中国汉族人群AGTR1基因与心肌梗死的关联研究tagging SNP选择和单体型分析
|
摘要
研究背景和目的
一直以来，肾素-血管紧张素系统(RAS)都被认为与高血压、心肌肥大和冠心病的发病机制密切相关。血管紧张素Ⅱ(ANG Ⅱ)是RAS系统最主要的生物活性产物，具有血管收缩、醛固酮释放、细胞增生以及细胞外周基质蛋白合成与积聚等多种功能。已知ANG Ⅱ的大多数生物学效应通过血管紧张素Ⅱ-1型受体(AT1受体)介导实现。鉴于该受体的生物学功能，编码AT1受体的基因(AGTR1)已成为高血压和冠心病遗传危险因素研究的重要候选基因。近些年来，有大量研究探讨AGTR1基因遗传变异同多种心血管事件的关系，但结果存在争议。本课题拟采用多阶段病例．对照研究策略，首先在中国汉族人群系统筛查AGTR1基因所有潜在功能性变异，阐明连锁不平衡模式和单体型分布，选择国人AGTR1基因tSNP；进而在病例-对照中充分探讨这些tSNP及其单体型和心肌梗死的关联，以期明确AGTR1基因与中国汉族人群心肌梗死发生的关系。
材料和方法
随机入选1997年10月至2000年9月期间阜外心血管病医院收治的居住在北京地区的急性心肌梗死男性患者419例。所有患者均发病3个月或3个月以上，且病情稳定，并经各项检查排除心脏瓣膜疾病、先天性心脏病、心力衰竭、严重的肾脏及肝脏疾病、继发性高血压、心肌病、家族性高胆固醇血症和严重肝肾及甲状腺疾病患者。随机选择居住在北京，年龄(±2岁)与病例匹配的社区人群400例健康男性做为对照组。对照组入选标准：既往无心脏病史，无胸痛、胸闷等心脏病症状且心脏查体正常，心电图无明显异常。参加者均详细填写调查表，包括疾病个人史、家族史、吸烟与饮酒史和药物使用情况，并测量血压、身高、体重、腰围及臀围以及血浆脂质等各项生化指标。所有研究对象均为汉族且无血缘关系。随机选取48例无血缘关系的病例样本，利用基因组DNA直接测序的方法筛查AGTR1基因外显子、启动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＞5％)的连锁不平衡系数D’和r~2，通过tagSNPs和htSNP2软件包选择tagging SNP(tSNP)。在819例研究对象中，以PCR-RFLP方法鉴定tSNP基因型。方差分析及X~2检验用于单变量分析，多元线性回归分析
Background
The renin-angiotensin system (RAS) is implicated in the pathogenesis of hypertension, cardiac hypertrophy and coronary heart disease. The major biologically active product of the RAS is angiotensin II (ANG II), a peptide with multiple functions, including vasoconstriction, aldosterone production, hypertrophic and hyperplastic effects on vascular smooth muscle cells and cardiomyocytes, and synthesis of the extracellular collagen matrix. In adult humans, the effects of ANG II are mainly mediated by the angiotensin II type 1 receptor (AT1R). Because of the physiological role of this receptor, the AT1R gene (AGTR1) has been a candidate gene for hypertension and coronary heart disease. The contributions of variants of AGTR1 gene to cardiovascular diseases are conflicted in previous reports. In the present study, a multi-step case-control study was designed for evaluating the contribution of AGTR1 variations to myocardial infarction (MI) in Chinese Han population. We first scanned the AGTR1 gene to identify all putative functional polymorphisms within a sub-sample. The pattern of linkage disequilibrium across the whole gene was characterized and tSNPs were selected. Then these tSNPs were further genotyped in the entire study population. Both locus-based and haplotype-based association tests were used to evaluate the possible effect of AGTR1 gene on MI.
Methods
A total of 419 males who survived an acute MI were eligible for this study. They were enrolled from Fu Wai Hospital & Cardiovascular Institute (Beijing, China) between October 1997 and September 2000. Diagnoses of all cases in this study follow strict diagnostic rules based on signs, symptoms, electrocardiograms and cardiac enzymes. Subjects with congenital heart disease, cardiomyopathy, valvular disease, and renal or hepatic disease were excluded. Age-matched (± 2 years) male
一直以来，肾素-血管紧张素系统(RAS)都被认为与高血压、心肌肥大和冠心病的发病机制密切相关。血管紧张素Ⅱ(ANG Ⅱ)是RAS系统最主要的生物活性产物，具有血管收缩、醛固酮释放、细胞增生以及细胞外周基质蛋白合成与积聚等多种功能。已知ANG Ⅱ的大多数生物学效应通过血管紧张素Ⅱ-1型受体(AT1受体)介导实现。鉴于该受体的生物学功能，编码AT1受体的基因(AGTR1)已成为高血压和冠心病遗传危险因素研究的重要候选基因。近些年来，有大量研究探讨AGTR1基因遗传变异同多种心血管事件的关系，但结果存在争议。本课题拟采用多阶段病例．对照研究策略，首先在中国汉族人群系统筛查AGTR1基因所有潜在功能性变异，阐明连锁不平衡模式和单体型分布，选择国人AGTR1基因tSNP；进而在病例-对照中充分探讨这些tSNP及其单体型和心肌梗死的关联，以期明确AGTR1基因与中国汉族人群心肌梗死发生的关系。
材料和方法
随机入选1997年10月至2000年9月期间阜外心血管病医院收治的居住在北京地区的急性心肌梗死男性患者419例。所有患者均发病3个月或3个月以上，且病情稳定，并经各项检查排除心脏瓣膜疾病、先天性心脏病、心力衰竭、严重的肾脏及肝脏疾病、继发性高血压、心肌病、家族性高胆固醇血症和严重肝肾及甲状腺疾病患者。随机选择居住在北京，年龄(±2岁)与病例匹配的社区人群400例健康男性做为对照组。对照组入选标准：既往无心脏病史，无胸痛、胸闷等心脏病症状且心脏查体正常，心电图无明显异常。参加者均详细填写调查表，包括疾病个人史、家族史、吸烟与饮酒史和药物使用情况，并测量血压、身高、体重、腰围及臀围以及血浆脂质等各项生化指标。所有研究对象均为汉族且无血缘关系。随机选取48例无血缘关系的病例样本，利用基因组DNA直接测序的方法筛查AGTR1基因外显子、启动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＞5％)的连锁不平衡系数D’和r~2，通过tagSNPs和htSNP2软件包选择tagging SNP(tSNP)。在819例研究对象中，以PCR-RFLP方法鉴定tSNP基因型。方差分析及X~2检验用于单变量分析，多元线性回归分析
Background
The renin-angiotensin system (RAS) is implicated in the pathogenesis of hypertension, cardiac hypertrophy and coronary heart disease. The major biologically active product of the RAS is angiotensin II (ANG II), a peptide with multiple functions, including vasoconstriction, aldosterone production, hypertrophic and hyperplastic effects on vascular smooth muscle cells and cardiomyocytes, and synthesis of the extracellular collagen matrix. In adult humans, the effects of ANG II are mainly mediated by the angiotensin II type 1 receptor (AT1R). Because of the physiological role of this receptor, the AT1R gene (AGTR1) has been a candidate gene for hypertension and coronary heart disease. The contributions of variants of AGTR1 gene to cardiovascular diseases are conflicted in previous reports. In the present study, a multi-step case-control study was designed for evaluating the contribution of AGTR1 variations to myocardial infarction (MI) in Chinese Han population. We first scanned the AGTR1 gene to identify all putative functional polymorphisms within a sub-sample. The pattern of linkage disequilibrium across the whole gene was characterized and tSNPs were selected. Then these tSNPs were further genotyped in the entire study population. Both locus-based and haplotype-based association tests were used to evaluate the possible effect of AGTR1 gene on MI.
