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Vol. 60, No. 3, 2005
Issue release date: 2005
Hum Hered 2005;60:164–176
(DOI:10.1159/000090118)

Haplotype Association Analysis of AGT Variants with Hypertension-Related Traits: The HyperGEN Study

Gu C.C.a · Chang Y.-P.C.e · Hunt S.C.d · Schwander K.a · Arnett D.f · Djousse L.g · Heiss G.h · Oberman A.i · Lalouel J.-M.d · Province M.a, b · Chakravarti A.e · Rao D.C.a, b, c
aDivision of Biostatistics, and Departments of bGenetics and cPsychiatry, Washington University School of Medicine, St. Louis, Mo.; dUniversity of Utah School of Medicine, Salt Lake City, Utah; eInstitute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.; fUniversity of Minnesota and Department of Epidemiology, Minneapolis, Minn.; gEvans Department of Medicine, Section of Preventive Medicine & Epidemiology, Boston University, Boston, Mass.; hUniversity of North Carolina, Department of Epidemiology and UNC-CH School of Public Health, Chapel Hill, N.C.; iUAB, Division of Preventive Medicine, Birmingham, Ala., USA
email Corresponding Author

Abstract

Objective: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. Methods: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. Results: In Blacks, two SNPs in exon 5 and 3′UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p =0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p = 0.009) and gripSBP emerged in Whites. Conclusion: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.


 goto top of outline Key Words

  • Hypertension
  • Intermediate phenotype
  • Blood pressure reactivity
  • BMI
  • Haplotype analysis
  • AGT
  • Genetic interaction

 goto top of outline Abstract

Objective: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. Methods: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. Results: In Blacks, two SNPs in exon 5 and 3′UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p =0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p = 0.009) and gripSBP emerged in Whites. Conclusion: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.

