Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Pharmacogenetic approaches to hypertension therapy: design and rationale for the Genetics of Hypertension Associated Treatment (GenHAT) study

The Pharmacogenomics Journal volume 2, pages 309–317 (2002)Cite this article

Abstract

The Genetics of Hypertension Associated Treatment (GenHAT) study will determine whether variants in hypertension susceptibility genes interact with antihypertensive medication to modify coronary heart disease (CHD) risk in hypertensives. GenHAT is an ancillary study of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial, ALLHAT, a double-blind, randomized trial of 42 418 hypertensives, 55 years of age or older, with systolic or diastolic hypertension and one or more risk factors for cardiovascular disease. About 50% are non-white, and about half are female. ALLHAT completes follow-up in March 2002. GenHAT is typing variants in hypertension genes; completion of genotyping is scheduled for 2003. Analysis of gene–treatment interactions in relation to outcomes include CHD, stroke, heart failure, and blood pressure lowering. To our knowledge, GenHAT is the largest pharmacogenetic study ever conducted. An added strength is its ability to link gene–treatment interactions with important clinical outcomes across diverse ethnic and gender groups.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Ferrari P, Bianchi G . Genetic mapping and tailored antihypertensive therapy Cardiovasc Drugs Ther 2000 14: 387–395

    Article  CAS  Google Scholar 

  2. O'Byrne S, Caulfield M . Genetics of hypertension. Therapeutic implications Drugs 1998 56: 203–214

    Article  CAS  Google Scholar 

  3. Pratt RE, Dzau VJ . Genomics and hypertension: concepts, potentials, and opportunities Hypertension 1999 33: 238–247

    Article  CAS  Google Scholar 

  4. Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M et al . Polymorphisms of α-adducin and salt sensitivity in patients with essential hypertension Lancet 1997 349: 1353–1357

    Article  CAS  Google Scholar 

  5. ALLHAT Collaborative Research Group. The Antihypertensive and Lipid–Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone JAMA 2000 283: 1967–1975

  6. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC et al . Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Amer J Hypertens 1996 9: 342–360

    Article  CAS  Google Scholar 

  7. Takayanagi R, Ohnaka K, Sakai Y, Ikuyama S, Nawata H . Molecular cloning and characterization of the promoter for human type-1 angiotensin II receptor gene Biochem Biophys Res Commun 1994 200: 1264–1270

    Article  CAS  Google Scholar 

  8. Bonnardeaux A, Davies E, Jeunemaitre X, Féry I, Charru A, Clauser E et al . Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension Hypertension 1994 24: 63–69

    Article  CAS  Google Scholar 

  9. Wu D-A, Bu X, Warden CH, Shen DDC, Jeng C-Y, Sheu WHH 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: 2111–2118

    Article  CAS  Google Scholar 

  10. Chen W, Srinivasan SR, Elkasabany A, Ellsworth DL, Boerwinkle E, Berenson GS . Influence of lipoprotein lipase serine 447 stop polymorphism on tracking triglycerides and HDL cholesterol from childhood to adulthood and familial risk of coronary artery disease: the Bogalusa heart study Antherosclerosis 2001 Dec 159: (2) 367–373

    Article  CAS  Google Scholar 

  11. Reihsaus E, Innis M, MacIntyre N, Liggett SB . Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects Am J Respir Cell Mol Biol 1993 8: 334–339

    Article  CAS  Google Scholar 

  12. Lentes K, Berrettini W, Hoeche M, Chung F, Gershon E . A biallelic DNA polymorphism of the human -adrenergic receptor detected by Ban I-Adrbr-2 Nucleic Acids Res 1988 16: 2359

    Article  CAS  Google Scholar 

  13. Anonymous. The American Society of Human Genetics ASHG Report–Statement on informed consent for genetic research Am J Hum Genet 1996 59: 471–474

  14. Peterson B, George SL . Sample size requirement and length of study for testing interaction in a 2 × 4 factorial design when time-to-failure is the outcome Cont Clin Trials 1993 14: 511–522

    Article  CAS  Google Scholar 

  15. Proschan MA, Waclawiw MA . Practical guidelines for multiplicity adjustment in clinical trials Cont Clin Trials 2000 21: 527–539

    Article  CAS  Google Scholar 

  16. Barzilay JI, Jones CL, Davis BR, Basile JN, Goff DC Jr, Ciocon JO et al . Baseline characteristics of the diabetic participants in the Antihypertensive and Lipid–Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Diabetes Care 2001 24: 654–658

    Article  CAS  Google Scholar 

  17. Grimm RH, Margolis KL, Papademetriou V, Cushman WC, Ford CE, Bettencourt J et al . Baseline characteristics of participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Hypertension 2001 37: 19–27

    Article  CAS  Google Scholar 

  18. Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A et al . Molecular basis of human hypertension: role of angiotensinogen Cell 1992 71: 169–180

    Article  CAS  Google Scholar 

  19. McNamara DM, Holubkov R, Janosko K, Palmer A, Wang JJ, MacGowan GA et al . Pharmacogenetic interactions between beta-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure Circulation 2001 103: 1644–1648