Methods
A total of 419 males who survived an acute MI were eligible for this study. They were enrolled from Fu Wai Hospital & Cardiovascular Institute (Beijing, China) between October 1997 and September 2000. Diagnoses of all cases in this study follow strict diagnostic rules based on signs, symptoms, electrocardiograms and cardiac enzymes. Subjects with congenital heart disease, cardiomyopathy, valvular disease, and renal or hepatic disease were excluded. Age-matched (± 2 years) male
引文
1 Lander ES, Linton LM, Birren B et al: Initial sequencing and analysis of the human genome. Nature 2001; 409: 860-921.
2 Sachidanandam R, Weissman D, Schmidt SC et al: A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001; 409: 928-933.
3 Kruglyak L, Nickerson DA: Variation is the spice of life. Nat Genet 2001; 27: 234-236.
4 Halushka MK, Fan JB, Bentley K et al: Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999; 22: 239-247.
5 Nickerson DA, Taylor SL, Weiss KM et al: DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet 1998; 19: 233-240.
6 Cambien F, Poirier O, Nicaud V et al: Sequence diversity in 36 candidate genes for cardiovascular disorders. Am J Hum Genet 1999; 65: 183-191.
7 Stephens JC, Schneider JA, Tanguay DA et al: Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001; 293: 489-493.
8 Johnson GC, Esposito L, Barratt BJ et al: Haplotype tagging for the identification of common disease genes. Nat Genet 2001; 29: 233-237.
9 Zhang K, Deng M, Chen T, Waterman MS, Sun F: A dynamic programming algorithm for haplotype block partitioning. Proc Natl Acad Sci U S A 2002; 99: 7335-7339.
10 Stram DO, Haiman CA, Hirschhorn JN et al: Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the Multiethnic Cohort Study. Hum Hered 2003; 55: 27-36.
11 Chapman JM, Cooper JD, Todd JA, Clayton DG: Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Hum Hered 2003; 56: 18-31.
12 Poirier O, Georges JL, Ricard S et al: New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study. Etude Cas-Temoin de l'Infarctus du Myocarde. J Hypertens 1998; 16: 1443-1447.
13 Kikuya M, Sugimoto K, Katsuya T et al: A/C1166 gene polymorphism of the angiotensin JJ type 1 receptor (AT1) and ambulatory blood pressure: the Ohasama Study. Hypertens Res 2003; 26: 141-145.
14 Erdmann J, Riedel K, Rohde K et al: Characterization of polymorphisms in the promoter of the human angiotensin JJ subtype 1 (AT1) receptor gene. Ann Hum Genet 1999; 63 ( Pt 4): 369-374.
15 Takahashi N, Murakami H, Kodama K et al: Association of a polymorphism at the 5'-region of the angiotensin JJ type 1 receptor with hypertension. Ann Hum Genet 2000; 64: 197-205.16 Jin W, Liu Y, Sheng HH et al: Single nucleotide polymorphisms in promoter of angiotensin II type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin 2003; 24: 1083-1088.
17 Weiss KM, Clark AG: Linkage disequilibrium and the mapping of complex human traits. Trends Genet 2002; 18: 19-24.
18 Reiner A, Yekutieli D, Benjamini Y: Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics 2003; 19: 368-375.
19 Bandelt HJ, Forster P, Sykes BC, Richards MB: Mitochondrial portraits of human populations using median networks. Genetics 1995; 141: 743-753.
20 Bonnardeaux A, Davies E, Jeunemaitre X et al: Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 1994; 24: 63-69.
21 Zondervan KT, Cardon LR: The complex interplay among factors that influence allelic association. Nat Rev Genet 2004; 5: 89-100.
22 Thompson EA, Deeb S, Walker D, Motulsky AG: The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes. Am J Hum Genet 1988; 42: 113-124.
23 Zhu X, Cooper RS: Linkage disequilibrium analysis of the renin-angiotensin system genes. Curr Hypertens Rep 2003; 5: 40-46.1 Chiu AT, Herblin WF, McCall DE et al: Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun 1989; 165: 196-203.
2 Timmermans PB, Wong PC, Chiu AT, Herblin WF: Nonpeptide angiotensin II receptor antagonists. Trends Pharmacol Sci 1991; 12: 55-62.
3 Ito M, Oliverio MI, Mannon PJ et al: Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci U S A 1995; 92: 3521-3525.
4 Le TH, Kim HS, Allen AM, Spurney RF, Smithies O, Coffman TM: Physiological impact of increased expression of the AT1 angiotensin receptor. Hypertension 2003; 42: 507-514.
5 Wong C, Mahapatra NR, Chitbangonsyn S et al: The angiotensin II receptor (Agtrla): functional regulatory polymorphisms in a locus genetically linked to blood pressure variation in the mouse. Physiol Genomics 2003; 14: 83-93.
6 Hein L: Genetic deletion and overexpression of angiotensin II receptors. J Mol Med 1998; 76: 756-763.
7 Paradis P, Dali-Youcef N, Paradis FW, Thibault G, Nemer M: Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci U S A 2000; 97: 931-936.