Copyright © 2005 S. Karger AG, Basel


 goto top of outline References
  1. Abecasis GR, Cookson WO: GOLD – graphical overview of linkage disequilibrium. Bioinformatics 2000;16:182–183.
  2. 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.
  3. Atwood LD, Kammerer CM, Samollow PB, Hixson JE, Shade RE, MacCluer JW: Linkage of essential hypertension to the angiotensinogen locus in Mexican Americans. Hypertension 1997;30:326–330.
  4. Bacanu SA, Devlin B, Roeder K: The power of genomic control. Am J Hum Genet 2000;66:1933–1944.
  5. Bloem LJ, Manatunga AK, Tewksbury DA, Pratt JH: The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. J Clin Invest 1995;95:948–953.
  6. Borecki IB, Province MA, Ludwig EH, Ellison RC, Folsom AR, Heiss G, Lalouel JM, Higgins M, Rao DC: Associations of candidate loci angiotensinogen and angiotensin-converting enzyme with severe hypertension: The NHLBI Family Heart Study. Ann Epidemiol 1997;7:13–21.
  7. Caulfield M, Lavender P, Farrall M, Munroe P, Lawson M, Turner P, Clark AJ: Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med 1994;330:1629–1633.
  8. 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.
  9. Chen X, Levine L, Kwok PY: Fluorescence polarization in homogeneous nucleic acid analysis. Genome Res 1999;9:492–498.
  10. Devlin B, Roeder K, Bacanu SA: Unbiased methods for population-based association studies. Genet Epidemiol 2001;21:273–284.
  11. DeWan AT, Arnett DK, Atwood LD, Province MA, Lewis CE, Hunt SC, Eckfeldt J: A genome scan for renal function among hypertensives: The HyperGEN study. Am J Hum Genet 2001;68:136–144.
  12. DINAMAP: Adult/Pediatric, and Neonatal Vital Signs Monitor: Models 1846 SX and 1846 SX/P Operations Manual. Critikon Corp, Tampa, 1988.
  13. Dyer AR, Elliott P: The INTERSALT study: relations of body mass index to blood pressure. INTERSALT Co-operative Research Group. J Hum Hypertens 1989;3:299–308.
  14. Fornage M, Turner ST, Sing CF, Boerwinkle E: Variation at the M235T locus of the angiotensinogen gene and essential hypertension: A population-based case-control study from Rochester, Minnesota. Hum Genet 1995;96:295–300.
  15. Frossard PM, Hill SH, Elshahat YI, Obineche EN, Bokhari AM, Lestringant GG, John A, Abdulle AM: Associations of angiotensinogen gene mutations with hypertension and myocardial infarction in a gulf population. Clin Genet 1998;54:285–293.
  16. Gaillard I, Clauser E, Corvol P: Structure of human angiotensinogen gene. DNA 1989;8:87–99.
  17. Hata A, Namikawa C, Sasaki M, Sato K, Nakamura T, Tamura K, Lalouel JM: Angiotensinogen as a risk factor for essential hypertension in Japan. J Clin Invest 1994;93:1285–1287.
  18. Hegele RA, Brunt JH, Connelly PW: Genetic and biochemical factors associated with variation in blood pressure in a genetic isolate. Hypertension 1996;27:308–312.
  19. Hubert HB, Feinleib M, McNamara PM, Castelli WP: Obesity as an independent risk factor for cardiovascular disease: A 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968–977.
  20. Inoue I, Nakajima T, Williams CS, Quackenbush J, Puryear R, Powers M, Cheng T, Ludwig EH, Sharma AM, Hata A, Jeunemaitre X, Lalouel JM: A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest 1997;99:1786–1797.
  21. Ishigami T, Umemura S, Tamura K, Hibi K, Nyui N, Kihara M, Yabana M, Watanabe Y, Sumida Y, Nagahara T, Ochiai H, Ishii M: Essential hypertension and 5′ upstream core promoter region of human angiotensinogen gene. Hypertension 1997;30:1325–1330.
  22. Iso H, Harada S, Shimamoto T, Sato S, Kitamura A, Sankai T, Tanigawa T, Iida M, Komachi Y: Angiotensinogen T174M and M235T variants, sodium intake and hypertension among non-drinking, lean Japanese men and women. J Hypertens 2000;18:1197–1206.
  23. Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM, et al: Molecular basis of human hypertension: role of angiotensinogen. Cell 1992;71:169–180.
  24. Kishimoto T, Suyama A, Igarashi A, Osaki Y, Okamoto M, Yamamoto T, Nanba E, Kurosawa Y, Fukumoto S: Angiotensinogen gene variation and hypertension in a cohort study in Japanese. J Epidemiol 2001;11:115–119.
  25. Kohonen T: Self-Organizing Maps. Springer, Berlin, 1995.
  26. Lander ES, Schork NJ: Genetic dissection of complex traits. Science 1994;265;2037–2048.
  27. Lewontin RC, Kojima K: The evolutionary dynamics of complex polymorphisms. Evolution 1960;14;450–472.
  28. MacMahon S, Cutler J, Brittain E, Higgins M: Obesity and hypertension: epidemiological and clinical issues. Eur Heart J 1987;8(suppl B):57–70.

