摘要
研究背景和目的
目前，探索原发性高血压遗传机制的研究方兴未艾，籍此识别相关的易感基因及基因在高血压发病中的可能作用，并进一步建立基因之间及基因与环境因素的交互作用引发高血压的模型，最终使人们更好的理解高血压发病的病理生理学机制。连锁分析法和候选基因法是探察基因组、描述高血压遗传病因的两种互相补充的方法。连锁分析是利用遗传连锁的原理研究致病基因与遗传标记的关系，通常采用家系分析的方法，在家系的相关个体中将候选基因位点的遗传标记与高血压表型进行连锁分析，以确定该位点是否与高血压连锁。目前已经有很多关于高血压的全基因扫描报道，一些研究认为人14号染色体与原发性高血压或血压性状有关，我们试图在中国人群中验证这一结果。关联研究目前广泛应用于阐述人类复杂疾病的遗传学基础。迄今为止，在人们所研究的与原发性高血压相关的候选基因中，载脂蛋白B(APOB)基因和组织激肽释放酶1(KLK1)基因引起研究人员的格外注意。apoB是低密度脂蛋白(LDL)颗粒的主要蛋白成分，在血浆LDL胆固醇代谢平衡中具有重要作用。研究表明，APOB基因对原发性高血压遗传易感性可能具有一定作用。KLK1基因编码人组织激肽释放酶1，该酶是肾脏合成的一种激肽形成酶，其主要生物学功能是切割激肽原释放血管活性的激肽。动物实验和人群研究都表明，KLK1基因可能与原发性高血压有关，我们基于HapMap计划中国人群(CGB)的数据，采用病例对照研究和标签SNP方法在中国汉族原发性高血压病例—对照人群中分别对APOB基因和KLK1基因多态进行了研究。
材料和方法(连锁分析部分)：
本研究采用平均密度大约为10cM的14个微卫星标记在147个中国高血压核心家系共计799名研究对象中对14号染色体进行连锁扫描。每个高血压核心家系的成员必须满足下列标准：(1)年龄大于15岁；(2)自我确认有4个汉族祖父母；(3)父母任意一方患有高血压；(5)三次测定的静息—坐位血压平均值为收缩压＞140 mmHg，和／或舒张压≥90 mmHg；(6)没有继发性高血压的临床或生物学指征。采用荧光标记PCR—聚丙烯酰胺凝胶电泳方法进行基因分型，通过GENEHUNTER软件进行多点非参数连锁分析和排除作图，使用SOLAR软件对
Background: One of the important tasks of hypertension research is the elucidation of the genetic basis of hypertension as a means to identify the genes involved, determine their respective role in causing high blood pressure, and establish how they interact with one another and with non-genetic factors to result in the hypertensive phenotype. This search should untimately lead to a better understanding of the pathophsiological mechanisms underlying hypertension. Linkage and association studies are complementary methods, together, provide the means to probe the genome and describe the genetic etiology of essential hypertension. The goal of linkage studies is to determine whether the two loci tend to cosegregate more often than they should if they were not physically close together on the same chromosome. The assumption is that the genetic marker is linked to the gene causing the specific phenotype. There are now many publications describing the results of genome-wide screens for genes controlling blood pressure. Some studies have linked human chromosome 14 with suggestive evidence of linkage to essential hypertension or blood pressure traits. With a Chinese population, we tried to replicate these findings.
Genetic association studies are central efforts to identify and characterize genomic variants underlying susceptibility to multifactorial disease. Among candidate genes thus investigated to data, apolipoprotein B (APOB) and tussue kallikreinl (KLK1) genes have drawn substantial attention. Apo B is the sole component of the low-density lipoprotein (LDL) particles and is thought to play an important role in the homeostasis of LDL cholesterol in plasma. Recent studies suggested the apolipoprotein B (APOB) gene played a role in determining susceptibility to essential hypertension. KLK1 gene codes the human tissue kallikreinl (hKl) which is the major kinin-forming enzyme in the kidney. The main biological function of hKl is to process kininogen substrates and release vasoactive kinin peptides. KLK1 gene had been implicated to be associated with blood pressure regulation through animal model and population research. Based on the data of CHB in the international HapMap Project, we investigated the association of KLK1 gene common polymorphisms with essential hypertension in Chinese Han population by tagging single nucleotide polymorphisms (tSNPs) strategy.
Methods (linkage analysis): We recruited 147 randomly ascertained families that containning 799 individuals. To be eligible for our study, the subjects had to meet the
引文
1. Staessen, J.A., J. Wang, G. Bianchi, and W.H. Birkenhager, Essential hypertension. Lancet, 2003.361(9369): p. 1629-41.
2. Cooper, R.S., A. Luke, X. Zhu, et al., Genome scan among Nigerians linking blood pressure to chromosomes 2, 3, and 19. Hypertension, 2002.40(5): p. 629-33.
3. de Lange, M., T.D. Spector, and T. Andrew, Genome-Wide Scan for Blood Pressure Suggests Linkage to Chromosome 11, and Replication of Loci on 16, 17, and 22. Hypertension, 2004. 44(6): p. 872-877.
4. von Wowern, F., K. Bengtsson, C.M. Lindgren, et al., A genome wide scan for early onset primary hypertension in Scandinavians. Hum Mol Genet, 2003.12(16): p. 2077-81.
5. Atwood, L.D., P.B. Samollow, J.E. Hixson, M.P. Stern, and J.W. MacCluer, Genome-wide linkage analysis of blood pressure in Mexican Americans. Genet Epidemiol, 2001.20(3): p. 373-82.
6. Rice, T., T. Rankinen, M.A. Province, et al., Genome-wide linkage analysis of systolic and diastolic blood pressure: the Quebec Family Study. Circulation, 2000. 102(16): p. 1956-63.