8 Bonnardeaux A, Davies E, Jeunemaitre X et al: Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 1994; 24: 63-69.
9 Ono K, Mannami T, Baba S, Yasui N, Ogihara T, Iwai N: Lack of association between angiotensin II type 1 receptor gene polymorphism and hypertension in Japanese. Hypertens Res 2003; 26: 131-134.
10 Kikuya M, Sugimoto K, Katsuya T et al: A/C1166 gene polymorphism of the angiotensin II type 1 receptor (AT1) and ambulatory blood pressure: the Ohasama Study. Hypertens Res 2003; 26: 141-145.
11 Benetos A, Gautier S, Ricard S et al: Influence of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation 1996; 94: 698-703.
12 Lajemi M, Labat C, Gautier S et al: Angiotensin II type 1 receptor-153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens 2001; 19: 407-413.
13 Tiret L, Bonnardeaux A, Poirier O et al: Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet 1994; 344: 910-913.
14 Nakauchi Y, Suehiro T, Yamamoto M et al: Significance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease. Atherosclerosis 1996; 125: 161-169.
15 Poirier O, Georges JL, Ricard S et al: New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and??blood pressure: the ECTIM study. Etude Cas-Temoin de l'Infarctus du Myocarde. J Hypertens 1998; 16: 1443-1447.
16 Paillard F, Chansel D, Brand E et al: Genotype-phenotype relationships for the renin-angiotensin-aldosterone system in a normal population. Hypertension 1999; 34: 423-429.
17 Herzig TC, Jobe SM, Aoki H et al: Angiotensin II type1a receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload. Proc Natl Acad Sci U S A 1997; 94: 7543-7548.
18 Erdmann J, Riedel K, Rohde K et al: Characterization of polymorphisms in the promoter of the human angiotensin II subtype 1 (AT1) receptor gene. Ann Hum Genet 1999; 63 (Pt 4): 369-374.
19 Takahashi N, Murakami H, Kodama K et al: Association of a polymorphism at the 5'-region of the angiotensin II type 1 receptor with hypertension. Ann Hum Genet 2000; 64: 197-205.
20 Jin W, Liu Y, Sheng HH et al: Single nucleotide polymorphisms in promoter of angiotensin II type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin 2003; 24: 1083-1088.
21 Akey J, Jin L, Xiong M: Haplotypes vs single marker linkage disequilibrium tests: what do we gain? Eur J Hum Genet 2001; 9: 291-300.
22 Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG: Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 2002; 53: 79-91.
23 Zhao JH, Curtis D, Sham PC: Model-free analysis and permutation tests for allelic associations. Hum Hered 2000; 50: 133-139.
24 Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978-989.
25 Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA: Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002; 70: 425-434.
26 Lake SL, Lyon H, Tantisira K et al: Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered 2003; 55: 56-65.
27 Zhu X, Cooper RS: Linkage disequilibrium analysis of the renin-angiotensin system genes. Curr Hypertens Rep 2003; 5: 40-46.
28 Chapman JM, Cooper JD, Todd JA, Clayton DG: Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Hum Hered 2003; 56: 18-31.
29 Stata. Stata Corp: Stata statistical software: release 8.0., Stata Corporation, College Station, TX, 2003.
30 Burnier M, Brunner HR: Angiotensin II receptor antagonists. Lancet 2000; 355: 637-645.
31 Kainulainen K, Perola M, Terwilliger J et al: Evidence for involvement of the??type 1 angiotensin Ⅱ receptor locus in essential hypertension. Hypertension 1999; 33: 844-849.
32 Neale BM, Sham PC: The future of association studies: gene-based analysis and replication. Am J Hum Genet 2004; 75: 353-362.
33 Miller JA, Thai K, Scholey JW: Angiotensin Ⅱ type 1 receptor gene polymorphism predicts response to losartan and angiotensin Ⅱ. Kidney Int 1999; 56: 2173-2180.
http://www.ncbi.nlm.nih.gov/Omim; Online Mendelian Inheritance in Man (OMIM); for AGTR1 gene [MIM 106165].
http://www.well.ox.ac.uk/asthma/GOLD; GOLD software.
http://www-gene.cimr.cam.ac.uk/clayton/software/; SNPHAP software.
http://www.fluxus-engineering.corn/sharenet.htm; NETWORK 4.0 software.
http://www-rcf.usc.edu/-stram/tagSNPs.html; tSNPs selection based on prediction of extended haplotypes (for tagsnps software).
http://www-gene.cimr.cam.ac.uk/clayton/software/stata/; tSNPs selection based on prediction of single loci (for htSNP2 software) and prediction (for genassoc software).
http://www.stat.washington.edu/stephens/software.html; PHASE 2.0 software.
http://www.mayo.edu/hsr/people/schaid.html; Haplo.stats software (haplo.score and haplo.glm).1 Chiu AT, Herblin WF, McCall DE et al: Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun 1989; 165: 196-203.
2 Burnier M, Brunner HR: Angiotensin II receptor antagonists. Lancet 2000; 355: 637-645.
3 Lindpaintner K, Ganten D: The cardiac renin-angiotensin system. An appraisal of present experimental and clinical evidence. Circ Res 1991; 68: 905-921.
4 Dzau VJ: Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation 1988; 77:14-13.
5 de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T: International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 2000; 52: 415-472.
6 Regitz-Zagrosek V, Neuss M, Holzmeister J, Warnecke C, Fleck E: Molecular biology of angiotensin receptors and their role in human cardiovascular disease. J Mol Med 1996; 74: 233-251.
7 Griendling KK, Ushio-Fukai M, Lassegue B, Alexander RW: Angiotensin II signaling in vascular smooth muscle. New concepts. Hypertension 1997; 29: 366-373.
8 Schieffer B, Paxton WG, Marrero MB, Bernstein KE: Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. Hypertension 1996; 27: 476-480.
9 Gallinat S, Busche S, Raizada MK, Sumners C: The angiotensin II type 2 receptor: an enigma with multiple variations. Am J Physiol Endocrinol Metab 2000; 278: E357-374.
10 Iwai N, Inagami T: Identification of two subtypes in the rat type I angiotensin II receptor. FEBS Lett 1992; 298: 257-260.
11 Bonnardeaux A, Davies E, Jeunemaitre X et al: Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 1994; 24: 63-69.
12 Erdmann J, Riedel K, Rohde K et al: Characterization of polymorphisms in the promoter of the human angiotensin II subtype 1 (AT1) receptor gene. Ann Hum Genet 1999; 63 (Pt 4): 369-374.