    External Resources

  29. Martinez E, Puras A, Escribano J, Sanchis C, Carrion L, Artigao M, Divison JA, Masso J, Fernandez JA: Threonines at position 174 and 235 of the angiotensinogen polypeptide chain are related to familial history of hypertension in a Spanish-Mediterranean population. Br J Biomed Sci 2002;59:95–100.
  30. Matthews KA, Woodall KL, Allen MT: Cardiovascular reactivity to stress predicts future blood pressure status. Hypertension 1993;22:479–485.
  31. Nakajima T, Jorde LB, Ishigami T, Umemura S, Emi M, Lalouel JM, Inoue I: Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations. Am J Hum Genet 2002;70:108–123.
  32. Niu T, Chen C, Yang J, Wang B, Wang Z, Schork N, Fang Z, Xu X: Blood pressure and the T174M and M235T polymorphisms of the angiotensinogen gene. Ann Epidemiol 1999;9:245–253.
  33. Patterson N, Hattangadi N, Lane B, Lohmueller KE, Hafler DA, Oksenberg JR, Hauser SL, Smith MW, O’Brien SJ, Altshuler D, Daly MJ, Reich D: Methods for high-density admixture mapping of disease genes. Am J Hum Genet 2004;74:979–1000.
  34. Phillips MS, Lawrence R, Sachidanandam R, Morris AP, Balding DJ, Donaldson MA, Studebaker JF, Ankener WM, Alfisi SV, Kuo FS, Camisa AL, Pazorov V, Scott KE, Carey BJ, Faith J, Katari G, Bhatti HA, Cyr JM, Derohannessian V, Elosua C, Forman AM, Grecco NM, Hock CR, Kuebler JM, Lathrop JA, Mockler MA, Nachtman EP, Restine SL, Varde SA, Hozza MJ, Gelfand CA, Broxholme J, Abecasis GR, Boyce-Jacino MT, Cardon LR: Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots. Nat Genet 2003;33:382–387.
  35. Posada D, Maxwell TJ, Templeton AR: TreeScan: A bioinformatic application to search for genotype/phenotype associations using haplotype trees. Bioinformatics 2005;21:2130–2132.
  36. Pritchard JK, Stephens M, Donnelly P: Inference of population structure using multilocus genotype data. Genetics 2000;155:945–959.
  37. Province MA, Boerwinkle E, Chakravarti A, Cooper R, Fornage M, Leppert M, Risch N, Ranade K: Lack of association of the angiotensinogen-6 polymorphism with blood pressure levels in the comprehensive NHLBI Family Blood Pressure Program. National Heart, Lung and Blood Institute. J Hypertens 2000;18:867–876.
  38. Rankinen T, Gagnon J, Perusse L, Chagnon YC, Rice T, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C: AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study. Am J Physiol Heart Circ Physiol 2000;279:H368–H374.
  39. Rice T, Rankinen T, Province MA, Chagnon YC, Perusse L, Borecki IB, Bouchard C, Rao DC: Genome-wide linkage analysis of systolic and diastolic blood pressure: The Quebec Family Study. Circulation 2000;102:1956–1963.
  40. Rotimi C, Morrison L, Cooper R, Oyejide C, Effiong E, Ladipo M, Osotemihen B, Ward R: Angiotensinogen gene in human hypertension. Lack of an association of the 235T allele among African Americans. Hypertension 1994;24:591–594.
