Published Online
on March 15, 2004

A more recent version of this article appeared on April 6, 2004

This Article Full Text (PDF) All Versions of this Article: 109/13/1640    most recent 01.CIR.0000124487.36586.26v1 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 Tsai, C.-T. Articles by Tseng, Y.-Z. Search for Related Content PubMed PubMed Citation Articles by Tsai, C.-T. Articles by Tseng, Y.-Z. Related Collections Clinical genetics Arrythmias-basic studies Genomics Genetics of cardiovascular disease

Submitted on July 16, 2002
Revised on December 29, 2003
Accepted on January 14, 2004

Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation

Chia-Ti Tsai MD, Ling-Ping Lai MD, PhD, Jiunn-Lee Lin MD, PhD, Fu-Tien Chiang MD, PhD^*, Juey-Jen Hwang MD, PhD, Marylyn D. Ritchie MS, Jason H. Moore PhD, Kuan-Lih Hsu MD, PhD, Chuen-Den Tseng MD, PhD, Chiau-Suong Liau MD, and Yung-Zu Tseng MD

From the Division of Cardiology, Department of Internal Medicine (C.-T.T., L.-P.L., J.-L.L., F.-T.C., J.-J.H., K.-L.H., C.-D.T., C.-S.L., Y.-Z.T.) and Department of Laboratory Medicine (F.-T.C.), National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine (C.-T.T.), Yunlin Hospital, Department of Health, Executive Yuan, Yulin, Taiwan; and Program in Human Genetics and Department of Molecular Physiology and Biophysics (M.D.R., J.H.M.), Vanderbilt University Medical School, Nashville, Tenn.

^* To whom correspondence should be addressed. E-mail: futienc{at}ha.mc.ntu.edu.tw.

Background--The activated local atrial renin-angiotensin system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation (AF). We hypothesized that RAS genes might be among the susceptibility genes of nonfamilial structural AF and conducted a genetic case-control study to demonstrate this.

Methods and Results--A total of 250 patients with documented nonfamilial structural AF and 250 controls were selected. The controls were matched to cases on a 1-to-1 basis with regard to age, gender, presence of left ventricular dysfunction, and presence of significant valvular heart disease. The ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen gene, and the A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In multilocus haplotype analysis, the angiotensinogen gene haplotype profile was significantly different between cases and controls (²=62.5, P=0.0002). In single-locus analysis, M235T, G-6A, and G-217A were significantly associated with AF. Frequencies of the M235, G-6, and G-217 alleles were significantly higher in cases than in controls (P=0.000, 0.005, and 0.002, respectively). The odds ratios for AF were 2.5 (95% CI 1.7 to 3.3) with M235/M235 plus M235/T235 genotype, 3.3 (95% CI 1.3 to 10.0) with G-6/G-6 genotype, and 2.0 (95% CI 1.3 to 2.5) with G-217/G-217 genotype. Furthermore, significant gene-gene interactions were detected by the multifactor-dimensionality reduction method and multilocus linkage disequilibrium tests.

Conclusions--This study demonstrates the association of RAS gene polymorphisms with nonfamilial structural AF and may provide the rationale for clinical trials to investigate the use of ACE inhibitor or angiotensin II antagonist in the treatment of structural AF.

Key words: arrhythmia • genetics • fibrillation • renin • angiotensin

This article has been cited by other articles:

				C.-T. Tsai, L.-P. Lai, J.-J. Hwang, J.-L. Lin, and F.-T. Chiang Molecular Genetics of Atrial Fibrillation J. Am. Coll. Cardiol., July 22, 2008; 52(4): 241 - 250. [Abstract] [Full Text] [PDF]

				J. L. Serra and M. Bendersky Review: Atrial fibrillation and renin-angiotensin system Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 215 - 223. [Abstract] [PDF]

				M. F. Sinner, A. Pfeufer, M. Akyol, B.-M. Beckmann, M. Hinterseer, A. Wacker, S. Perz, W. Sauter, T. Illig, M. Nabauer, et al. The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG) Eur. Heart J., April 1, 2008; 29(7): 907 - 914. [Abstract] [Full Text] [PDF]

				B. London An irregularly irregular inheritance. J. Am. Coll. Cardiol., March 18, 2008; 51(11): 1090 - 1091. [Full Text] [PDF]

				T. T. Issac, H. Dokainish, and N. M. Lakkis Role of Inflammation in Initiation and Perpetuation of Atrial Fibrillation: A Systematic Review of the Published Data J. Am. Coll. Cardiol., November 20, 2007; 50(21): 2021 - 2028. [Abstract] [Full Text] [PDF]

				M.-C. Chang, Y.-T. Chang, Y.-W. Tien, P.-C. Liang, I-S. Jan, S.-C. Wei, and J.-M. Wong T-Cell Regulatory Gene CTLA-4 Polymorphism/Haplotype Association with Autoimmune Pancreatitis Clin. Chem., September 1, 2007; 53(9): 1700 - 1705. [Abstract] [Full Text] [PDF]

				D. Fatkin, R. Otway, and J. I. Vandenberg Genes and Atrial Fibrillation: A New Look at an Old Problem Circulation, August 14, 2007; 116(7): 782 - 792. [Full Text] [PDF]

				A. P. Pilbrow, B. R. Palmer, C. M. Frampton, T. G. Yandle, R. W. Troughton, E. Campbell, L. Skelton, J. G. Lainchbury, A. M. Richards, and V. A. Cameron Angiotensinogen M235T and T174M Gene Polymorphisms in Combination Doubles the Risk of Mortality in Heart Failure Hypertension, February 1, 2007; 49(2): 322 - 327. [Abstract] [Full Text] [PDF]

