotechnology, Applications in Diagnosis and Therapeutics. Curr. Pharm. Des., 2005, 11, 2091.
[50] Corot C. Robert P. Idee J. M. Port M. Recent advances in iron oxide nanocrystal technology for medical imaging.AdV. Drug DeliVery ReV., 2006, 58 (14), 1471.
[51] Modo M. M. J., Bulte J. W. M., An Outlook on Molecular and Cellular MR Imaging.Molecular and Cellular MR Imaging. CRC Press: Boca Raton, FL, 2007.
[52] Gupta A. K. Gupta M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 2005, 26 (18), 3995.
[53] Charles S. W. Popplewell J. Agglomerate formation in a magnetic fluid. EndeaVour 1982, 6, 153.
[54] Fernando Patolsky, Yossi Weizmann, Eugenii Katz, and Itamar Willner, Magnetically Amplified DNA Assays (MADA): Sensing of Viral DNA and Single-Base Mismatches by Using Nucleic Acid Modified Magnetic particles, Angew. Chem. Int. Ed. 42 (2003), 2372-2376
[55] Yossi Weizmann, Fernando Patolsky, Oleg Lioubashevski, and Itamar Willner, Magneto-Mechanical Detection of Nucleic Acids and Telomerase Activity in Cancer Cells, J. Am. Chem. Soc. 126(2004), 1073-1080
[56] Yossi Weizmann, Fernando Patolsky, Eugenii Katz, and Itamar Willner, Amplified DNA Sensing and Immunosensing by the Rotation of Functional Magnetic Particles, J. Am. Chem.Soc. 125(2003), 3452-3454
[57] Chastellain M. Petri A. Gupta A. Rao K. V. Hofmann, H. Superparamagnetic iron oxide particles embedded in silica is studied for application in hyperthermia. AdV. Eng. Mater. 2004, 6 (4), 235.
[58] Taylor J I, Hurst C D, Davies M J, Sachsinger N K, Bruce I J. Application of magnetite and silica-magnetite composites to the isolation of genomic DNA. J. C hromatogr. A 2000, 890: 159-166.
[59] Campo A D, Sen T, Lellouche J P, Bruce I J. Multifunctional magnetite and silica-magnetite nanoparticles: synthesis, surface activation and aplications in life sciences. J. Magn. Magn. Mater. 2005, 293:33-40.
[60] Rudi K, kroken M, Dahlberg O J, et al. Rapid universal method to isolate PCR ready DNA using magnetic beads, Biotechniques, 1997, 22; 506
[61] Xie Xin, Zhang Huan, et al, Preparation and application of surface-coated superaramagenetic nanobeads in the isolation of genomic DNA, Journal of magnetism and magnetic materials, 2004, 277: 16
[62]谢欣,张旭,高华方等.基于多功能纳米磁珠的DNA制备与基因分型.科学通报, 2004, 49(6): 541
[63] P Tartaj. T Gonzalez-Carreno. C J Serna. Single-step nanoengineering of silica coated maghemite Hollow Sphere with Tunable Magnetic Properties. Adv. Mater., 2001, 13 (21): 1620-1624.
[64] X Battle. Labarta A. Finite-size effects in fine particles: magnetic and transport properties. J. Phys. D: Appl. Phys., 2002, 35 (6): R15-R42.
[65] Sun S. Murray C. B. Weller D. Folks, L. Moser, A. Monodisperse FePt Nanoparticles and Ferromagnetic FePt Nanocrystal Superlattices. Science 2000, 287, 1989.
[66] Miller M. M. Prinz, G. A. Cheng S. F. Bounnak, S. Detection of a micron-sized magnetic sphere using a ring-shaped anisotropic magnetoresistance-based sensor: A model for a magnetoresistance-based biosensor , Appl. Phys. Lett. 2002, 81, 2211.
[67] Jain T. K. Morales M. A. Sahoo, S. K. Leslie-Pelecky, D. L. Labhasetwar, V. Iron oxide nanoparticles for sustained delivery of anticancer agents.Mol. Pharm. 2005, 2 (3), 194.
[68] Chourpa I. Douziech-Eyrolles L. Ngaboni-Okassa L. Fouquenet J. F. Cohen-Jonathan S. Souce, M. Marchais H. Dubois P. Molecular composition of iron oxide nanoparticles, precursors for magnetic drug targeting, as characterized by confocal Raman microspectroscopy. Analyst 2005, 130 (10), 1395.