13 Takahashi N, Murakami H, Kodama K et al: Association of a polymorphism at the 5'-region of the angiotensin II type 1 receptor with hypertension. Ann Hum Genet 2000; 64: 197-205.
14 Jin W, Liu Y, Sheng HH et al: Single nucleotide polymorphisms in promoter of angiotensin II type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin 2003; 24: 1083-1088.
15 Poirier O, Georges JL, Ricard S et al: New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTM study. Etude Cas-Temoin de l'Infarctus du Myocarde. J Hypertens 1998; 16: 1443-1447.16 Kikuya M, Sugimoto K, Katsuya T et al: A/C1166 gene polymorphism of the angiotensin II type 1 receptor (AT1) and ambulatory blood pressure: the Ohasama Study. Hypertens Res 2003; 26: 141-145.
17 Wang WY, Zee RY, Morris BJ: Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin Genet 1997; 51: 31-34.
18 Kainulainen K, Perola M, Terwilliger J et al: Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension. Hypertension 1999; 33: 844-849.
19 Castellano M, Glorioso N, Cusi D et al: Genetic polymorphism of the renin-angiotensin-aldosterone system and arterial hypertension in the Italian population: the GENIPER Project. J Hypertens 2003; 21: 1853-1860.
20 Tiret L, Blanc H, Ruidavets JB et al: Gene polymorphisms of the renin-angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke: the PEGASE study. Projet d'Etude des Genes de l'Hypertension Arterielle Severe a moderee Essentielle. J Hypertens 1998; 16: 37-44.
21 Schmidt S, Beige J, Walla-Friedel M, Michel MC, Sharma AM, Ritz E: A polymorphism in the gene for the angiotensin II type 1 receptor is not associated with hypertension. J Hypertens 1997; 15: 1385-1388.
22 Hingorani AD, Jia H, Stevens PA, Hopper R, Dickerson JE, Brown MJ: Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition. J Hypertens 1995; 13: 1602-1609.
23 Castellano M, Muiesan ML, Beschi M et al: Angiotensin II type 1 receptor A/C1166 polymorphism. Relationships with blood pressure and cardiovascular structure. Hypertension 1996; 28: 1076-1080.
24 Zhang X, Erdmann J, Regitz-Zagrosek V, Kurzinger S, Hense HW, Schunkert H: Evaluation of three polymorphisms in the promoter region of the angiotensin II type I receptor gene. J Hypertens 2000; 18: 267-272.
25 Gardier S, Vincent M, Lantelme P, Rial MO, Bricca G, Milon H: A1166C polymorphism of angiotensin II type 1 receptor, blood pressure and arterial stiffness in hypertension. J Hypertens 2004; 22: 2135-2142.
26 Miyamoto Y, Yoshimasa T, Arai H et al: Alternative RNA splicing of the human endothelin-A receptor generates multiple transcripts. Biochem J 1996; 313(Pt 3): 795-801.
27 Takami S, Katsuya T, Rakugi H et al: Angiotensin II type 1 receptor gene polymorphism is associated with increase of left ventricular mass but not with hypertension. Am J Hypertens 1998; 11: 316-321.
28 Sugimoto K, Katsuya T, Ohkubo T et al: Association between angiotensin II type 1 receptor gene polymorphism and essential hypertension: the Ohasama Study. Hypertens Res 2004; 27: 551-556.
29 Ono K, Mannami T, Baba S, Yasui N, Ogihara T, Iwai N: Lack of association between angiotensin II type 1 receptor gene polymorphism and hypertension in Japanese. Hypertens Res 2003; 26: 131-134.30 Hamon M, Amant C, Bauters C et al: Association of angiotensin converting enzyme and angiotensin II type 1 receptor genotypes with left ventricular function and mass in patients with angiographically normal coronary arteries. Heart 1997; 77: 502-505.
31 Osterop AP, Kofflard MJ, Sandkuijl LA et al: AT1 receptor A/C1166 polymorphism contributes to cardiac hypertrophy in subjects with hypertrophic cardiomyopathy. Hypertension 1998; 32: 825-830.
32 Tiret L, Mallet C, Poirier O et al: Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study. J Am Coll Cardiol 2000; 35: 29-35.
33 Tiret L, Bonnardeaux A, Poirier O et al: Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet 1994; 344: 910-913.
34 Alvarez R, Reguero JR, Batalla A et al: Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease. Cardiovasc Res 1998; 40: 375-379.
35 Fatini C, Abbate R, Pepe G et al: Searching for a better assessment of the individual coronary risk profile. The role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms. Eur Heart J 2000; 21. 633-638.
36 Gardemann A, Nguyen QD, Humme J et al: Angiotensin II type 1 receptor A1166C gene polymorphism. Absence of an association with the risk of coronary artery disease and myocardial infarction and of a synergistic effect with angiotensin-converting enzyme gene polymorphism on the risk of these diseases. Eur Heart J 1998; 19: 1657-1665.
37 Hernandez Ortega E, Medina Fernandez-Aceituno A, Rodriguez Esparragon FJ et al: [The involvement of the renin-angiotensin system gene polymorphisms in coronary heart disease]. Rev Esp Cardiol 2002; 55: 92-99.
38 Andrikopoulos GK, Richter DJ, Needham EW et al: The paradoxical association of common polymorphisms of the renin-angiotensin system genes with risk of myocardial infarction. Eur J Cardiovasc Prev Rehabil 2004; 11: 477-483.
39 Ye S, Dhillon S, Seear R et al: Epistatic interaction between variations in the angiotensin I converting enzyme and angiotensin II type 1 receptor genes in relation to extent of coronary atherosclerosis. Heart 2003; 89: 1195-1199.
40 Nakauchi Y, Suehiro T, Yamamoto M et al: Significance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease. Atherosclerosis 1996; 125: 161-169.
41 van Geel PP, Pinto YM, Voors AA et al: Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries. Hypertension 2000; 35: 717-721.
42 Amant C, Hamon M, Bauters C et al: The angiotensin II type 1 receptor gene polymorphism is associated with coronary artery vasoconstriction. J Am Coll Cardiol 1997; 29: 486-490.43 Steeds RP, Toole LO, Channer KS, Morice AH: Human vascular reactivity and polymorphisms of the angiotensin-converting enzyme and the angiotensin type 1 receptor genes. J Vasc Res 1999; 36: 445-455; discussion 535-448.
44 Benetos A, Topouchian J, Ricard S et al: Influence of angiotensin Ⅱ type 1 receptor polymorphism on aortic stiffness in never-treated hypertensive patients. Hypertension 1995; 26: 44-47.