				M-C Chang, Y-T Chang, Y-W Tien, P-C Liang, S-C Wei, and J-M Wong Association of tumour necrosis factor {alpha} promoter haplotype with chronic pancreatitis Gut, November 1, 2006; 55(11): 1674 - 1676. [Full Text] [PDF]

				C.-H. Hsieh, K.-H. Liang, Y.-J. Hung, L.-C. Huang, D. Pei, Y.-T. Liao, S.-W. Kuo, M. S.-J. Bey, J.-L. Chen, and E. Y. Chen Analysis of epistasis for diabetic nephropathy among type 2 diabetic patients Hum. Mol. Genet., September 15, 2006; 15(18): 2701 - 2708. [Abstract] [Full Text] [PDF]

				J. R. Ehrlich, S. H. Hohnloser, and S. Nattel Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence Eur. Heart J., March 1, 2006; 27(5): 512 - 518. [Abstract] [Full Text] [PDF]

				R. Roberts Genomics and Cardiac Arrhythmias J. Am. Coll. Cardiol., January 3, 2006; 47(1): 9 - 21. [Abstract] [Full Text] [PDF]

				C. J. Boos, R. A. Anderson, and G. Y.H. Lip Is atrial fibrillation an inflammatory disorder? Eur. Heart J., January 2, 2006; 27(2): 136 - 149. [Abstract] [Full Text] [PDF]

				M. V. Podgoreanu and J. P. Mathew Prophylaxis Against Postoperative Atrial Fibrillation: Current Progress and Future Directions JAMA, December 28, 2005; 294(24): 3140 - 3142. [Full Text] [PDF]

				M. V. Podgoreanu and D. A. Schwinn New Paradigms in Cardiovascular Medicine: Emerging Technologies and Practices: Perioperative Genomics J. Am. Coll. Cardiol., December 6, 2005; 46(11): 1965 - 1977. [Abstract] [Full Text] [PDF]

				J. Xu, J. Lowey, F. Wiklund, J. Sun, F. Lindmark, F.-C. Hsu, L. Dimitrov, B. Chang, A. R. Turner, W. Liu, et al. The Interaction of Four Genes in the Inflammation Pathway Significantly Predicts Prostate Cancer Risk Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2563 - 2568. [Abstract] [Full Text] [PDF]

				A. C.P. Wiesfeld, M. E.W. Hemels, J. P. Van Tintelen, M. P. Van den Berg, D. J. Van Veldhuisen, and I. C. Van Gelder Genetic aspects of atrial fibrillation Cardiovasc Res, August 15, 2005; 67(3): 414 - 418. [Abstract] [Full Text] [PDF]

				J. R. Ehrlich, S. Zicha, P. Coutu, T. E. Hebert, and S. Nattel Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization Cardiovasc Res, August 15, 2005; 67(3): 520 - 528. [Abstract] [Full Text] [PDF]

				K. Wachtell, M. Lehto, E. Gerdts, M. H. Olsen, B. Hornestam, B. Dahlof, H. Ibsen, S. Julius, S. E. Kjeldsen, L. H. Lindholm, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: The Losartan Intervention For End point reduction in hypertension (LIFE) study J. Am. Coll. Cardiol., March 1, 2005; 45(5): 712 - 719. [Abstract] [Full Text] [PDF]

				M. G. Bourassa Angiotensin II inhibition and prevention of atrial fibrillation and stroke J. Am. Coll. Cardiol., March 1, 2005; 45(5): 720 - 721. [Full Text] [PDF]

				E. Adler and V. Fuster SCN5A--A Mechanistic Link Between Inherited Cardiomyopathies and a Predisposition to Arrhythmias? JAMA, January 26, 2005; 293(4): 491 - 493. [Full Text] [PDF]

				R. Khan Identifying and understanding the role of pulmonary vein activity in atrial fibrillation Cardiovasc Res, December 1, 2004; 64(3): 387 - 394. [Abstract] [Full Text] [PDF]

				M. Tomaszewski, F. J. Charchar, B. Lacka, U. Pesonen, W. Y.S. Wang, E. Zukowska-Szczechowska, W. Grzeszczak, and A. F. Dominiczak Epistatic Interaction Between {beta}2-Adrenergic Receptor and Neuropeptide Y Genes Influences LDL-Cholesterol in Hypertension Hypertension, November 1, 2004; 44(5): 689 - 694. [Abstract] [Full Text] [PDF]

				A. Ogimoto, J. Higaki, T. Miki, C.-T. Tsai, L.-P. Lai, J.-L. Lin, F.-T. Chiang, J.-J. Hwang, K.-L. Hsu, C.-D. Tseng, et al. Polymorphism of Inhibitory Renin-Angiotensin System as a Genetic Risk Factor for Atrial Fibrillation * Response Circulation, September 28, 2004; 110(13): e329 - e329. [Full Text] [PDF]

				C. S. Fox, H. Parise, R. B. D'Agostino Sr, D. M. Lloyd-Jones, R. S. Vasan, T. J. Wang, D. Levy, P. A. Wolf, and E. J. Benjamin Parental Atrial Fibrillation as a Risk Factor for Atrial Fibrillation in Offspring JAMA, June 16, 2004; 291(23): 2851 - 2855. [Abstract] [Full Text] [PDF]