[69] Bulte J. W. Intracellular Endosomal Magnetic Labeling of Cells.Methods Mol. Med. 2006,124, 419.
[70] Modo M. Bulte, J. W. Cellular MR imaging. Mol. Imaging, 2005, 4(3), 143.
[71] Ltlbbe A .S.,B ergemann C., H uhntW., Riess,H. Schriever, P., Reichardt,P., Possinge. Preclinical Experiences with Magnetic Drug Targeting: Tolerance and Efficacy.CancerR es. 1996, 56, 4694-4701.
[72] Aiping Fan,Choiwan Lau,and Jianzhong Lu.Magnetic bead-Based chemiluminescent metal immunoassay with a Colloidal gold Label. Anal. Chem, 2005, 77: 3238-3242. Man-Wai Louie, Marco Ho-Chuen Lam, Kenneth Kam-Wing. LoLuminescent Polypyridinerhenium (I) Bis-Biotin Complexes as Crosslinkers for Avidin. European Journal of Inorganic Chemistry. 2009, 4265-4273.
[73] Shen, G.-X. Zhou, R.-L. Current Protocols for Immunology. Hubei Science and Technology Press, Wuhan, 2002: 220.
[74] Tan WH, Wang KM, He XX, Zhao XJ, Drake T, Wang L, Bagwe RP. Bionanotechnology based on silica nanoparticles. Med. Res. Rev. 2004, 24: 621–638.
[75] Song Li, Hongna Liu, Zhifei Wang, Peng Hou, Yafei Guo, Quanguo He, Nongyue He.Magnetic-particles-based high-throughput genotyping method with dual-color Fluorescence hybridization. Analytical Biochemistry, 2006, 359: 277-279.
[76] Hongna Liu, Song Li , Meiju Ji, Libo Nie, Jianrong Chen, Yuqing Miao and Nongyue He. Fabrication and Application of Single Nucleotide Polymorphisms Library on Magnetic Nanoparticles Using Adaptor PCR, Journal of Nanoscience and Nanotechnology, 2007, 8: 1-5.
[77] Hongna Liu, Song Li, Zhifei Wang, Nongyue He. Solid-Phase Amplification on Magnetic Nanoparticles for Detection of Single Nucleotide Polymorphism. The forth International Forum on Post-genome Technologie(4’IFPT)─Progress on Post-genome Technologies, Hangzhou, 25th-26th, September, 2006, 159-162.
[78]刘洪娜.基于磁性纳米粒子PCR的高通量单核苷酸多态性分型方法:[硕士学位论文].株洲.湖南工业大学,2008.
[79] Yie Q, Wu KG, Xie LD, et al. The relationship of polymorphism of angiotensinogen and angiotensin converting enzyme with essential hypertension. Chin J Med Genet, 2000, 17(1): 28-29
[80]沈国民,龚平原,赵晓,骆延,彭贺梅,席守民.AGT基因M235T多态与原发性高血压相关研究.河南师范大学学报(自然科学版),2009,37(2):113-116
[81]王爱玲,余元勋,尹长森,杨善志,刘萍.血管紧张素原基因M235T多态性与原发性高血压的关系.安徽医科大学学报,2001, 36(5)159-361
[82]蔡思宇,俞锋,施育平.血管紧张素原基因M235T多态性与原发性高血压的相关研究.浙江大学学报(医学版),2004,33(2),151-154
[83] Zhan YY,Jiang X,Sheng HH, Lin G, Li J, Cheng YL, Huang J. Association between partial indexes of angiotensinogen gene polymorphisms and the risk of essential hypertension: A community case-control study.Chinse Journal of Clinical Rehabilitation,2006,10(48),208-212
[84]李南方,周玲,吴卫东.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.中华医学遗传学杂志,2004, 21(1):23-28.
[85]杨春,邱长春,卢圣栋.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.中华医学遗传学杂志,2000,17:149-152.
[86]卓玛次仁,庄兰平,崔超英.藏族原发性高血压的遗传学研究.中华医学杂志,2002, 82(15):1009-1012.