7. Caulfield, M., P. Munroe, J. Pembroke, et al., Genome-wide mapping of human loci for essential hypertension. Lancet, 2003.361 (9375): p. 2118-23.
8. Kristjansson, K., A. Manolescu, A. Kristinsson, et al., Linkage of essential hypertension to chromosome 18q. Hypertension, 2002.39(6): p. 1044-9.
9. Cheng, L.S., R.C. Davis, L.J. Raffel, et al., Coincident linkage of fasting plasma insulin and blood pressure to chromosome 7q in hypertensive hispanic families. Circulation, 2001. 104(11): p. 1255-60.
10. Sharma, P., J. Fatibene, F. Ferraro, et al., A genome-wide search for susceptibility loci to human essential hypertension. Hypertension, 2000. 35(6): p. 1291-6.
11. Pankow, J.S., K.M. Rose, A. Oberman, et al., Possible locus on chromosome 18q influencing postural systolic blood pressure changes. Hypertension, 2000. 36(4): p. 471-6.
12. Avery, C.L., B.I. Freedman, G. Heiss, et al., Linkage analysis of diabetes status among hypertensive families: the Hypertension Genetic Epidemiology Network study. Diabetes, 2004. 53(12): p. 3307-12.
13. Hsueh, W.C., B.D. Mitchell, J.L. Schneider, et al., QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31-34 in Old Order Amish. Circulation, 2000. 101(24): p. 2810-6.
14. Rice, T., T. Rankinen, Y.C. Chagnon, et al., Genomewide linkage scan of resting blood pressure: HERITAGE Family Study. Health, Risk Factors, Exercise Training, and Genetics. Hypertension, 2002.39(6): p. 1037-43.
15. Samani, N.J., Genome scans for hypertension and blood pressure regulation. Am J Hypertens, 2003. 16(2): p. 167-71.
16. Province, M.A., S.L. Kardia, K. Ranade, et al., A meta-analysis of genome-wide linkage scans for hypertension: the National Heart, Lung and Blood Institute Family Blood Pressure Program. Am J Hypertens, 2003.16(2): p. 144-7.
17. Joseph S, D.W., Isolation of high-molecular-weight DNA from mammalian cells using proteinase K and phenol. In: Joseph S, David WR, ed. Molecular cloning: a laboratory manual. 3rd ed.. 2001:6.4-6.11.
18. Kruglyak, L., M.J. Daly, M.P. Reeve-Daly, and E.S. Lander, Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet, 1996. 58(6): p. 1347-63.
19. Kruglyak, L. anti E.S. Lander, Complete multipoint sib-pair analysis of qualitative and quantitative traits Am J Hum Genet, 1995.57(2): p. 439-54.
20. Tsao, B.E, R.M. Cantor, J.M. Grossman, et al., Linkage and interaction of loci on 1q23 and 16q12 may contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum, 2002.46(11): p. 2928-36.
21. Gu, D., K. Reynolds, X. Wu, et al., Prevalence, awareness, treatment, and control of hypertension in china. Hypertension, 2002.40(6): p. 920-7.
22. Yang, W.J., J.E Huang, C.L. Yao, et al., Evidence for linkage and association of the markers near the LPL gene with hypertension in Chinese families. J Med Genet, 2003.40(5): p. e57.
23. Williams, J.T. and J. Blangero, Comparison of variance components and sibpair-based approaches to quantitative trait linkage analysis in unselected samples. Genet Epidemiol, 1999. 16(2): p. 113-34.
24. Harrap, S.B., Where are all the blood-pressure genes? Lancet, 2003. 361: p. 2149-2151.
25. Xu, X., J.J. Rogus, H.A. Terwedow, et al., An extreme-sib-pair genome scan for genes regulating blood pressure. Am J Hum Genet, 1999.64(6): p. 1694-701.
26. Zhu, D.L., H.Y. Wang, M.M. Xiong, et al., Linkage of hypertension to chromosome 2q14-q23 in Chinese families. J Hypertens, 2001. 19(1): p. 55-61.
27. Ranade, K., D. Hinds, C.A. Hsiung, et al., A genome scan for hypertension susceptibility loci in populations of Chinese and Japanese origins. Am J Hypertens, 2003. 16(2): p. 158-62.
28. Gong, M., H. Zhang, H. Schulz, et al., Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p. Hum Mol Genet, 2003. 12(11): p. 1273-7.
29. Goring, H.H., J.D. Terwilliger, and J. Blangero, Large upward bias in estimation of locus-specific effects from genomewide scans. Am J Hum Genet, 2001.69(6): p. 1357-69.
30. Garcia, E.A., S. Newhouse, M.J. Caulfieid, and P.B. Munroe, Genes and hypertension. Curr Pharm Des, 2003.9(21): p. 1679-89.
31. Mein, C.A., M.J. Caulfield, R.J. Dobson, and P.B. Munroe, Genetics of essential hypertension. Hum Mol Genet, 2004. 13 Spec No 1: p. R169-75.
32. Angius, A., E. petretto, G.B. Maestrale, et al., A new essential hypertension susceptibility locus on chromosome 2p24-p25, detected by genomewide search. Am J Hum Genet, 2002. 71(4): p. 893-90:5.
33. Thiel, B.A., A Chakravarti, R.S. Cooper, et al., A genome-wide linkage analysis investigating the determinants of blood pressure in whites and African Americans. Am J Hypertens, 2003.16(2): p. 151-3.
34. Kardia, S.L., L.S. Rozek, J. Krushkal, et al., Genome-wide linkage analyses for hypertension genes in two ethnically and geographically diverse populations. Am J Hypertens, 2003.16(2): p. 154-7.
35. Rao, D.C., M.A. Province, M.E Leppert, et al., A genome-wide affected sibpair linkage analysis of hypertension: the HyperGEN network. Am J Hypertens, 2003.16(2): p. 148-50.