  41. Sethi AA, Nordestgaard BG, Agerholm-Larsen B, Frandsen E, Jensen G, Tybjaerg-Hansen A: Angiotensinogen polymorphisms and elevated blood pressure in the general population: the Copenhagen City Heart Study. Hypertension 2001;37:875–881.
  42. Sethi AA, Nordestgaard BG, Gronholdt ML, Steffensen R, Jensen G, Tybjaerg-Hansen A: Angiotensinogen single nucleotide polymorphisms, elevated blood pressure, and risk of cardiovascular disease. Hypertension 2003;41:1202–1211.
  43. Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A: Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease: A meta-analysis. Arterioscler Thromb Vasc Biol 2003;23:1269–1275.
  44. Slatkin M, Excoffier L: Testing for linkage disequilibrium in genotypic data using the Expectation-Maximization algorithm. Heredity 1996;76(Pt 4):377–383.
  45. Stamler R, Stamler J, Riedlinger WF, Algera G, Roberts RH: Weight and blood pressure. Findings in hypertension screening of 1 million Americans. JAMA 1978;240:1607–1610.
  46. Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003;73:1162–1169.
  47. Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001;68:978–989.
  48. Tamayo P, Slonim D, Mesirov J, Zhu Q, Kitareewan S, Dmitrovsky E, Lander ES, Golub TR: Interpreting patterns of gene expression with self-organizing maps: Methods and application to hematopoietic differentiation. Proc Natl Acad Sci USA 1999;96:2907–2912.
  49. Tang H, Quertermous T, Rodriguez B, Kardia SL, Zhu X, Brown A, Pankow JS, Province MA, Hunt SC, Boerwinkle E, Schork NJ, Risch NJ: Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies·Am J Hum Genet 2005;76:268–275.
  50. Templeton AR, Maxwell T, Posada D, Stengard JH, Boerwinkle E, Sing CF: Tree scanning: A method for using haplotype trees in phenotype/genotype association studies. Genetics 2005;169:441–453.
  51. Thomas DC, Witte JS: Point: Population stratification: A problem for case-control studies of candidate-gene associations? Cancer Epidemiol Biomarkers Prev 2002;11:505–512.
  52. Wacholder S, Rothman N, Caporaso N: Counterpoint: Bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiol Biomarkers Prev 2002;11:513–520.
  53. Wang WY, Glenn CL, Zhang W, Benjafield AV, Nyholt DR, Morris BJ: Exclusion of angiotensinogen gene in molecular basis of human hypertension: Sibpair linkage and association analyses in Australian anglo-caucasians. Am J Med Genet 1999;87:53–60.
  54. Williams RR, Rao DC, Ellison RC, Arnett DK, Heiss G, Oberman A, Eckfeldt JH, Leppert MF, Province MA, Mockrin SC, Hunt SC: NHLBI family blood pressure program: methodology and recruitment in the HyperGEN network. Hypertension genetic epidemiology network. Ann Epidemiol 2000;10:389–400.
  55. Zhang K, Jin L: HaploBlockFinder: haplotype block analyses. Bioinformatics 2003;19:1300–1301.
  56. Zhu X, Yan D, Cooper RS, Luke A, Ikeda MA, Chang Y-PC, Weder A, Chakravarti A: Linkage Disequilibrium and Haplotype Diversity in the Genes of the Renin-Angiotensin System: Findings From the Family Blood Pressure Program. Genome Res. 2003;13:173–181.