[87] Ortlepp JR,Metrikat J,Mevissen V,et al. Relation between the angiotensinogen (AGT) M235T gene polymorphism and blood pressure in a large, homogeneous study population. Journal of Human Hypertension, 2003, 17, 555-559
[88] Liu Y, Qin W, Hou S,et a1.A-6G variant of the an giotensinogen gene and essential hypertension in Han, Tibetan,and Yi populations.Hypertens Res,2001, 24:159-163.
[89] Wang JH, Lin CM, Wang LS,et a1.Association between molecular variants of the angiotensinogen gene and hypertension in Amis tribes of eastern Taiwan.J. Formos Med Assoc, 2002, 101:183-188.
[90] Fornage M, Turner ST, Sing CF, et a1.Variation at the M235T locus of the angiotensinogen gene and essential hypertension: a population-based case-control study from Rochester, Minnesota. Hum Genet, 1995,96:295-300.
[91]孔祥东,杨宇霞,张思仲. AGT基因单倍型与原发性高血压.遗传,2004,26(6),797-802
[92]孔祥东,杨宇霞.简化的血管紧张素原基因单倍型分析与原发性高血压的关系.临床内科杂志,2005,22(7):495-497
[93]李南方,周玲,殷晓娟,吴卫东,杨忠礼,普雄明,石岩,李红建,王新玲,王君,张德莲,祖合热,欧阳玮进,布克力,周克明,成秋艳,努尔古丽,朱登浩,马拉提.新疆哈萨克族人血管紧张素原基因M235T多态性与原发性高血压相关性研究.科学技术与工程,2004,4(3):193-197
[94]朱铁兵,杨志健,徐雯,谢勇,张馥敏,曹克将,马文珠.血管紧张素原M235T多态性与原发高血压的相关性研究.南京医科大学学报(自然科学版),2002,22(5):363-394
[95]周晓红,路方红,金世宽,刘振东,孙尚文,赵颖馨,王舒键,杨建民.血管紧张素原M235T基因多态性及体重指数与原发性高血压的关系.中国老年学杂志,2008,5(28):875-877
[96]孔祥东,张思仲,杨宇霞,郑克勤,童煜,施佳军,张克兰,苏智广,陈炜.血管紧张素原基因单倍型与原发性高血压的关联研究.中华医学遗传学杂志, 2006, 19(6)
[97]刘艳,金玮,姜正文,张奎星,盛海辉,金璘,沈亚云,黄薇,于金德.血管紧张素原基因的六种单核苷酸多态与原发性高血压的相关性.中华医学遗传学杂志,2004,21(2):116-119
[98]赵晓丽,胡大春,邵剑春,钱净,张鸿青,蒋杰.云南汉族健康人群6个原发性高血压候选基因多态性分布.现代检验医学杂志,2009, 24(2):99-101
[99] Wang T, Chen ZB, Jin SJ, Su QJ,Correlation between angiotensinogen gene and primary hypertension with cerebral infarction in the Li nationality of China. Neuroscience Bulletin 2007 23(5), 287-292
[100]沈志霞,吴寿岭,李宏芬,任燕,王秀艳,王菊惠.血管紧张素原基因多态性与原发性高血压之间的关系.中国现代医学杂志,2008,18(6):722-728
[101]呼日勒,张春雨,赵世刚,牛广明,李宏芬,呼日乐,王智光,江名芳.蒙古族人群原发性高血压与AGT M235T及CYPl 1 B2 C一344T基因多态性的相关性研究.中国医师杂志,2007, 9(1):31-33
[2] Richard A G, Mark J, Zhang H C, et a1.International HapMap Consortium.A haplotype map of the human genome.Nature, 2005, 437:1241-1242
[3] Camargo A A, Samaia H P, Diasneto E, et a1. One contribution of 700 000 ORF sequence tags to the definition of the huron transcriptome. Proc Nati Acad Sci USA, 2001, 98: 12103. 12108
[4] Hieter P, Boguski M. Fuuctionai genomies: it’s all you read it. Science, 1997, 278:601—602
[5]刘万清,贺林. SNP--为人类基因组描绘新的蓝图.遗传,1998,20:38-40
[6] Ito A, Shinkai M,Honda H, Kobayashi T,Medical application of founctionalized magnetic nanoparticals. J Biosci bioeng, 2005, 100(1): 1
[7] Wang XianXiang, Huang Shuo, Shan Zhi, Yang WanShen. Preparation of Fe3O4@Au nano-composites by self-assembly technique for immobilization of glucose oxidase. Chinese Science Bulletin 2009, 54, 1176.