36. Multi-center genetic study of hypertension: The Family Blood Pressure Program (FBPP). Hypertension, 2002. 39(1): p. 3-9.
37. Li, J. and M. Burmeister, Genetical genomics: combining genetics with gene expression analysis. Hum Mol Genet, 2005.14 Spec No. 2: p. R163-9.
38. Hubner, N., C. Yagil, and Y. Yagil, Novel integrative approaches to the identification of candidate genes in hypertension. Hypertension, 2006. 47(1): p. 1-5.
39. Hubner, N., C.A. Wallace, H. Zimdahl, et al., Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat Genet, 2005.37(3): p. 243-53.
40. Yagil, C., N. Hubner, J. Monti, et al., Identification of hypertension-related genes through an integrated genomic-transcriptomic approach. Circ Res, 2005.96(6): p. 617-25.
41. Bell, J.T., C. Wallace, R. Dobson, et al., Two-dimensional genome-scan identifies novel epistatic loci for essential hypertension. Hum Mol Genet, 2006. 15(8): p. 1365-74.
42. Cordell, H.J., J.A. Todd, S.T. Bennett, Y. Kawaguchi, and M. Farrall, Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type 1 diabetes. Am J Hum Genet, 1995.57(4): p. 920-34.
43. Farrall, M., Affected sibpair linkage tests for multiple linked susceptibility genes. Genet Epidemiol, 1997. 14(2): p. 103-15.
1. He, J., et al., Major causes of death among men and women in China. N Engl J Med, 2005. 353(11): p. 1124-1134.
2. Chobanian, A.V., et al., The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. Jama, 2003. 289(19): p. 2560-72.
3. Stojiljkovic, M.P., et al., Hemodynamic effects of lipids in humans. Am J Physiol Regul Integr Comp Physiol, 2001. 280(6): p. R1674-9.
4. Lopes, H.E, et al., The pressor response to acute hyperlipidemia is enhanced in lean normotensive offspring of hypertensive parents. Am J Hypertens, 2001.14(10): p. 1032-7.
5. Wu, D.A., et al., Quantitative trait locus mapping of human blood pressure to a genetic region at or near the lipoprotein lipase gene locus on chromosome 8p22. J Clin Invest, 1996. 97(9): p. 2111-8.
6. Bhavani, A.B., et al., Lipid profile and apolipoprotein E polymorphism in essential hypertension. Indian Heart J, 2005.57(2): p. 151-7.
7. Nabel, E.G., Cardiovascular disease. N Engl J Med, 2003. 349(1): p. 60-72.
8. Rajput-Williams, J., et al., Variation of apolipoprotein-B gene is associated with obesity, high blood cholesterol levels, and increased risk of coronary heart disease. Lancet, 1988. 2(8626-8627): p. 1442-6.
9. Frossard, P.M., E.N. Obineche, and G.G. Lestringant, Association of an apolipoprotein B gene marker with essential hypertension. Hypertension, 1999.33(4): p. 1052-6.
10. Liljedahl, U., et al., Single nucleotide polymorphisms in the apolipoprotein B and low density lipoprotein receptor genes affect response to antihypertensive treatment. BMC Cardiovasc Disord, 2004. 4(1): p. 16.
11. Rantala, M., et al., Apolipoprotein B gene polymorphisms and serum lipids: meta-analysis of the role of genetic variation in responsiveness to diet. Am J Clin Nutr, 2000. 71(3): p. 713-24.
12. Turner, P.R., et al., DNA polymorphisms of the apoprotein B gene are associated with altered plasma lipoprotein concentrations but not with perceived risk of cardiovascular disease: European Atherosclerosis Research Study. Atherosclerosis, 1995.116(2): p. 221-34.
13. Korhonen, T., M.J. Savolainen, and Y.A. Kesaniemi, Variation of apolipoprotein B as a possible cause of decreased low density lipoprotein clearance and hypercholesterolemia. Atherosclerosis, 1999. 146(1): p. 1-10.
14. Boekholdt, S.M., et al., Molecular variation at the apolipoprotein B gene locus in relation to lipids and cardiovascular disease: a systematic meta-analysis. Hum Genet, 2003. 113(5): p. 417-25.
15. Chiodini, B.D., et al., APO B gene polymorphisms and coronary artery disease: a meta-analysis. Atherosclerosis, 2003.167(2): p. 355-66.
16. Bohn, M., et al., Xbal polymorphism in DNA at the apolipoprotein B locus is associated with myocardial infarction (MI). Clin Genet, 1993.44(5): p. 241-8.
17. Gu, D., et al., Prevalence, awareness, treatment, and control of hypertension in china. Hypertension, 2002.40(6): p. 920-7.
18. Joseph S, D.W., Isolation of high-molecular-weight DNA from mammalian cells using proteinase K and phenol. In: Joseph S, David WR, ed. Molecular cloning: a laboratory manual. 3rd ed., 2001:6.4-6.11.
19. Zhao, J.H., 2LD. GENECOUNTING and HAP: Computer programs for linkage disequilibrium analysis. Bioinformatics, 2004.20(8): p. 1325-6.
20. Schaid, D.J., et al., Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet, 2002.70(2): p. 425-34.
21. Hegele, R.A., et al., Apolipoprotein B-gene DNA polymorphisms associated with myocardial infarction. N Engl J Med, 1986. 315(24): p. 1509-15.
22. Higashimori, K., et al., Analysis of the apolipoprotein B3' hypervariable region in patients with essential hypertension. Clin Exp Pharmacol Physiol Suppl, 1992.20: p. 21-3.
23. Salazar, L.A., et al., Seven DNA polymorphisms at the candidate genes of atherosclerosis in Brazilian women with angiographically documented coronary artery disease. Clin Chim Acta, 2000. 300(1-2): p. 139-49.