 goto top of outline Author Contacts

Dr. C. Charles Gu
Division of Biostatistics, Washington University School of Medicine
Campus Box 8067, 660 S. Euclid Avenue
St. Louis, MO 63110 (USA)
Tel. +1 314 362 3642, Fax +1 314 362 2693, E-Mail gc@wubios.wustl.edu


 goto top of outline Article Information

Received: February 14, 2005
Accepted: September 19, 2005
Published online: December 12, 2005
Number of Print Pages : 13
Number of Figures : 5, Number of Tables : 5, Number of References : 56


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 60, No. 3, Year 2005 (Cover Date: 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objective: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. Methods: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. Results: In Blacks, two SNPs in exon 5 and 3′UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p =0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p = 0.009) and gripSBP emerged in Whites. Conclusion: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.



 goto top of outline Author Contacts

Dr. C. Charles Gu
Division of Biostatistics, Washington University School of Medicine
Campus Box 8067, 660 S. Euclid Avenue
St. Louis, MO 63110 (USA)
Tel. +1 314 362 3642, Fax +1 314 362 2693, E-Mail gc@wubios.wustl.edu


 goto top of outline Article Information

Received: February 14, 2005
Accepted: September 19, 2005
Published online: December 12, 2005
Number of Print Pages : 13
Number of Figures : 5, Number of Tables : 5, Number of References : 56