[8] Lubbe A S, Alexiou C, Bergemann C.Clinical application of magnetic drug targeting. Surg Res, 2001, 95(2): 200-206.
[9] Unak, Perihan. Imaging and therapy with radionuclide labeled magnetic nanoparticles. Brazilian Archives of Biology and Technology. 2008, 51, 31.
[10] Pankhurst, Q. A. Connolly, J. Jones, S. K. Dobson, J. Applications of magnetic nanoparticles in biomedicine. J. Phys. D: Appl. Phys., 2003, 36, 167.
[11] Loots G G, Locksley R M, Blankespoor CM, et al. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science, 2000, 288:136-140
[12] Jiang X, Sheng H H, Lin G, et al, Effect of rennin-angiotensinal-dosterone system gene polymorphisms on blood pressure response to antihypertensive treatment. Chin Med J.,2007,120:782-786
[13] Gottgens B, Barton LM, Gilbert J G, et al, Analysis of vertebrate SCL loci identifies conserved enhancers, Nature Biotechnol,2000, 18:181-186
[14] Ulf L, Nilsson M, Kwok P Y. Reading Bits of Genetic Information: Methods for Single-Nucleotide Polymorphism Analysis. GenomeResearch, 1998, 8:769-776.
[15] Francis S C, Mark S G, Aravinda Chakravarti. Variations on a Theme: Cataloging Human DNA Sequence Variation. Science, 1997, 278: 1580-1581.
[16] Mullikin jc,Hunt SE,Cole CG.An SNP map of human chromosome22.Natum,2000,4O7:516
[17]陈汉奎,冯忻.温度梯度凝胶电泳技术及应用.生物化学与生物物理进展, 1999, 26 (3): 297-299.
[18]陆利华,张家洵,朱一川.变性梯度凝胶电泳装置及其在DNA突变检测中的初步应用.生物技术通讯, 2001,12(3):208-210.
[19] Cohen J B, A D Levinson. A point mutation in the last intron responsible for increased expression and transforming activity of the cHaras oncogene. Nature, 1988, 334: 119-124.
[20] Day I N M, S E Humphries. Electrophoresis for genotyping: Microtiter array diagonal gel electrophoresis on horizontal poly2acrylamide gels, hydrolink, or agarose. Anal Biochem, 1994, 222: 389-395.
[21] Holland PM, Abramson R D, Watson R, Gelfand D H. Detectionof specific polymerase chain reaction p roduct by utilizing the 5’-3’exonuclease activity of thermus aquaticus DNA polymerase. Proc. Natl. Acad. Sci. USA, 1991, 88: 7276-7280.
[22] Yagi S, Kramer F R. Molecular beacons: probes that fluoresce upon hybridization. Nat. Biotechnol, 1996, 14: 303-308.
[23] Lyamichev V, Mast A L, Hall J G, Prudent J R, KaiserM W, Takova T, Kwiatkowski R W, Sander T J, de ArrudaM, Arco DA, Neri B P, BrowM A. Polymorphism identification and quantitative detection of genomicDNA by invasive cleavage of oligonucleotide p robes. Nat. Biotechnol, 1999, 17: 292-296.
[24] Pickering J, Bamford A, Godbole V, Briggs J, Scozzafava G, RoeP, Wheeler C, Ghouze F, Cuss S. Integration of DNA ligation androlling circle amp lification for the homogeneous, end2point detection of single nucleotide polymorphisms. Nucleic Acids Res, 2002, 30: 60.
[25]晏春根. Toll样受体单核苷酸多态性与疾病易感性的关系.中华医院感染学杂志, 2006, 16(3): 358-360.
[26] Lida A, Ohnishi Y, Ozaki K, et al. High-density single-nucleotide polymorphism(SNP) map in the 96-kb region containing the entire humanDigeorge syndrome critical region 2 (DGCR2) gene at 22q11.2.Journalof Human genetics, 2001, 46: 604-608.