24. Corbo, R.M., et al., Apolipoprotein B, apolipoprotein E, and angiotensin-converting enzyme polymorphisms in 2 Italian populations at different risk for coronary artery disease and comparison of allele frequencies among European populations. Hum Biol, 1999. 71(6): p. 933-45.
25. de Padua Mansur, A., et al., Angiotensin-converting enzyme and apolipoprotein B polymorphisms in coronary artery disease. Am J Cardiol, 2000.85(9): p. 1089-93.
26. Ye, P., B. Chen, and S. Wang, Association of polymorphisms of the apolipoprotein B gene with coronary heart disease in Han Chinese. Atherosclerosis, 1995. 117(1): p. 43-50.
27. Saha, N., J.S. Tay, and S.E. Humphries, Apolipoprotein B-gene DNA polymorphisms (Xbal and EcoRI), serum lipids, and apolipoproteins in healthy Chinese. Genet Epidemiol, 1992. 9(1): p. 1-10.
28. Hong, S.H., C.C. Lee, and J.Q. Kim, Genetic variation of the apolipoprotein B gene in Korean patients with coronary artery disease. Mol Cells, 1997.7(4): p. 521-5.
29. Heng, C.K., N. Saha, and P.S. Low, Evolution of the apolipoprotein B gene and coronary artery disease: a study in low and high risk Asians. Ann Hum Genet, 1999. 63 (Pt 1): p. 45-62.
30. Hong, S.H., J. Song, and J.Q. Kim, The haplotype analyses using multiple markers of the apolipoprotein B gene in patients with coronary artery disease. J Korean Med Sci, 2001. 16(6): p. 719-24.
31. Cardon, L.R. and J.I. Bell, Association study designs for complex diseases. Nat Rev Genet, 2001.2(2): p. 91-9.
32. Gu, D., et al., Prevalence of the metabolic syndrome and overweight among adults in China. Lancet, 2005.365(9468): p. 1398-405.
33. Crisan, D. and J. Carr, Angiotensin I-converting enzyme: genotype and disease associations. J Mol Diagn, 2000. 2(3): p. 105-15.
34. Aalto-Setala, K., et al., Genetic risk factors and ischaemic cerebrovascular disease: role of common variation of the genes encoding apolipoproteins and angiotensin-converting enzyme. Ann Med, 1998.30(2): p. 224-33.
35. The International HapMap Project. Nature, 2003.426(6968): p. 789-96.
1. Reddy, K.S., C.ardiovascular disease in non-Western countries. N Engl J Med, 2004. 350(24): p. 2438-40.
2. Kearney, P.M., M. Whelton, K. Reynolds, et al., Global burden of hypertension: analysis of worldwide data. Lancet, 2005.365(9455): p. 217-23.
3. Staessen, J.A., J. Wang, G. Bianchi, and W.H. Birkenhager, Essential hypertension. Lancet, 2003. 361(9369): p. 1629-41.
4. Evans, B.A., Z.X. Yun, J.A. Close, et al., Structure and chromosomal localization of the human renal kallikrein gene. Biochemistry, 1988.27(9): p. 3124-9.
5. Zhao, Y., Q. Qiu, F. Mahdi, et al., Assembly and activation of HK-PK complex on endothelial cells results in bradykinin liberation and NO formation. Am J Physiol Heart Circ Physiol, 2001. 280(4): p. H1821-9.
6. Busse, R. and I. Fleming, Molecular responses of endothelial tissue to kinins. Diabetes, 1996.45 Suppl 1: p. S8-13.
7. Mahabeer, R. and K.D. Bhoola, Kallikrein and kinin receptor genes. Pharmacol Ther, 2000. 88(1): p. 77-89.
8. Elliot, R.N., FR Urinary excretion of a depressor substance (kallikrein of Frey and Kraut) in arterial hypertension. Endocrinology, 1934. 18: p. 462-474.
9. Scicli, A.G. and O.A. Carretero, Renal kallikrein-kinin system. Kidney Int, 1986. 29(1): p. 120-30.
10. Margolius, H.S., Tissue kallikreins and kinins: regulation and roles in hypertensive and diabetic diseases. Annu Rev Pharmacol Toxicol, 1989. 29: p. 343-64.
11. Margolius, H.S., R. Geller, W. De Jong, J.J. Pisano, and A. Sjoerdsma, Altered urinary kallikrein excretion in rats with hypertension. Circ Res, 1972.30(3): p. 358-62.
12. Margolius, H.S., D. Horwitz, J.J. Pisano, and H.R. Keiser, Urinary kallikrein excretion in hypertensive man. Relationships to sodium intake and sodium-retaining steroids. Circ Res, 1974.35(6): p. 820-5.
13. Zinner, S.H., H.S. Margolius, B. Rosner, and E.H. Kass, Stability of blood pressure rank and urinary kallikrein concentration in childhood: an eight-year follow-up. Circulation, 1978.58(5): p. 908-15.
14. Berry, T.D., S.J. Hasstedt, S.C. Hunt, et al., A gene for high urinary kallikrein may protect against hypertension in Utah kindreds. Hypertension, 1989. 13(1): p. 3-8.
15. Iwai, N., N. Yasui, H. Naraba, et al., Klkl as One of the Genes Contributing to Hypertension in Dahl Salt-Sensitive Rat. Hypertension, 2005.
16. Wang, J., W. Xiong, Z. Yang, et al., Human tissue kallikrein induces hypotension in transgenic mice. Hypertension, 1994.23(2): p. 236-43.
17. Ma, J.X., Z. Yang, J. Chao, and L. Chao, Intramuscular delivery of rat kallikrein-binding protein gene reverses hypotension in transgenic mice expressing human tissue kallikrein. J Biol Chem, 1995. 270(1): p. 451-5.