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 60, No. 3, Year 2005 (Cover Date: 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Abecasis GR, Cookson WO: GOLD – graphical overview of linkage disequilibrium. Bioinformatics 2000;16:182–183.
  2. 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.
  3. Atwood LD, Kammerer CM, Samollow PB, Hixson JE, Shade RE, MacCluer JW: Linkage of essential hypertension to the angiotensinogen locus in Mexican Americans. Hypertension 1997;30:326–330.
  4. Bacanu SA, Devlin B, Roeder K: The power of genomic control. Am J Hum Genet 2000;66:1933–1944.
  5. Bloem LJ, Manatunga AK, Tewksbury DA, Pratt JH: The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. J Clin Invest 1995;95:948–953.
  6. Borecki IB, Province MA, Ludwig EH, Ellison RC, Folsom AR, Heiss G, Lalouel JM, Higgins M, Rao DC: Associations of candidate loci angiotensinogen and angiotensin-converting enzyme with severe hypertension: The NHLBI Family Heart Study. Ann Epidemiol 1997;7:13–21.
  7. Caulfield M, Lavender P, Farrall M, Munroe P, Lawson M, Turner P, Clark AJ: Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med 1994;330:1629–1633.
  8. 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.
  9. Chen X, Levine L, Kwok PY: Fluorescence polarization in homogeneous nucleic acid analysis. Genome Res 1999;9:492–498.
  10. Devlin B, Roeder K, Bacanu SA: Unbiased methods for population-based association studies. Genet Epidemiol 2001;21:273–284.
  11. DeWan AT, Arnett DK, Atwood LD, Province MA, Lewis CE, Hunt SC, Eckfeldt J: A genome scan for renal function among hypertensives: The HyperGEN study. Am J Hum Genet 2001;68:136–144.
  12. DINAMAP: Adult/Pediatric, and Neonatal Vital Signs Monitor: Models 1846 SX and 1846 SX/P Operations Manual. Critikon Corp, Tampa, 1988.
  13. Dyer AR, Elliott P: The INTERSALT study: relations of body mass index to blood pressure. INTERSALT Co-operative Research Group. J Hum Hypertens 1989;3:299–308.
  14. Fornage M, Turner ST, Sing CF, Boerwinkle E: Variation at the M235T locus of the angiotensinogen gene and essential hypertension: A population-based case-control study from Rochester, Minnesota. Hum Genet 1995;96:295–300.
  15. Frossard PM, Hill SH, Elshahat YI, Obineche EN, Bokhari AM, Lestringant GG, John A, Abdulle AM: Associations of angiotensinogen gene mutations with hypertension and myocardial infarction in a gulf population. Clin Genet 1998;54:285–293.
  16. Gaillard I, Clauser E, Corvol P: Structure of human angiotensinogen gene. DNA 1989;8:87–99.
  17. Hata A, Namikawa C, Sasaki M, Sato K, Nakamura T, Tamura K, Lalouel JM: Angiotensinogen as a risk factor for essential hypertension in Japan. J Clin Invest 1994;93:1285–1287.
  18. Hegele RA, Brunt JH, Connelly PW: Genetic and biochemical factors associated with variation in blood pressure in a genetic isolate. Hypertension 1996;27:308–312.
  19. Hubert HB, Feinleib M, McNamara PM, Castelli WP: Obesity as an independent risk factor for cardiovascular disease: A 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968–977.
  20. Inoue I, Nakajima T, Williams CS, Quackenbush J, Puryear R, Powers M, Cheng T, Ludwig EH, Sharma AM, Hata A, Jeunemaitre X, Lalouel JM: A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest 1997;99:1786–1797.
  21. Ishigami T, Umemura S, Tamura K, Hibi K, Nyui N, Kihara M, Yabana M, Watanabe Y, Sumida Y, Nagahara T, Ochiai H, Ishii M: Essential hypertension and 5′ upstream core promoter region of human angiotensinogen gene. Hypertension 1997;30:1325–1330.
  22. Iso H, Harada S, Shimamoto T, Sato S, Kitamura A, Sankai T, Tanigawa T, Iida M, Komachi Y: Angiotensinogen T174M and M235T variants, sodium intake and hypertension among non-drinking, lean Japanese men and women. J Hypertens 2000;18:1197–1206.
  23. Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM, et al: Molecular basis of human hypertension: role of angiotensinogen. Cell 1992;71:169–180.
  24. Kishimoto T, Suyama A, Igarashi A, Osaki Y, Okamoto M, Yamamoto T, Nanba E, Kurosawa Y, Fukumoto S: Angiotensinogen gene variation and hypertension in a cohort study in Japanese. J Epidemiol 2001;11:115–119.
  25. Kohonen T: Self-Organizing Maps. Springer, Berlin, 1995.
  26. Lander ES, Schork NJ: Genetic dissection of complex traits. Science 1994;265;2037–2048.
  27. Lewontin RC, Kojima K: The evolutionary dynamics of complex polymorphisms. Evolution 1960;14;450–472.
  28. MacMahon S, Cutler J, Brittain E, Higgins M: Obesity and hypertension: epidemiological and clinical issues. Eur Heart J 1987;8(suppl B):57–70.