    Article  CAS  Google Scholar 

  20. Caulfield M, Lavender P, Farrall M, Munroe P, Lawson M, Turner P et al . Linkage of the angiotensinogen gene to essential hypertension N Engl J Med 1994 330: 1629–1633

    Article  CAS  Google Scholar 

  21. 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

    Article  CAS  Google Scholar 

  22. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F . An insertion/deletion polymorphism in the angiotensin 1-converting enzyme gene accounting for half the variance of serum enzyme levels J Clin Invest 1990 86: 1343–1346

    Article  CAS  Google Scholar 

  23. Samani NJ, Thompson JR, O'Toole L, Channer K, Woods KL . A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction Circulation 1996 94: 708–712

    Article  CAS  Google Scholar 

  24. Inoue I, Nakajima T, Williams CS, Quackenbush J, Puryear R, Powers M et al . A nucleotide substitution in the promotor of human angiotensinogen is associated with essential hypertension and affects basal transcription in vivo J Clin Invest 1997 99: 1786–1797

    Article  CAS  Google Scholar 

  25. Hall JE . Renal and cardiovascular mechanisms of hypertension in obesity Hypertension 1994 23: 381–394

    Article  CAS  Google Scholar 

  26. Castellano M, Barlassina C, Muiesan L, Beschi M, Cinelli A, Rossi F et al . α-adducin gene polymorphism and cardiovascular phenotypes in a general population J Hypertens 1997 15: 1707–1710

    Article  CAS  Google Scholar 

  27. Casari G, Barlassina C, Cusi D, Zagato L, Muirhead R, Righetti M et al . Association of the α-adducin locus with essential hypertension Hypertension 1995 25: 320–326

    Article  CAS  Google Scholar 

  28. Moriyama T, Kitamura H, Ochi S, Izumi M, Yokoyama K, Yamauchi A et al . Association of angiotensin I-converting enzyme gene polymorphism with susceptibility to antiproteinuric effect of angiotensin I-converting enzyme inhibitors in patients with proteinuria J Am Soc Nephrol 1995 6: 1676–1678

    CAS  PubMed  Google Scholar 

  29. Sasaki M, Oki T, Iuchi A, Tabata T, Yamada H, Manabe K et al . Relationship between the angiotensin converting enzyme gene polymorphism and the effects of enalapril on left ventricular hypertrophy and impaired diastolic filling in essential hypertension: M-mode and pulsed Doppler echocardiographic studies J Hypertens 1996 14: 1403–1408

    Article  CAS  Google Scholar 

  30. Dudley C, Keavney B, Casadei B, Conway J, Bird R, Ratcliffe P . Prediction of patient responses to antihypertensive drugs using genetic polymorphisms: investigation of renin-angiotensin system genes J Hypertens 1996 4: 259–262

    Article  Google Scholar 

  31. Yoshida H, Mitarai T, Kawamura T, Kitajima T, Miyazaki Y, Nagasawa R et al . Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy J Clin Invest 1995 96: 2100–2102

    Article  Google Scholar 

  32. O'Toole L, Stewart M, Padfield P, Channer K . Effect of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene on response to angiotensin-converting enzyme inhibitors in patients with heart failure J Cardio Pharmacol 1998 32: 988–994

    Article  CAS  Google Scholar 

  33. Kohno M, Yokokawa K, Minami M, Kano H, Yasunari K, Hanehira T et al . Association between angiotensin-converting enzyme gene polymorphisms and regression of left ventricular hypertrophy in patients treated with angiotensin-converting enzyme inhibitors Am J Med 1999 106: 544–549

    Article  CAS  Google Scholar 

  34. Hernandez D, Lacalzada J, Salido E, Linares J, Barragan A, Lorenzo V et al . Regression of left ventricular hypertrophy by lisinopril after renal transplantation: role of ACE gene polymorphism Kidney Int 2000 58: 889–897

    Article  CAS  Google Scholar 

  35. Myerson SG, Montgomery HE, Whittingham M, Jubb M, World MJ, Humphries SE et al . Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: a randomized controlled trial with Losartan Circulation 2001 103: 226–230

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Epidemiology, University of Minnesota, Minneapolis, USA

    DK Arnett

  2. University of Texas-Houston, School of Public Health, Houston, TX, USA

    E Boerwinkle, BR Davis & CE Ford

  3. Fairview-University Medical Center, Minneapolis, MN, USA

    J Eckfeldt

  4. Rush Presbyterian-St Luke's Medical Center, Chicago, IL, USA

    H Black

Authors
  1. DK Arnett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Boerwinkle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. BR Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Eckfeldt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. CE Ford
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Black
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to DK Arnett.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arnett, D., Boerwinkle, E., Davis, B. et al. Pharmacogenetic approaches to hypertension therapy: design and rationale for the Genetics of Hypertension Associated Treatment (GenHAT) study. Pharmacogenomics J 2, 309–317 (2002). https://doi.org/10.1038/sj.tpj.6500113

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500113

Keywords

This article is cited by

Search

Advanced search

Quick links