18. Wang, C., L. Chao, and J. Chao, Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats. J Clin Invest, 1995.95(4): p. 1710-6.
19. Kruglyak, L. and D.A. Nickerson, Variation is the spice of life. Nat Genet, 2001. 27(3): p. 234-6.
20. Johnson, G.C., L. Esposito, B.J. Barratt, et al., Haplotype tagging for the identification of common disease genes. Nat Genet, 2001.29(2): p. 233-7.
21. Zhang, K., M. Deng, T. Chen, M.S. Waterman, and F. Sun, A dynamic programming algorithm for haplotype block partitioning. Proc NatlAcad Sci U S A, 2002.99(11): p. 7335-9.
22. Stram, D.O., C.A. Haiman, J.N. Hirschhorn, 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(1): p. 27-36.
23. Chapman, J.M., J.D. Cooper, J.A. Todd, and D.G. Clayton, Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Hum Hered, 2003.56(1-3): p. 18-31.
24. Schmidt, C.W., HapMap: building a database with blocks. EHP Toxicogenomics, 2003. 111(1T): p. A16.
25. de Bakker, P.I., R. Yelensky, I. Pe'er. et al., Efficiency and power in genetic association studies. Nat Genet, 2005.37(11): p. 1217-23.
26. Liu, T., J.A. Johnson, G.Casella, and R. Wu, Sequencing complex diseases With HapMap. Genetics, 2004. 168(1): p. 503-11.
27. Deloukas, P. and D. Bentley, The HapMap project and its application to genetic studies of drug response. Pharmacogenomics J,2004.4(2): p. 88-90.
28. Gu, D., K. Reynolds, X. Wu, et al., Prevalence, awareness, treatment, and control of hypertension in china. Hypertension, 2002.40(6): p. 920-7.
29. Perloff, D., C. Grim, J. Flack, et al., Human blood pressure determination by sphygmomanometry. Circulation, 1993.88(5 Pt 1): p. 2460-70.
30. Levy, D., A.L. DeStefano, M.G. Larson, et al., Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the framingham heart study. Hypertension, 2000. 36(4): p. 477-83.
31. Gu, D., D. Ge, J. He, et al., Haplotypic analyses of the aldosterone synthase gene CYP11B2 associated with stage-2 hypertension in northern Han Chinese. Clin Genet, 2004. 66(5): p. 409-16.
32. Ge, D., J. Huang, J. He, et al., beta2-Adrenergic receptor gene variations associated with stage-2 hypertension in northern Han Chinese. Ann Hum Genet, 2005.69(Pt 1): p. 36-44.
33. Schaid, D.J., C.M. Rowland, D.E. Tines, R.M. Jacobson, and G.A. Poland, Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet, 2002.70(2): p. 425-34.
34. Lake, S.L., H. Lyon, K. Tantisira, et al., Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered, 2003.55(1): p. 56-65.
35. Zhang, K., Z. Qin, T. Chen, et al., HapBlock: haplotype block partitioning and tag SNP selection software using a set of dynamic programming algorithms. Bioinformatics. 2005.21 (1): p. 131-4.
36. Hu, X., S.J. Schrodi, D.A. Ross, and M. Cargill, Selecting tagging SNPs for association studies using power calculations from genotype data. Hum Hered, 2004. 57(3): p. 156-70.
37. Byung Yong Kang, J.S.B.a.K.O.L., Genetic analysis of kallikrein-kinin system in the Korean hypertensives. Korean J Biol Sci, 2004. 8: p. 41-47.
38. Iwai, N., N. Tago, N. Yasui, et al., Genetic analysis of 22 candidate genes for hypertension in the Japanese population. J Hypertens, 2004. 22(6): p. 1119-26.
39. Slim, R., F. Torremocha, T. Moreau, et al., Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. J Am Soc Nephrol, 2002. 13(4): p. 968-76.
40. Berge, K.E., A. Bakken, M. Bohn, J. Erikssen, and K. Berg, Analyses of mutations in the human renal kallikrein (hKLK1) gene and their possible relevance to blood pressure regulation and risk of myocardial infarction. Clin Genet, 1997. 52(2): p. 86-95.
41. Chan, H., E.B. Springman, and J.M. Clark, Expression and characterization of human tissue kallikrein variants. Protein Expr Purif, 1998. 12(3): p. 361-70.
42. Iwai, N., S. Baba, T. Mannami, T. Ogihara, and J. Ogata, Association of a sodium channel alpha subunit promoter variant with blood pressure. J Am Soc Nephrol, 2002. 13(1): p. 80-5.
43. Integrating ethics and science in the International HapMap Project. Nat Rev Genet, 2004. 5(6): p. 467-75.
44. Consortium, T.I.H., The International HapMap Project. Nature, 2003. 426(6968): p. 789-96.
45. Cardon, L.R. and J.I. Bell, Association study designs for complex diseases. Nat Rev Genet, 2001. 2(2): p. 91-9.
46. Hattersley, A.T. and M.I. McCarthy, What makes a good genetic association study? Lancet, 2005. 366(9493): p. 1315-23.
47. Marchini, J., L.R. Cardon, M.S. Phillips, and P. Donnelly, The effects of human population structure on large genetic association studies. Nat Genet, 2004. 36(5): p. 512-7.
48. Song, Q., J. Chao, and L. Chao, DNA polymorphisms in the 5'-flanking region of the human tissue kallikrein gene. Hum Genet, 1997. 99(6): p. 727-34.
49. Yu, H., Q. Song, B.I. Freedman, et al., Association of the tissue kallikrein gene promoter with ESRD and hypertension. Kidney Int, 2002.61(3): p. 1030-9.