[27] Tsang S, Sun Z H, Luke B, et al. A comprehensive SNP-based geneticanalysis of inbred mouse strains. Mammalian Genome, 2005, 16: 476-480.
[28] Sattarzadeh A, Achenbach U, Lubeck J, et al. Single nucleotide polymorphism(SNP) genotyping as basis for developing a PCR-based markerhighly diagnostic for potato varieties with high resistance to Globoderapallida pathotype Pa2/3.Molecular Breeding,2006,18: 301-312.
[29] Kaessmann H, Zollner S, Gustasson A C, et al. Extensive linkage disequilibriumin small human populations in Eurasia.American Journal of Human Genetics, 2002,70(3): 673-685.
[30] Germano J, Klein A S. Species specific nuclear and chloroplast singlenucleotide polymorphisms to distinguish Picea glauca, P.mariana, and P.rubens.Theoretical and Applied Genetics, 1999, 99: 37-49.
[31] E.Cardinal, N.Bureau, B.Aubin, R.Chhem. Role of ultrasound in musculoskeletal infections. Radiologic Clinics of North America, 39: 191-201
[32] Caulfield M, Lavender P. Farrall M, et al. Linkange of the angiotensinogen gene to essential hypertension. N. Engl. J Med 1994, 330: 1629-1633
[33] Caillard 1, Clauser E, Corvol P. Structure of human angiotensinogen gene. DNA, 1989, 8:87-99
[34] Gu Dongfeng,eynolds K,Wu Xigui . Prevenlance,awareness,treatment,and control of hypertension in China.Hypertension,2002,40:920-927.
[35] He J,Whelton PK,Wu X,Burt VL, Tao S, Roccella EJ, Klag MJ.Comparison of secular trends in prevalence of hypertension in the People's Republic of China and the United States of America.Am J Hypertens,1996,9:74.
[36] Inoue I,Nakajima T,illiams CS,J Quackenbush, R Puryear, M Powers, T Cheng, E H Ludwig, A M Sharma, A Hata, X Jeunemaitre, and J M Lalouel.A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro.J Clin Invest, 1997, 99:1786-1797.
[37] Tamura K, Umemura S,Fukamizu A,Ishii M, Murakami K.Recent advances in the study of rennin and angiotensinogen gene;from molecules to the whole body. Hypertension Res., 1995,18:7-18.
[38] Kim HS,Krege JH,Kluckman KD,Hagaman JR, Hodgin JB, Best CF, Jennette JC, Coffman TM, Maeda N, Smithies O.Genetic control of blood pressure and the angiotensinogen Iocus.Proc Natl Acad Sci UAS,1995,92:2735-2739.
[39] Jeunermatire X,Soubraer F,Kotelvtsev YV,Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM.Molecular basis of human hypertension, role of angitensinogen.Cell,1992,71:169-180.
[40] Sun S. Murray C. B. Weller D. Folks, L. Moser, A. Monodisperse FePt Nanoparticles and Ferromagnetic FePt Nanocrystal Superlattices. Science 2000, 287:1989.
[41] Miller M. M. Prinz, G. A. Cheng S. F. Bounnak, S. Detection of a micron-sized magnetic sphere using a ring-shaped anisotropic magnetoresistance-based sensor: A model for a magnetoresistance-based biosensor, Appl. Phys. Lett. 2002, 81:2211.
[42] Jain T. K. Morales M. A. Sahoo, S. K. Leslie-Pelecky, D. L. Labhasetwar, V. Iron oxide nanoparticles for sustained delivery of anticancer agents.Mol. Pharm. 2005, 2:194.
[43] Chourpa I. Douziech-Eyrolles L. Ngaboni-Okassa L. Fouquenet J. F. Cohen-Jonathan S. Souce, M. Marchais H. Dubois P. Molecular composition of iron oxide nanoparticles, precursors for magnetic drug targeting, as characterized by confocal Raman microspectroscopy. Analyst, 2005, 130: 1395.
[44] Bulte J. W. Intracellular Endosomal Magnetic Labeling of Cells. Methods Mol. Med. 2006, 124, 419.
[45] Modo M. Bulte, J. W. Cellular MR imaging. Mol. Imaging 2005, 4: 143.