45 Benetos A, Cambien F, Gautier S et al: Influence of the angiotensin Ⅱ type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine on arterial stiffness in hypertensive individuals. Hypertension 1996; 28: 1081-1084.
46 Benetos A, Gautier S, Ricard S et al: Influence of angiotensin-converting enzyme and angiotensin Ⅱ type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation 1996; 94: 698-703.
47 Lajemi M, Labat C, Gautier S et al: Angiotensin Ⅱ type 1 receptor-153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens 2001; 19: 407-413.
48 Tamow L, Cambien F, Rossing P et al: Angiotensin-Ⅱ type 1 receptor gene polymorphism and diabetic microangiopathy. Nephrol Dial Transplant 1996; 11: 1019-1023.
49 Chowdhury TA, Dyer PH, Kumar S et al: Lack of association of angiotensin Ⅱ type 1 receptor gene polymorphism with diabetic nephropathy in insulin-dependent diabetes mellitus. Diabet Med 1997; 14: 837-840.
50 Doria A, Onuma T, Warram JH, Krolewski AS: Synergistic effect of angiotensin Ⅱ type 1 receptor genotype and poor glycaemic control on risk of nephropathy in IDDM. Diabetologia 1997; 40: 1293-1299.
51 Moczulski DK, Rogus JJ, Antonellis A, Warram JH, Krolewski AS: Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. Diabetes 1998; 47:1164-1169.
52 Miller JA, Thai K, Scholey JW: Angiotensin Ⅱ type 1 receptor gene polymorphism and the response to hyperglycemia in early type 1 diabetes. Diabetes 2000; 49: 1585-1589.
53 Paillard F, Chansel D, Brand E et al: Genotype-phenotype relationships for the renin-angiotensin-aldosterone system in a normal population. Hypertension 1999; 34: 423-429.
54 Herzig TC, Jobe SM, Aoki H et al: Angiotensin Ⅱ typela receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload. Proc Natl Acad Sci U S A 1997; 94: 7543-7548.
55 Baudin B: Angiotensin Ⅰ-converting enzyme gene polymorphism and drug response. Clin Chem Lab Med 2000; 38: 853-856.
56 Miller JA, Thai K, Scholey JW: Angiotensin Ⅱ type 1 receptor gene polymorphism predicts response to losartan and angiotensin Ⅱ. Kidney Int 1999; 56: 2173-2180.
57 Spiering W, Kroon AA, Fuss-Lejeune MM, Daemen MJ, de Leeuw PW:??Angiotensin II sensitivity is associated with the angiotensin II type 1 receptor A(1166)C polymorphism in essential hypertensives on a high sodium diet. Hypertension 2000; 36: 411-416.
58 Kurland L, Melhus H, Sarabi M, Millgard J, Ljunghall S, Lind L: Polymorphisms in the renin-angiotensin system and endothelium-dependent vasodilation in normotensive subjects. Clin Physiol 2001; 21: 343-349.
59 Dieguez-Lucena JL, Aranda-Lara P, Ruiz-Galdon M, Garcia-Villanova J, Morell-Ocana M, Reyes-Engel A: Angiotensin I-converting enzyme genotypes and angiotensin II receptors. Response to therapy. Hypertension 1996; 28: 98-103.
60 Delles C, Erdmann J, Jacobi J, Fleck E, Regitz-Zagrosek V, Schmieder RE: Lack of association between polymorphisms of angiotensin II receptor genes and response to short-term angiotensin II infusion. J Hypertens 2000; 18: 1573-1578.
61 Ortlepp JR, Breithardt O, Ohme F, Hanrath P, Hoffmann R: Lack of association among five genetic polymorphisms of the renin-angiotensin system and cardiac hypertrophy in patients with aortic stenosis. Am Heart J 2001; 141: 671-676.
62 Nakagawa K, Ishizaki T: Therapeutic relevance of pharmacogenetic factors in cardiovascular medicine. Pharmacol Ther 2000; 86: 1-28.
63 Stearns RA, Chakravarty PK, Chen R, Chiu SH: Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Drug Metab Dispos 1995; 23: 207-215.
2 Sachidanandam R, Weissman D, Schmidt SC et al: A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001; 409: 928-933.
3 Kruglyak L, Nickerson DA: Variation is the spice of life. Nat Genet 2001; 27: 234-236.
4 Halushka MK, Fan JB, Bentley K et al: Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999; 22: 239-247.
5 Nickerson DA, Taylor SL, Weiss KM et al: DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet 1998; 19: 233-240.
6 Cambien F, Poirier O, Nicaud V et al: Sequence diversity in 36 candidate genes for cardiovascular disorders. Am J Hum Genet 1999; 65: 183-191.
7 Stephens JC, Schneider JA, Tanguay DA et al: Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001; 293: 489-493.
8 Johnson GC, Esposito L, Barratt BJ et al: Haplotype tagging for the identification of common disease genes. Nat Genet 2001; 29: 233-237.
9 Zhang K, Deng M, Chen T, Waterman MS, Sun F: A dynamic programming algorithm for haplotype block partitioning. Proc Natl Acad Sci U S A 2002; 99: 7335-7339.
10 Stram DO, Haiman CA, Hirschhorn JN et al: Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the Multiethnic Cohort Study. Hum Hered 2003; 55: 27-36.
11 Chapman JM, Cooper JD, Todd JA, Clayton DG: Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Hum Hered 2003; 56: 18-31.
12 Poirier O, Georges JL, Ricard S et al: New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study. Etude Cas-Temoin de l'Infarctus du Myocarde. J Hypertens 1998; 16: 1443-1447.
13 Kikuya M, Sugimoto K, Katsuya T et al: A/C1166 gene polymorphism of the angiotensin JJ type 1 receptor (AT1) and ambulatory blood pressure: the Ohasama Study. Hypertens Res 2003; 26: 141-145.
14 Erdmann J, Riedel K, Rohde K et al: Characterization of polymorphisms in the promoter of the human angiotensin JJ subtype 1 (AT1) receptor gene. Ann Hum Genet 1999; 63 ( Pt 4): 369-374.
15 Takahashi N, Murakami H, Kodama K et al: Association of a polymorphism at the 5'-region of the angiotensin JJ type 1 receptor with hypertension. Ann Hum Genet 2000; 64: 197-205.16 Jin W, Liu Y, Sheng HH et al: Single nucleotide polymorphisms in promoter of angiotensin II type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin 2003; 24: 1083-1088.