50. Hua, H., S. Zhou, Y. Liu, et al., Relationship between the regulatory region polymorphism of human tissue kallikrein gene and essential hypertension. J Hum Hypertens, 2005. 19(9): p. 715-21.
51. Berge, K.E. and K. Berg, A TaqI RFLP at the human renal kallikrein (KLK1) locus. Clin Genet, 1991.40(3): p. 256.
1. Ezzati, M., et al., Rethinking the "diseases of affluence" paradigm: global patterns of nutritional risks in relation to economic development. PLoS Med, 2005.2(5): p. e133.
2. Reddy, K.S., Cardiovascular disease in non-Western countries. N Engl J Med, 2004. 350(24): p. 2438-40.
3. Kearney, P.M., et al., Global burden of hypertension: analysis of worldwide data. Lancet, 2005.365(9455): p. 217-23.
4. Gu, D., et al., Prevalence, awareness, treatment, and control of hypertension in china. Hypertension, 2002.40(6): p. 920-7.
5. Whelton, P.K., J. He, and P.Muntner, Prevalence, awareness, treatment and control of hypertension in North America, North Africa and Asia. J Hum Hypertens, 2004. 15(8): p. 545-51.
6. Wolf-Maier, K., et al., Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension, 2004.43(1): p. 10-7.
7. Turnbull, E, Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet, 2003.362(9395): p. 1527-35.
8. Staessen, J.A., J.G. Wang, and L. Thijs, Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens, 2003.21(6): p. 1055-76.
9. Staessen, J.A., et al., Essential hypertension. Lancet, 2003. 361(9369): p. 1629-41.
10. Emanueli, C., et al., Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscler Thromb Vasc Biol, 2000. 20(11): p. 2379-85.
11. Cheung, B.M., et al., Association of essential hypertension with a microsatellite marker on chromosome 17. J Hum Hypertens, 2005.
12. Fong, D., D.I. Smith, and W.T. Hsieh, The human kininogen gene (KNG) mapped to chromosome 3q26-qter by analysis of somatic cell hybrids using the polymerase chain reaction. Hum Genet, 1991. 87(2): p. 189-92.
13. Kitamura, N., et al., Structural organization of the human kininogen gene and a model for its evolution. J Biol Chem, 1985. 260(14): p. 8610-7.
14. Guo, Y.L. and R.W. Colman, Two faces of high-molecular-weight kininogen (HK) in angiogenesis: bradykinin turns it on and cleaved HK (HKa) turns it off. J Thromb Haemost, 2005.3(4): p. 670-6.
15. Tayeh, M.A., S.T. Olson, and J.D. Shore, Surface-induced alterations in the kinetic pathway for cleavage of human high molecular weight kininogen by plasma kallikrein. J Biol Chem, 1994. 269(23): p. 16318-25.
16. Weisel, J.W., et al., The shape of high molecular weight kininogen. Organization into structural domains, changes with activation, and interactions with prekallikrein, as determined by electron microscopy. J Biol Chem, 1994. 269(13): p. 10100-6.
17. Colman, R.W. and A.H. Schmaier, Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood, 1997.90(10): p. 3819-43.
18. Abelous, J.B., E, Les substances hypotensives de l'urine humaine normale. Compt Rend Soc Biol, 1909. 66: p. 511-512.
19. Kraut H,F.E., Werle E, Der Nachweis eines Kreislaufhormon in de Pankreasdruse. Hoppe-Seylers Z Physiol Chem, 1930. 189: p. 97-106.
20. Werle, E., Zur Kenntnis des haushalts des Kallikreins. Biochem Z 1934. 269: p. 415-434.
21. Fiedler,F., Enzymology of glandular kallikreins. In: Erdos EG (ed) Bradykinin, Kallidin and Kallikrein. Springer-Verlag, Berlin,, 1979: p. 103-161
22. Movat, H., The plasma kallikrein-kinin system ad its interrelationship with other components of blood. In: Erdos EG (ed) Bradykinin, Kallidin and Kallikrein, Springer-Verlag, Berlin,, 1979: p. 1-89
23. Yu, H., et al., Identification of human plasma kallikrein gene polymorphisms and evaluation of their role in end-stage renal disease. Hypertension, 1998. 31(4): p. 906-11.
24. Asakai, R., E.W. Davie, and D.W. Chung, Organization of the gene for human factor Ⅺ. Biochemistry, 1987.26(23): p.7221-8.
25. Motta, G, et al., High molecular weight kininogen regulates prekallikrein assembly and activation on endothelial cells: a novel mechanism for contact activation. Blood, 1998. 91(2): p. 516-28.
26. Rojkjaer, R., et al., Factor XII does not initiate prekallikrein activation on endothelial cells. Thromb Haemost, 1998. 80(1): p. 74-81.
27. Mandle, R., Jr. and A.P. Kaplan, Hageman factor substrates. Human plasma prekallikrein: mechanism of activation by Hageman factor and participation in hageman factor-dependent fibrinolysis. J Biol Chem, 1977. 252(17): p. 6097-104.
28. Bhoola, K.D., C.D. Figueroa, and K. Worthy, Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev, 1992. 44(1): p. 1-80.
29. Diamandis, E.P., et al., The new human kallikrein gene family: implications in carcinogenesis. Trends Endocrinol Metab, 2000.11(2): p. 54-60.
30. Evans, B.A., et al., Structure and chromosomal localization of the human renal kallikrein gene. Biochemistry, 1988. 27(9): p. 3124-9.
31. Elliott, D.F., E.W. Horton, and GP. Lewis, Actions of pure bradykinin. J Physiol, 1960. 153: p. 473-80.
32. Boissonnas, R.A., et al., Synthesis and biological activity of peptides related to bradykinin. Experientia, 1960.16: p. 326.