[46] Burtea C. Laurent S. Roch A. Vander Elst L. Muller R. N. CMALISA (cellular magnetic-linked immunosorbent assay), a new application of cellular ELISA for MRI. J. Inorg. Biochem., 2005, 99: 1135.
[47] Boutry S. Laurent S. Vander Elst L. Muller, R. N. Specific Eselectin targeting with a superparamagnetic MRI contrast agent. Contrast Med. Mol. Imaging, 2006, 1: 15.
[48] Babes L. Denizot B. Tanguy G. Le Jeune J. J. Jallet P., Synthesis of Iron Oxide Nanoparticles Used as MRI Contrast Agents: A Parametric Study. J. Colloid Interface Sci., 1999, 212 (2), 474-482.
[49] Sonvico F. Dubernet C. Colombo P. Couvreur P., Metallic Colloid Nanotechnology, Applications in Diagnosis and Therapeutics. Curr. Pharm. Des., 2005, 11, 2091.
[50] Corot C. Robert P. Idee J. M. Port M. Recent advances in iron oxide nanocrystal technology for medical imaging.AdV. Drug DeliVery ReV., 2006, 58 (14), 1471.
[51] Modo M. M. J., Bulte J. W. M., An Outlook on Molecular and Cellular MR Imaging.Molecular and Cellular MR Imaging. CRC Press: Boca Raton, FL, 2007.
[52] Gupta A. K. Gupta M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 2005, 26 (18), 3995.
[53] Charles S. W. Popplewell J. Agglomerate formation in a magnetic fluid. EndeaVour 1982, 6, 153.
[54] Fernando Patolsky, Yossi Weizmann, Eugenii Katz, and Itamar Willner, Magnetically Amplified DNA Assays (MADA): Sensing of Viral DNA and Single-Base Mismatches by Using Nucleic Acid Modified Magnetic particles, Angew. Chem. Int. Ed. 42 (2003), 2372-2376
[55] Yossi Weizmann, Fernando Patolsky, Oleg Lioubashevski, and Itamar Willner, Magneto-Mechanical Detection of Nucleic Acids and Telomerase Activity in Cancer Cells, J. Am. Chem. Soc. 126(2004), 1073-1080
[56] Yossi Weizmann, Fernando Patolsky, Eugenii Katz, and Itamar Willner, Amplified DNA Sensing and Immunosensing by the Rotation of Functional Magnetic Particles, J. Am. Chem.Soc. 125(2003), 3452-3454
[57] Chastellain M. Petri A. Gupta A. Rao K. V. Hofmann, H. Superparamagnetic iron oxide particles embedded in silica is studied for application in hyperthermia. AdV. Eng. Mater. 2004, 6 (4), 235.
[58] Taylor J I, Hurst C D, Davies M J, Sachsinger N K, Bruce I J. Application of magnetite and silica-magnetite composites to the isolation of genomic DNA. J. C hromatogr. A 2000, 890: 159-166.
[59] Campo A D, Sen T, Lellouche J P, Bruce I J. Multifunctional magnetite and silica-magnetite nanoparticles: synthesis, surface activation and aplications in life sciences. J. Magn. Magn. Mater. 2005, 293:33-40.
[60] Rudi K, kroken M, Dahlberg O J, et al. Rapid universal method to isolate PCR ready DNA using magnetic beads, Biotechniques, 1997, 22; 506
[61] Xie Xin, Zhang Huan, et al, Preparation and application of surface-coated superaramagenetic nanobeads in the isolation of genomic DNA, Journal of magnetism and magnetic materials, 2004, 277: 16
[62]谢欣,张旭,高华方等.基于多功能纳米磁珠的DNA制备与基因分型.科学通报, 2004, 49(6): 541
[63] P Tartaj. T Gonzalez-Carreno. C J Serna. Single-step nanoengineering of silica coated maghemite Hollow Sphere with Tunable Magnetic Properties. Adv. Mater., 2001, 13 (21): 1620-1624.
[64] X Battle. Labarta A. Finite-size effects in fine particles: magnetic and transport properties. J. Phys. D: Appl. Phys., 2002, 35 (6): R15-R42.
[65] Sun S. Murray C. B. Weller D. Folks, L. Moser, A. Monodisperse FePt Nanoparticles and Ferromagnetic FePt Nanocrystal Superlattices. Science 2000, 287, 1989.