17 Weiss KM, Clark AG: Linkage disequilibrium and the mapping of complex human traits. Trends Genet 2002; 18: 19-24.
18 Reiner A, Yekutieli D, Benjamini Y: Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics 2003; 19: 368-375.
19 Bandelt HJ, Forster P, Sykes BC, Richards MB: Mitochondrial portraits of human populations using median networks. Genetics 1995; 141: 743-753.
20 Bonnardeaux A, Davies E, Jeunemaitre X et al: Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 1994; 24: 63-69.
21 Zondervan KT, Cardon LR: The complex interplay among factors that influence allelic association. Nat Rev Genet 2004; 5: 89-100.
22 Thompson EA, Deeb S, Walker D, Motulsky AG: The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes. Am J Hum Genet 1988; 42: 113-124.
23 Zhu X, Cooper RS: Linkage disequilibrium analysis of the renin-angiotensin system genes. Curr Hypertens Rep 2003; 5: 40-46.1 Chiu AT, Herblin WF, McCall DE et al: Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun 1989; 165: 196-203.
2 Timmermans PB, Wong PC, Chiu AT, Herblin WF: Nonpeptide angiotensin II receptor antagonists. Trends Pharmacol Sci 1991; 12: 55-62.
3 Ito M, Oliverio MI, Mannon PJ et al: Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci U S A 1995; 92: 3521-3525.
4 Le TH, Kim HS, Allen AM, Spurney RF, Smithies O, Coffman TM: Physiological impact of increased expression of the AT1 angiotensin receptor. Hypertension 2003; 42: 507-514.
5 Wong C, Mahapatra NR, Chitbangonsyn S et al: The angiotensin II receptor (Agtrla): functional regulatory polymorphisms in a locus genetically linked to blood pressure variation in the mouse. Physiol Genomics 2003; 14: 83-93.
6 Hein L: Genetic deletion and overexpression of angiotensin II receptors. J Mol Med 1998; 76: 756-763.
7 Paradis P, Dali-Youcef N, Paradis FW, Thibault G, Nemer M: Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci U S A 2000; 97: 931-936.
8 Bonnardeaux A, Davies E, Jeunemaitre X et al: Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 1994; 24: 63-69.
9 Ono K, Mannami T, Baba S, Yasui N, Ogihara T, Iwai N: Lack of association between angiotensin II type 1 receptor gene polymorphism and hypertension in Japanese. Hypertens Res 2003; 26: 131-134.
10 Kikuya M, Sugimoto K, Katsuya T et al: A/C1166 gene polymorphism of the angiotensin II type 1 receptor (AT1) and ambulatory blood pressure: the Ohasama Study. Hypertens Res 2003; 26: 141-145.
11 Benetos A, Gautier S, Ricard S et al: Influence of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation 1996; 94: 698-703.
12 Lajemi M, Labat C, Gautier S et al: Angiotensin II type 1 receptor-153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens 2001; 19: 407-413.
13 Tiret L, Bonnardeaux A, Poirier O et al: Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet 1994; 344: 910-913.
14 Nakauchi Y, Suehiro T, Yamamoto M et al: Significance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease. Atherosclerosis 1996; 125: 161-169.
15 Poirier O, Georges JL, Ricard S et al: New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and??blood pressure: the ECTIM study. Etude Cas-Temoin de l'Infarctus du Myocarde. J Hypertens 1998; 16: 1443-1447.
16 Paillard F, Chansel D, Brand E et al: Genotype-phenotype relationships for the renin-angiotensin-aldosterone system in a normal population. Hypertension 1999; 34: 423-429.
17 Herzig TC, Jobe SM, Aoki H et al: Angiotensin II type1a receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload. Proc Natl Acad Sci U S A 1997; 94: 7543-7548.
18 Erdmann J, Riedel K, Rohde K et al: Characterization of polymorphisms in the promoter of the human angiotensin II subtype 1 (AT1) receptor gene. Ann Hum Genet 1999; 63 (Pt 4): 369-374.
19 Takahashi N, Murakami H, Kodama K et al: Association of a polymorphism at the 5'-region of the angiotensin II type 1 receptor with hypertension. Ann Hum Genet 2000; 64: 197-205.
20 Jin W, Liu Y, Sheng HH et al: Single nucleotide polymorphisms in promoter of angiotensin II type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin 2003; 24: 1083-1088.
21 Akey J, Jin L, Xiong M: Haplotypes vs single marker linkage disequilibrium tests: what do we gain? Eur J Hum Genet 2001; 9: 291-300.
22 Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG: Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 2002; 53: 79-91.
23 Zhao JH, Curtis D, Sham PC: Model-free analysis and permutation tests for allelic associations. Hum Hered 2000; 50: 133-139.
24 Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978-989.
25 Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA: Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002; 70: 425-434.
26 Lake SL, Lyon H, Tantisira K et al: Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered 2003; 55: 56-65.
27 Zhu X, Cooper RS: Linkage disequilibrium analysis of the renin-angiotensin system genes. Curr Hypertens Rep 2003; 5: 40-46.
28 Chapman JM, Cooper JD, Todd JA, Clayton DG: Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Hum Hered 2003; 56: 18-31.
29 Stata. Stata Corp: Stata statistical software: release 8.0., Stata Corporation, College Station, TX, 2003.
30 Burnier M, Brunner HR: Angiotensin II receptor antagonists. Lancet 2000; 355: 637-645.
31 Kainulainen K, Perola M, Terwilliger J et al: Evidence for involvement of the??type 1 angiotensin Ⅱ receptor locus in essential hypertension. Hypertension 1999; 33: 844-849.
32 Neale BM, Sham PC: The future of association studies: gene-based analysis and replication. Am J Hum Genet 2004; 75: 353-362.
33 Miller JA, Thai K, Scholey JW: Angiotensin Ⅱ type 1 receptor gene polymorphism predicts response to losartan and angiotensin Ⅱ. Kidney Int 1999; 56: 2173-2180.
http://www.ncbi.nlm.nih.gov/Omim; Online Mendelian Inheritance in Man (OMIM); for AGTR1 gene [MIM 106165].
http://www.well.ox.ac.uk/asthma/GOLD; GOLD software.
http://www-gene.cimr.cam.ac.uk/clayton/software/; SNPHAP software.
http://www.fluxus-engineering.corn/sharenet.htm; NETWORK 4.0 software.
http://www-rcf.usc.edu/-stram/tagSNPs.html; tSNPs selection based on prediction of extended haplotypes (for tagsnps software).
http://www-gene.cimr.cam.ac.uk/clayton/software/stata/; tSNPs selection based on prediction of single loci (for htSNP2 software) and prediction (for genassoc software).
http://www.stat.washington.edu/stephens/software.html; PHASE 2.0 software.
http://www.mayo.edu/hsr/people/schaid.html; Haplo.stats software (haplo.score and haplo.glm).1 Chiu AT, Herblin WF, McCall DE et al: Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun 1989; 165: 196-203.