33. Boissonnas, R.A., et al., The synthesis of bradykinin and of related peptides. Ann N Y Acad Sci, 1963.104: p. 5-14.
34. Zhao, Y., et al, Assembly and activation of HK-PK complex on endothelial cells results in bradykinin liberation and NO formation. Am J Physiol Heart Circ Physiol, 2001. 280(4): p. H1821-9.
35. Busse, R. and I. Fleming, Molecular responses of endothelial tissue to kinins. Diabetes, 1996. 45 Suppl 1: p. S8-13.
36. Mahabeer, R. and K.D. Bhoola, Kallikrein and kinin receptor genes. Pharmacol Ther, 2000. 88(1): p. 77-89.
37. Regoli, D. and J. Barabe, Pharmacology of bradykinin and related kinins. Pharmacol Rev, 1980. 32(1): p. 1-46.
38. Leeb-Lundberg, L.M., et al., International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev, 2005.57(1): p. 27-77.
39. Hall, J.M., Bradykinin receptors: pharmacological properties and biological roles. Pharmacol Ther, 1992.56(2): p. 131-90.
40. Dray, A., Kinins and their receptors in hyperalgesia. Can J Physiol Pharmacol, 1997. 75(6): p. 704-12.
41. Regoli, D., et al., Kinin receptor subtypes. J Cardiovasc Pharmacol, 1990. 15 Suppl 6: p. S30-8.
42. Ura, N., O.A. Carretero, and E.G. Erdos, Role of renal endopeptidase 24.11 in kinin metabolism in vitro and in vivo. Kidney Int, 1987.32(4): p. 507-13.
43. Erdos, E.G., Some old and some new ideas on kinin metabolism. J Cardiovasc Pharmacol, 1990. 15 Suppl 6: p. S20-4.
44. Sealey, J.E., S.A. Atlas, and J.H. Laragh, Linking the kallikrein and renin systems via activation of inactive renin: new data and a hypothesis. Am J Med, 1978.65(6): p. 994-1000.
45. Hasan, A.A., S. Amenta, and A.H. Schmaier, Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitors of alpha-thrombin-induced platelet activation. Circulation, 1996.94(3): p. 517-28.
46. Erdos, E.G. and P.A. Deddish, The kinin system: suggestions to broaden some prevailing concepts. Int Immunopharmacol, 2002.2(13-14): p. 1741-6.
47. Shariat-Madar, Z., F.Mahdi, and A.H. Schmaier, Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Biol Chem, 2002. 277(20): p. 17962-9.
48. Odya, C.E., et al., Purification and properties of prolylcarboxypeptidase (angiotensinase C)from human kidney. J Bioi Chem, 1978. 253(17): p. 5927-31.
49. Schmaier, A.H., The plasma kallikrein-kinin system counterbalances the renin-angiotensin system. J Clin Invest, 2002.109(8): p. 1007-9.
50. Hornig, B., C. Kohler, and H. Drexler, Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation, 1997. 95(5): p. 1115-8.
51. Fujita, N., et al., Inhibition of angiotensin-converting enzyme protects endothelial cell against hypoxia/reoxygenation injury. Biofactors, 2000. 11(4): p. 257-66.
52. Watanabe, T., T.A. Barker, and B.C. Berk, Angiotensin Ⅱ and the endothelium: diverse signals and effects. Hypertension, 2005.45(2): p. 163-9.
53. Elliot, R.N., FR Urinary excretion of a depressor substance (kallikrein of Frey and Kraut) in arterial hypertension. Endocrinology, 1934. 18: p. 462-474.
54. Scicli, A.G. and O.A. Carretero, Renal kallikrein-kinin system. Kidney Int, 1986. 29(1): p. 120-30.
55. Margolius, H.S., Tissue kallikreins and kinins: regulation and roles in hypertensive and diabetic diseases. Annu Rev Pharmacol Toxicol, 1989.29: p. 343-64.
56. Margolius, H.S., et al., Altered urinary kallikrein excretion in rats with hypertension. Circ Res, 1972.30(3): p. 358-62.
57. Margolius, H.S., et al., Urinary kallikrein excretion in hypertensive man. Relationships to sodium intake and sodium-retaining steroids. Circ Res, 1974.35(6): p. 820-5.
58. Zinner, S.H., et al., Stability of blood pressure rank and urinary kallikrein concentration in childhood: an eight-year follow-up. Circulation, 1978. 58(5): p. 908-15.
59. Berry, T.D., et al., A gene for high urinary kallikrein may protect against hypertension in Utah kindreds. Hypertension, 1989. 13(1): p. 3-8.
60. Iwai, N., et al., Klkl as One of the Genes Contributing to Hypertension in Dahl Salt-Sensitive Rat. Hypertension, 2005.
61. Phillips, M.I., Is gene therapy for hypertension possible? Hypertension, 1999. 33(1): p. 8-13.
62. Pachori, A.S., et al., The future of hypertension therapy: sense, antisense, or nonsense? Hypertension, 2001.37(2 Part 2): p. 357-64.
63. Raizada, M.K. and S. Der Sarkissian, Potential of gene therapy strategy for the treatment of hypertension. Hypertension, 2006.47(1): p. 6-9.
64. Wang, J., et al., Human tissue kallikrein induces hypotension in transgenic mice. Hypertension, 1994.23(2): p. 236-43.
65. Ma, J.X., et al., Intramuscular delivery of rat kallikrein-binding protein gene reverses hypotension in transgenic mice expressing human tissue kallikrein. J Biol Chem, 1995.270(1): p. 451-5.
66. Xiong, W., J. Chao, and L. Chao, Muscle delivery of human kallikrein gene reduces blood pressure in hypertensive rats. Hypertension, 1995.25(4 Pt 2): p. 715-9.
67. Wang, C., L. Chao, and J. Chao, Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats. J Clin Invest, 1995.95(4): p. 1710-6.