[66] Miller M. M. Prinz, G. A. Cheng S. F. Bounnak, S. Detection of a micron-sized magnetic sphere using a ring-shaped anisotropic magnetoresistance-based sensor: A model for a magnetoresistance-based biosensor , Appl. Phys. Lett. 2002, 81, 2211.
[67] Jain T. K. Morales M. A. Sahoo, S. K. Leslie-Pelecky, D. L. Labhasetwar, V. Iron oxide nanoparticles for sustained delivery of anticancer agents.Mol. Pharm. 2005, 2 (3), 194.
[68] Chourpa I. Douziech-Eyrolles L. Ngaboni-Okassa L. Fouquenet J. F. Cohen-Jonathan S. Souce, M. Marchais H. Dubois P. Molecular composition of iron oxide nanoparticles, precursors for magnetic drug targeting, as characterized by confocal Raman microspectroscopy. Analyst 2005, 130 (10), 1395.
[69] Bulte J. W. Intracellular Endosomal Magnetic Labeling of Cells.Methods Mol. Med. 2006,124, 419.
[70] Modo M. Bulte, J. W. Cellular MR imaging. Mol. Imaging, 2005, 4(3), 143.
[71] Ltlbbe A .S.,B ergemann C., H uhntW., Riess,H. Schriever, P., Reichardt,P., Possinge. Preclinical Experiences with Magnetic Drug Targeting: Tolerance and Efficacy.CancerR es. 1996, 56, 4694-4701.
[72] Aiping Fan,Choiwan Lau,and Jianzhong Lu.Magnetic bead-Based chemiluminescent metal immunoassay with a Colloidal gold Label. Anal. Chem, 2005, 77: 3238-3242. Man-Wai Louie, Marco Ho-Chuen Lam, Kenneth Kam-Wing. LoLuminescent Polypyridinerhenium (I) Bis-Biotin Complexes as Crosslinkers for Avidin. European Journal of Inorganic Chemistry. 2009, 4265-4273.
[73] Shen, G.-X. Zhou, R.-L. Current Protocols for Immunology. Hubei Science and Technology Press, Wuhan, 2002: 220.
[74] Tan WH, Wang KM, He XX, Zhao XJ, Drake T, Wang L, Bagwe RP. Bionanotechnology based on silica nanoparticles. Med. Res. Rev. 2004, 24: 621–638.
[75] Song Li, Hongna Liu, Zhifei Wang, Peng Hou, Yafei Guo, Quanguo He, Nongyue He.Magnetic-particles-based high-throughput genotyping method with dual-color Fluorescence hybridization. Analytical Biochemistry, 2006, 359: 277-279.
[76] Hongna Liu, Song Li , Meiju Ji, Libo Nie, Jianrong Chen, Yuqing Miao and Nongyue He. Fabrication and Application of Single Nucleotide Polymorphisms Library on Magnetic Nanoparticles Using Adaptor PCR, Journal of Nanoscience and Nanotechnology, 2007, 8: 1-5.
[77] Hongna Liu, Song Li, Zhifei Wang, Nongyue He. Solid-Phase Amplification on Magnetic Nanoparticles for Detection of Single Nucleotide Polymorphism. The forth International Forum on Post-genome Technologie(4’IFPT)─Progress on Post-genome Technologies, Hangzhou, 25th-26th, September, 2006, 159-162.
[78]刘洪娜.基于磁性纳米粒子PCR的高通量单核苷酸多态性分型方法:[硕士学位论文].株洲.湖南工业大学,2008.
[79] Yie Q, Wu KG, Xie LD, et al. The relationship of polymorphism of angiotensinogen and angiotensin converting enzyme with essential hypertension. Chin J Med Genet, 2000, 17(1): 28-29
[80]沈国民,龚平原,赵晓,骆延,彭贺梅,席守民.AGT基因M235T多态与原发性高血压相关研究.河南师范大学学报(自然科学版),2009,37(2):113-116
[81]王爱玲,余元勋,尹长森,杨善志,刘萍.血管紧张素原基因M235T多态性与原发性高血压的关系.安徽医科大学学报,2001, 36(5)159-361
[82]蔡思宇,俞锋,施育平.血管紧张素原基因M235T多态性与原发性高血压的相关研究.浙江大学学报(医学版),2004,33(2),151-154
[83] Zhan YY,Jiang X,Sheng HH, Lin G, Li J, Cheng YL, Huang J. Association between partial indexes of angiotensinogen gene polymorphisms and the risk of essential hypertension: A community case-control study.Chinse Journal of Clinical Rehabilitation,2006,10(48),208-212
[84]李南方,周玲,吴卫东.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.中华医学遗传学杂志,2004, 21(1):23-28.