    External Resources

  29. Martinez E, Puras A, Escribano J, Sanchis C, Carrion L, Artigao M, Divison JA, Masso J, Fernandez JA: Threonines at position 174 and 235 of the angiotensinogen polypeptide chain are related to familial history of hypertension in a Spanish-Mediterranean population. Br J Biomed Sci 2002;59:95–100.
  30. Matthews KA, Woodall KL, Allen MT: Cardiovascular reactivity to stress predicts future blood pressure status. Hypertension 1993;22:479–485.
  31. Nakajima T, Jorde LB, Ishigami T, Umemura S, Emi M, Lalouel JM, Inoue I: Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations. Am J Hum Genet 2002;70:108–123.
  32. Niu T, Chen C, Yang J, Wang B, Wang Z, Schork N, Fang Z, Xu X: Blood pressure and the T174M and M235T polymorphisms of the angiotensinogen gene. Ann Epidemiol 1999;9:245–253.
  33. Patterson N, Hattangadi N, Lane B, Lohmueller KE, Hafler DA, Oksenberg JR, Hauser SL, Smith MW, O’Brien SJ, Altshuler D, Daly MJ, Reich D: Methods for high-density admixture mapping of disease genes. Am J Hum Genet 2004;74:979–1000.
  34. Phillips MS, Lawrence R, Sachidanandam R, Morris AP, Balding DJ, Donaldson MA, Studebaker JF, Ankener WM, Alfisi SV, Kuo FS, Camisa AL, Pazorov V, Scott KE, Carey BJ, Faith J, Katari G, Bhatti HA, Cyr JM, Derohannessian V, Elosua C, Forman AM, Grecco NM, Hock CR, Kuebler JM, Lathrop JA, Mockler MA, Nachtman EP, Restine SL, Varde SA, Hozza MJ, Gelfand CA, Broxholme J, Abecasis GR, Boyce-Jacino MT, Cardon LR: Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots. Nat Genet 2003;33:382–387.
  35. Posada D, Maxwell TJ, Templeton AR: TreeScan: A bioinformatic application to search for genotype/phenotype associations using haplotype trees. Bioinformatics 2005;21:2130–2132.
  36. Pritchard JK, Stephens M, Donnelly P: Inference of population structure using multilocus genotype data. Genetics 2000;155:945–959.
  37. Province MA, Boerwinkle E, Chakravarti A, Cooper R, Fornage M, Leppert M, Risch N, Ranade K: Lack of association of the angiotensinogen-6 polymorphism with blood pressure levels in the comprehensive NHLBI Family Blood Pressure Program. National Heart, Lung and Blood Institute. J Hypertens 2000;18:867–876.
  38. Rankinen T, Gagnon J, Perusse L, Chagnon YC, Rice T, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C: AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study. Am J Physiol Heart Circ Physiol 2000;279:H368–H374.
  39. Rice T, Rankinen T, Province MA, Chagnon YC, Perusse L, Borecki IB, Bouchard C, Rao DC: Genome-wide linkage analysis of systolic and diastolic blood pressure: The Quebec Family Study. Circulation 2000;102:1956–1963.
  40. Rotimi C, Morrison L, Cooper R, Oyejide C, Effiong E, Ladipo M, Osotemihen B, Ward R: Angiotensinogen gene in human hypertension. Lack of an association of the 235T allele among African Americans. Hypertension 1994;24:591–594.
  41. Sethi AA, Nordestgaard BG, Agerholm-Larsen B, Frandsen E, Jensen G, Tybjaerg-Hansen A: Angiotensinogen polymorphisms and elevated blood pressure in the general population: the Copenhagen City Heart Study. Hypertension 2001;37:875–881.
  42. Sethi AA, Nordestgaard BG, Gronholdt ML, Steffensen R, Jensen G, Tybjaerg-Hansen A: Angiotensinogen single nucleotide polymorphisms, elevated blood pressure, and risk of cardiovascular disease. Hypertension 2003;41:1202–1211.
  43. Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A: Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease: A meta-analysis. Arterioscler Thromb Vasc Biol 2003;23:1269–1275.
  44. Slatkin M, Excoffier L: Testing for linkage disequilibrium in genotypic data using the Expectation-Maximization algorithm. Heredity 1996;76(Pt 4):377–383.
  45. Stamler R, Stamler J, Riedlinger WF, Algera G, Roberts RH: Weight and blood pressure. Findings in hypertension screening of 1 million Americans. JAMA 1978;240:1607–1610.
  46. Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003;73:1162–1169.
  47. Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001;68:978–989.
  48. Tamayo P, Slonim D, Mesirov J, Zhu Q, Kitareewan S, Dmitrovsky E, Lander ES, Golub TR: Interpreting patterns of gene expression with self-organizing maps: Methods and application to hematopoietic differentiation. Proc Natl Acad Sci USA 1999;96:2907–2912.
  49. Tang H, Quertermous T, Rodriguez B, Kardia SL, Zhu X, Brown A, Pankow JS, Province MA, Hunt SC, Boerwinkle E, Schork NJ, Risch NJ: Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies·Am J Hum Genet 2005;76:268–275.
  50. Templeton AR, Maxwell T, Posada D, Stengard JH, Boerwinkle E, Sing CF: Tree scanning: A method for using haplotype trees in phenotype/genotype association studies. Genetics 2005;169:441–453.
  51. Thomas DC, Witte JS: Point: Population stratification: A problem for case-control studies of candidate-gene associations? Cancer Epidemiol Biomarkers Prev 2002;11:505–512.
  52. Wacholder S, Rothman N, Caporaso N: Counterpoint: Bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiol Biomarkers Prev 2002;11:513–520.
  53. Wang WY, Glenn CL, Zhang W, Benjafield AV, Nyholt DR, Morris BJ: Exclusion of angiotensinogen gene in molecular basis of human hypertension: Sibpair linkage and association analyses in Australian anglo-caucasians. Am J Med Genet 1999;87:53–60.
  54. Williams RR, Rao DC, Ellison RC, Arnett DK, Heiss G, Oberman A, Eckfeldt JH, Leppert MF, Province MA, Mockrin SC, Hunt SC: NHLBI family blood pressure program: methodology and recruitment in the HyperGEN network. Hypertension genetic epidemiology network. Ann Epidemiol 2000;10:389–400.
  55. Zhang K, Jin L: HaploBlockFinder: haplotype block analyses. Bioinformatics 2003;19:1300–1301.
  56. Zhu X, Yan D, Cooper RS, Luke A, Ikeda MA, Chang Y-PC, Weder A, Chakravarti A: Linkage Disequilibrium and Haplotype Diversity in the Genes of the Renin-Angiotensin System: Findings From the Family Blood Pressure Program. Genome Res. 2003;13:173–181.