2 Burnier M, Brunner HR: Angiotensin II receptor antagonists. Lancet 2000; 355: 637-645.
3 Lindpaintner K, Ganten D: The cardiac renin-angiotensin system. An appraisal of present experimental and clinical evidence. Circ Res 1991; 68: 905-921.
4 Dzau VJ: Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation 1988; 77:14-13.
5 de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T: International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 2000; 52: 415-472.
6 Regitz-Zagrosek V, Neuss M, Holzmeister J, Warnecke C, Fleck E: Molecular biology of angiotensin receptors and their role in human cardiovascular disease. J Mol Med 1996; 74: 233-251.
7 Griendling KK, Ushio-Fukai M, Lassegue B, Alexander RW: Angiotensin II signaling in vascular smooth muscle. New concepts. Hypertension 1997; 29: 366-373.
8 Schieffer B, Paxton WG, Marrero MB, Bernstein KE: Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. Hypertension 1996; 27: 476-480.
9 Gallinat S, Busche S, Raizada MK, Sumners C: The angiotensin II type 2 receptor: an enigma with multiple variations. Am J Physiol Endocrinol Metab 2000; 278: E357-374.
10 Iwai N, Inagami T: Identification of two subtypes in the rat type I angiotensin II receptor. FEBS Lett 1992; 298: 257-260.
11 Bonnardeaux A, Davies E, Jeunemaitre X et al: Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension 1994; 24: 63-69.
12 Erdmann J, Riedel K, Rohde K et al: Characterization of polymorphisms in the promoter of the human angiotensin II subtype 1 (AT1) receptor gene. Ann Hum Genet 1999; 63 (Pt 4): 369-374.
13 Takahashi N, Murakami H, Kodama K et al: Association of a polymorphism at the 5'-region of the angiotensin II type 1 receptor with hypertension. Ann Hum Genet 2000; 64: 197-205.
14 Jin W, Liu Y, Sheng HH et al: Single nucleotide polymorphisms in promoter of angiotensin II type 1 receptor gene associated with essential hypertension and coronary heart disease in Chinese population. Acta Pharmacol Sin 2003; 24: 1083-1088.
15 Poirier O, Georges JL, Ricard S et al: New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTM study. Etude Cas-Temoin de l'Infarctus du Myocarde. J Hypertens 1998; 16: 1443-1447.16 Kikuya M, Sugimoto K, Katsuya T et al: A/C1166 gene polymorphism of the angiotensin II type 1 receptor (AT1) and ambulatory blood pressure: the Ohasama Study. Hypertens Res 2003; 26: 141-145.
17 Wang WY, Zee RY, Morris BJ: Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension. Clin Genet 1997; 51: 31-34.
18 Kainulainen K, Perola M, Terwilliger J et al: Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension. Hypertension 1999; 33: 844-849.
19 Castellano M, Glorioso N, Cusi D et al: Genetic polymorphism of the renin-angiotensin-aldosterone system and arterial hypertension in the Italian population: the GENIPER Project. J Hypertens 2003; 21: 1853-1860.
20 Tiret L, Blanc H, Ruidavets JB et al: Gene polymorphisms of the renin-angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke: the PEGASE study. Projet d'Etude des Genes de l'Hypertension Arterielle Severe a moderee Essentielle. J Hypertens 1998; 16: 37-44.
21 Schmidt S, Beige J, Walla-Friedel M, Michel MC, Sharma AM, Ritz E: A polymorphism in the gene for the angiotensin II type 1 receptor is not associated with hypertension. J Hypertens 1997; 15: 1385-1388.
22 Hingorani AD, Jia H, Stevens PA, Hopper R, Dickerson JE, Brown MJ: Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition. J Hypertens 1995; 13: 1602-1609.
23 Castellano M, Muiesan ML, Beschi M et al: Angiotensin II type 1 receptor A/C1166 polymorphism. Relationships with blood pressure and cardiovascular structure. Hypertension 1996; 28: 1076-1080.
24 Zhang X, Erdmann J, Regitz-Zagrosek V, Kurzinger S, Hense HW, Schunkert H: Evaluation of three polymorphisms in the promoter region of the angiotensin II type I receptor gene. J Hypertens 2000; 18: 267-272.
25 Gardier S, Vincent M, Lantelme P, Rial MO, Bricca G, Milon H: A1166C polymorphism of angiotensin II type 1 receptor, blood pressure and arterial stiffness in hypertension. J Hypertens 2004; 22: 2135-2142.
26 Miyamoto Y, Yoshimasa T, Arai H et al: Alternative RNA splicing of the human endothelin-A receptor generates multiple transcripts. Biochem J 1996; 313(Pt 3): 795-801.
27 Takami S, Katsuya T, Rakugi H et al: Angiotensin II type 1 receptor gene polymorphism is associated with increase of left ventricular mass but not with hypertension. Am J Hypertens 1998; 11: 316-321.
28 Sugimoto K, Katsuya T, Ohkubo T et al: Association between angiotensin II type 1 receptor gene polymorphism and essential hypertension: the Ohasama Study. Hypertens Res 2004; 27: 551-556.
29 Ono K, Mannami T, Baba S, Yasui N, Ogihara T, Iwai N: Lack of association between angiotensin II type 1 receptor gene polymorphism and hypertension in Japanese. Hypertens Res 2003; 26: 131-134.30 Hamon M, Amant C, Bauters C et al: Association of angiotensin converting enzyme and angiotensin II type 1 receptor genotypes with left ventricular function and mass in patients with angiographically normal coronary arteries. Heart 1997; 77: 502-505.
31 Osterop AP, Kofflard MJ, Sandkuijl LA et al: AT1 receptor A/C1166 polymorphism contributes to cardiac hypertrophy in subjects with hypertrophic cardiomyopathy. Hypertension 1998; 32: 825-830.
32 Tiret L, Mallet C, Poirier O et al: Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study. J Am Coll Cardiol 2000; 35: 29-35.
33 Tiret L, Bonnardeaux A, Poirier O et al: Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet 1994; 344: 910-913.
34 Alvarez R, Reguero JR, Batalla A et al: Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease. Cardiovasc Res 1998; 40: 375-379.