[85]杨春,邱长春,卢圣栋.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.中华医学遗传学杂志,2000,17:149-152.
[86]卓玛次仁,庄兰平,崔超英.藏族原发性高血压的遗传学研究.中华医学杂志,2002, 82(15):1009-1012.
[87] Ortlepp JR,Metrikat J,Mevissen V,et al. Relation between the angiotensinogen (AGT) M235T gene polymorphism and blood pressure in a large, homogeneous study population. Journal of Human Hypertension, 2003, 17, 555-559
[88] Liu Y, Qin W, Hou S,et a1.A-6G variant of the an giotensinogen gene and essential hypertension in Han, Tibetan,and Yi populations.Hypertens Res,2001, 24:159-163.
[89] Wang JH, Lin CM, Wang LS,et a1.Association between molecular variants of the angiotensinogen gene and hypertension in Amis tribes of eastern Taiwan.J. Formos Med Assoc, 2002, 101:183-188.
[90] Fornage M, Turner ST, Sing CF, et a1.Variation at the M235T locus of the angiotensinogen gene and essential hypertension: a population-based case-control study from Rochester, Minnesota. Hum Genet, 1995,96:295-300.
[91]孔祥东,杨宇霞,张思仲. AGT基因单倍型与原发性高血压.遗传,2004,26(6),797-802
[92]孔祥东,杨宇霞.简化的血管紧张素原基因单倍型分析与原发性高血压的关系.临床内科杂志,2005,22(7):495-497
[93]李南方,周玲,殷晓娟,吴卫东,杨忠礼,普雄明,石岩,李红建,王新玲,王君,张德莲,祖合热,欧阳玮进,布克力,周克明,成秋艳,努尔古丽,朱登浩,马拉提.新疆哈萨克族人血管紧张素原基因M235T多态性与原发性高血压相关性研究.科学技术与工程,2004,4(3):193-197
[94]朱铁兵,杨志健,徐雯,谢勇,张馥敏,曹克将,马文珠.血管紧张素原M235T多态性与原发高血压的相关性研究.南京医科大学学报(自然科学版),2002,22(5):363-394
[95]周晓红,路方红,金世宽,刘振东,孙尚文,赵颖馨,王舒键,杨建民.血管紧张素原M235T基因多态性及体重指数与原发性高血压的关系.中国老年学杂志,2008,5(28):875-877
[96]孔祥东,张思仲,杨宇霞,郑克勤,童煜,施佳军,张克兰,苏智广,陈炜.血管紧张素原基因单倍型与原发性高血压的关联研究.中华医学遗传学杂志, 2006, 19(6)
[97]刘艳,金玮,姜正文,张奎星,盛海辉,金璘,沈亚云,黄薇,于金德.血管紧张素原基因的六种单核苷酸多态与原发性高血压的相关性.中华医学遗传学杂志,2004,21(2):116-119
[98]赵晓丽,胡大春,邵剑春,钱净,张鸿青,蒋杰.云南汉族健康人群6个原发性高血压候选基因多态性分布.现代检验医学杂志,2009, 24(2):99-101
[99] Wang T, Chen ZB, Jin SJ, Su QJ,Correlation between angiotensinogen gene and primary hypertension with cerebral infarction in the Li nationality of China. Neuroscience Bulletin 2007 23(5), 287-292
[100]沈志霞,吴寿岭,李宏芬,任燕,王秀艳,王菊惠.血管紧张素原基因多态性与原发性高血压之间的关系.中国现代医学杂志,2008,18(6):722-728
[101]呼日勒,张春雨,赵世刚,牛广明,李宏芬,呼日乐,王智光,江名芳.蒙古族人群原发性高血压与AGT M235T及CYPl 1 B2 C一344T基因多态性的相关性研究.中国医师杂志,2007, 9(1):31-33