Published Online
on June 20, 2005

A more recent version of this article appeared on June 28, 2005

This Article Full Text (PDF) All Versions of this Article: 111/25/3374    most recent CIRCULATIONAHA.104.504639v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arnett, D. K. Articles by Eckfeldt, J. H. Search for Related Content PubMed PubMed Citation Articles by Arnett, D. K. Articles by Eckfeldt, J. H. Related Collections Cardiovascular Pharmacology ACE/Angiotension receptors Clinical Studies Epidemiology Genetics of cardiovascular disease

Submitted on September 3, 2004
Revised on March 4, 2005
Accepted on March 24, 2005

Pharmacogenetic Association of the Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism on Blood Pressure and Cardiovascular Risk in Relation to Antihypertensive Treatment. The Genetics of Hypertension-Associated Treatment (GenHAT) Study

Donna K. Arnett PhD^*, Barry R. Davis MD, PhD, Charles E. Ford PhD, Eric Boerwinkle PhD, Cathie Leiendecker-Foster MS, Michael B. Miller PhD, Henry Black MD, and John H. Eckfeldt MD, PhD

From the University of Minnesota, Division of Epidemiology (D.K.A., M.B.M.) and Department of Laboratory Medicine and Pathology (C.L.-F., J.H.E.), Minneapolis; University of Texas-Houston, School of Public Health, Houston (B.R.D., C.E.F., E.B.); and Rush Presbyterian-St Luke’s Medical Center, Chicago, Ill (H.B.). Dr Arnett is currently affiliated with the University of Alabama, Department of Epidemiology, Birmingham.

^* To whom correspondence should be addressed. E-mail: arnett{at}ms.soph.uab.edu.

Background--Previous studies have reported that blood pressure response to antihypertensive medications is influenced by genetic variation in the renin-angiotensin-aldosterone system, but no clinical trails have tested whether the ACE insertion/deletion (I/D) polymorphism modifies the association between the type of medication and multiple cardiovascular and renal phenotypes.

Methods and Results--We used a double-blind, active-controlled randomized trial of antihypertensive treatment that included hypertensives 55 years of age with 1 risk factor for cardiovascular disease. ACE I/D genotypes were determined in 37 939 participants randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatments and followed up for 4 to 8 years. Primary outcomes included fatal coronary heart disease (CHD) and/or nonfatal myocardial infarction. Secondary outcomes included stroke, all-cause mortality, combined CHD, and combined cardiovascular disease. Fatal and nonfatal CHD occurred in 3096 individuals during follow-up. The hazard rates for fatal and nonfatal CHD and the secondary outcomes were similar across antihypertensive treatments. ACE I/D genotype group was not associated with fatal and nonfatal CHD (relative risk of DD versus ID and II, 0.99; 95% CI, 0.91 to 1.07) or any secondary outcome. The 6-year hazard rate for fatal and nonfatal CHD in the DD genotype group was not statistically different from the ID and II genotype group by type of treatment. No secondary outcome measure was statistically different across antihypertensive treatment and ACE I/D genotype strata.

Conclusions--ACE I/D genotype group was not a predictor of CHD, nor did it modify the response to antihypertensive treatment. We conclude that the ACE I/D polymorphism is not a useful marker to predict antihypertensive treatment response.

Key words: drugs • genetics • hypertension • pharmacogenetics

This article has been cited by other articles:

				B. Ozben, I. Altun, V. Sabri Hancer, A. K. Bilge, A. M. Tanrikulu, R. Diz-Kucukkaya, A. S. Fak, E. Yilmaz, and K. Adalet Angiotensin-converting enzyme gene polymorphism in arrhythmogenic right ventricular dysplasia: is DD genotype helpful in predicting syncope risk? Journal of Renin-Angiotensin-Aldosterone System, December 1, 2008; 9(4): 215 - 220. [Abstract] [PDF]

				D. Rosskopf and M. C. Michel Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine Pharmacol. Rev., December 1, 2008; 60(4): 513 - 535. [Abstract] [Full Text] [PDF]

				J. A. Johnson Ethnic Differences in Cardiovascular Drug Response: Potential Contribution of Pharmacogenetics Circulation, September 23, 2008; 118(13): 1383 - 1393. [Full Text] [PDF]

				E. Zintzaras, G. Raman, G. Kitsios, and J. Lau Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphic Variant as a Marker of Coronary Artery Disease: A Meta-analysis Arch Intern Med, May 26, 2008; 168(10): 1077 - 1089. [Abstract] [Full Text] [PDF]

				K. D. Marciante, J. C. Bis, M. J. Rieder, A. P. Reiner, T. Lumley, S. A. Monks, C. Kooperberg, C. Carlson, S. R. Heckbert, and B. M. Psaty Renin-Angiotensin System Haplotypes and the Risk of Myocardial Infarction and Stroke in Pharmacologically Treated Hypertensive Patients Am. J. Epidemiol., July 1, 2007; 166(1): 19 - 27. [Abstract] [Full Text] [PDF]

				K. M. Momary Cardiovascular Pharmacogenomics Journal of Pharmacy Practice, June 1, 2007; 20(3): 265 - 276. [Abstract] [PDF]

				S. Padmanabhan, C. Wallace, P. B. Munroe, R. Dobson, M. Brown, N. Samani, D. Clayton, M. Farrall, J. Webster, M. Lathrop, et al. Chromosome 2p Shows Significant Linkage to Antihypertensive Response in the British Genetics of Hypertension Study Hypertension, March 1, 2006; 47(3): 603 - 608. [Abstract] [Full Text] [PDF]

				H. Schelleman, O. H Klungel, C. M van Duijn, J. C. Witteman, A. Hofman, A. de Boer, and B. H. Stricker Drug-Gene Interaction Between the Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Antihypertensive Therapy Ann. Pharmacother., February 1, 2006; 40(2): 212 - 218. [Abstract] [Full Text] [PDF]