35 Fatini C, Abbate R, Pepe G et al: Searching for a better assessment of the individual coronary risk profile. The role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms. Eur Heart J 2000; 21. 633-638.
36 Gardemann A, Nguyen QD, Humme J et al: Angiotensin II type 1 receptor A1166C gene polymorphism. Absence of an association with the risk of coronary artery disease and myocardial infarction and of a synergistic effect with angiotensin-converting enzyme gene polymorphism on the risk of these diseases. Eur Heart J 1998; 19: 1657-1665.
37 Hernandez Ortega E, Medina Fernandez-Aceituno A, Rodriguez Esparragon FJ et al: [The involvement of the renin-angiotensin system gene polymorphisms in coronary heart disease]. Rev Esp Cardiol 2002; 55: 92-99.
38 Andrikopoulos GK, Richter DJ, Needham EW et al: The paradoxical association of common polymorphisms of the renin-angiotensin system genes with risk of myocardial infarction. Eur J Cardiovasc Prev Rehabil 2004; 11: 477-483.
39 Ye S, Dhillon S, Seear R et al: Epistatic interaction between variations in the angiotensin I converting enzyme and angiotensin II type 1 receptor genes in relation to extent of coronary atherosclerosis. Heart 2003; 89: 1195-1199.
40 Nakauchi Y, Suehiro T, Yamamoto M et al: Significance of angiotensin I-converting enzyme and angiotensin II type 1 receptor gene polymorphisms as risk factors for coronary heart disease. Atherosclerosis 1996; 125: 161-169.
41 van Geel PP, Pinto YM, Voors AA et al: Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries. Hypertension 2000; 35: 717-721.
42 Amant C, Hamon M, Bauters C et al: The angiotensin II type 1 receptor gene polymorphism is associated with coronary artery vasoconstriction. J Am Coll Cardiol 1997; 29: 486-490.43 Steeds RP, Toole LO, Channer KS, Morice AH: Human vascular reactivity and polymorphisms of the angiotensin-converting enzyme and the angiotensin type 1 receptor genes. J Vasc Res 1999; 36: 445-455; discussion 535-448.
44 Benetos A, Topouchian J, Ricard S et al: Influence of angiotensin Ⅱ type 1 receptor polymorphism on aortic stiffness in never-treated hypertensive patients. Hypertension 1995; 26: 44-47.
45 Benetos A, Cambien F, Gautier S et al: Influence of the angiotensin Ⅱ type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine on arterial stiffness in hypertensive individuals. Hypertension 1996; 28: 1081-1084.
46 Benetos A, Gautier S, Ricard S et al: Influence of angiotensin-converting enzyme and angiotensin Ⅱ type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation 1996; 94: 698-703.
47 Lajemi M, Labat C, Gautier S et al: Angiotensin Ⅱ type 1 receptor-153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens 2001; 19: 407-413.
48 Tamow L, Cambien F, Rossing P et al: Angiotensin-Ⅱ type 1 receptor gene polymorphism and diabetic microangiopathy. Nephrol Dial Transplant 1996; 11: 1019-1023.
49 Chowdhury TA, Dyer PH, Kumar S et al: Lack of association of angiotensin Ⅱ type 1 receptor gene polymorphism with diabetic nephropathy in insulin-dependent diabetes mellitus. Diabet Med 1997; 14: 837-840.
50 Doria A, Onuma T, Warram JH, Krolewski AS: Synergistic effect of angiotensin Ⅱ type 1 receptor genotype and poor glycaemic control on risk of nephropathy in IDDM. Diabetologia 1997; 40: 1293-1299.
51 Moczulski DK, Rogus JJ, Antonellis A, Warram JH, Krolewski AS: Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. Diabetes 1998; 47:1164-1169.
52 Miller JA, Thai K, Scholey JW: Angiotensin Ⅱ type 1 receptor gene polymorphism and the response to hyperglycemia in early type 1 diabetes. Diabetes 2000; 49: 1585-1589.
53 Paillard F, Chansel D, Brand E et al: Genotype-phenotype relationships for the renin-angiotensin-aldosterone system in a normal population. Hypertension 1999; 34: 423-429.
54 Herzig TC, Jobe SM, Aoki H et al: Angiotensin Ⅱ typela receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload. Proc Natl Acad Sci U S A 1997; 94: 7543-7548.
55 Baudin B: Angiotensin Ⅰ-converting enzyme gene polymorphism and drug response. Clin Chem Lab Med 2000; 38: 853-856.
56 Miller JA, Thai K, Scholey JW: Angiotensin Ⅱ type 1 receptor gene polymorphism predicts response to losartan and angiotensin Ⅱ. Kidney Int 1999; 56: 2173-2180.
57 Spiering W, Kroon AA, Fuss-Lejeune MM, Daemen MJ, de Leeuw PW:??Angiotensin II sensitivity is associated with the angiotensin II type 1 receptor A(1166)C polymorphism in essential hypertensives on a high sodium diet. Hypertension 2000; 36: 411-416.
58 Kurland L, Melhus H, Sarabi M, Millgard J, Ljunghall S, Lind L: Polymorphisms in the renin-angiotensin system and endothelium-dependent vasodilation in normotensive subjects. Clin Physiol 2001; 21: 343-349.
59 Dieguez-Lucena JL, Aranda-Lara P, Ruiz-Galdon M, Garcia-Villanova J, Morell-Ocana M, Reyes-Engel A: Angiotensin I-converting enzyme genotypes and angiotensin II receptors. Response to therapy. Hypertension 1996; 28: 98-103.
60 Delles C, Erdmann J, Jacobi J, Fleck E, Regitz-Zagrosek V, Schmieder RE: Lack of association between polymorphisms of angiotensin II receptor genes and response to short-term angiotensin II infusion. J Hypertens 2000; 18: 1573-1578.
61 Ortlepp JR, Breithardt O, Ohme F, Hanrath P, Hoffmann R: Lack of association among five genetic polymorphisms of the renin-angiotensin system and cardiac hypertrophy in patients with aortic stenosis. Am Heart J 2001; 141: 671-676.
62 Nakagawa K, Ishizaki T: Therapeutic relevance of pharmacogenetic factors in cardiovascular medicine. Pharmacol Ther 2000; 86: 1-28.
63 Stearns RA, Chakravarty PK, Chen R, Chiu SH: Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Drug Metab Dispos 1995; 23: 207-215.