68. Dobrzynski, E., et al., Adenovirus-mediated kallikrein gene delivery attenuates hypertension and protects against renal injury in deoxycorticosterone-salt rats. Immunopharmacology, 1999.44(1-2): p. 57-65.
69. Emanueli, C., et al., Rescue of impaired angiogenesis in spontaneously hypertensive rats by intramuscular human tissue kallikrein gene transfer Hypertension, 2001. 38(1): p. 136-41.
70. Woodley-Miller, C., J. Chao, and L. Chao, Restriction fragment length polymorphisms mapped in spontaneously hypertensive rats using kallikrein probes. J Hypertens, 1989.7(11): p. 865-71.
71. Pravenec, M., et al., Cosegregation of blood pressure with a kallikrein gene family polymorphism. Hypertension, 1991.17(2): p. 242-6.
72. Berge, K.E. and K. Berg, A Taql RFLP at the human renal kallikrein (KLK1) locus. Clin Genet, 1991.40(3): p. 256.
73. Berge, K.E. and K. Berg, No effect of Taql polymorphism at the human renal kallikrein (KLK1) locus on normal blood pressure level or variability. Clin Genet, 1993.44(4): p. 196-202.
74. The International HapMap Project. Nature, 2003.426(6968): p. 789-96.
75. Venter, J.C., et al., The sequence of the human genome. Science, 2001. 291(5507): p. 1304-51.
76. Nelson, M.R., et al., Large-scale validation of single nucleotide polymorphisms in gene regions. Genome Res, 2004. 14(8): p. 1664-8.
77. Carlson, C.S., et al., Mapping complex disease loci in whole-genome association studies. Nature, 2004. 429(6990): p. 446-52.
78. Sachidanandam, R., et al., A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature, 2001. 409(6822): p. 928-33.
79. Hirakawa, M., et al., JSNP: a database of common gene variations in the Japanese population. Nucleic Acids Res, 2002.30(1): p. 158-62.
80. Song, Q., J. Chao, and L. Chao, DNA polymorphisms in the 5'-flanking region of the human tissue kallikrein gene. Hum Genet, 1997.99(6): p. 727-34.
81. Yu, H., et al., Association of the tissue kallikrein gene promoter with ESRD and hypertension. Kidney Int, 2002.61(3): p. 1030-9.
82. Slim, R., et al., Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. J Am Soc Nephrol, 2002. 13(4): p. 968-76.
83. Hua, H., et al., Relationship between the regulatory region polymorphism of human tissue kallikrein gene and essential hypertension. J Hum Hypertens, 2005. 19(9): p. 715-21.
84. Berge, K.E., et al., Analyses of mutations in the human renal kallikrein (hKLK1) gene and their possible relevance to blood pressure regulation and risk of myocardial infarction. Clin Genet, 1997.52(2): p. 86-95.
85. Azizi, M., et al., Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans. J Clin Invest, 2005. 115(3): p. 780-7.
86. Chan, H., E.B. Springman, and J.M. Clark, Expression and characterization of human tissue kallikrein variants. Protein Expr Purif, 1998.12(3): p. 361-70.
87. Mannami, T., et al., Prevalence of asymptomatic carotid atherosclerotic lesions detected by high-resolution ultrasonography and its relation to cardiovascular risk factors in the general population of a Japanese city: the Suita study. Stroke, 1997. 28(3): p. 518-25.
88. Iwai, N., et al., Association of a sodium channel alpha subunit promoter variant with blood pressure. J Am Soc Nephrol, 2002.13(1): p. 80-5.
89. Iwai, N., et al., Genetic analysis of 22 candidate genes for hypertension in the Japanese population. J Hypertens, 2004.22(6): p. 1119-26.
90. Byung Yong Kang, J.S.B.a.K.O.L., Genetic analysis of kallikrein-kinin system in the Korean hypertensives. Korean J Biol Sci, 2004.8: p. 41-47.
91. Integrating ethics and science in the International HapMap Project. Nat Rev Genet, 2004.5(6): p. 467-75.
92. Schmidt, C.W., HapMap: building a database with blocks. EHP Toxicogenomics, 2003. 111(1T): p. A16.
93. de Bakker, P.I., et al., Efficiency and power in genetic association studies. Nat Genet, 2005.37(11): p. 1217-23.
94. Liu, T., et al., Sequencing complex diseases With HapMap. Genetics, 2004. 168(1): p. 503-11.
95. Deloukas, P. and D. Bentley, The HapMap project and its application to genetic studies of drug response. Pharmacogenomics J, 2004.4(2): p. 88-90.
96. Altshuler, D., et al., A haplotype map of the human genome. Nature, 2005.437(7063): p. 1299-320.
97. Iles, M.M., The Effect of SNP Marker Density on the Efficacy of Haplotype Tagging SNPs-α Warning. Ann Hum Genet, 2005. 69(Pt 2): p. 209-15.
98. Agarwal, A., G.H. Williams, and N.D. Fisher, Genetics of human hypertension. Trends Endocrinol Metab, 2005.16(3): p. 127-33.
99. Saavedra, J.M., Studies on genes and hypertension: a daunting task. J Hypertens, 2005.23(5): p. 929-32.
100. Smith, G.D. and S. Ebrahim, Mendelian randomization: prospects, potentials, and limitations.Int J Epidemiol, 2004.33(1): p. 30-42.
101. Davey Smith, G., et al., Genetic epidemiology and public health: hope, hype, and future prospects. Lancet, 2005.366(9495): p. 1484-98.
102. Boerwinkle, E., All for one and one for all: introduction to a coordinated analysis of the Gly-460-Trp alpha-adducin polymorphism. Am J Hypertens, 2000. 13(6 Pt 1): p. 734-5.