title: Renin-angiotensin system gene polymorphisms predict the risk of stroke in patients with atrial fibrillation: a 10-year prospective follow-up study.
abstract: BACKGROUND
  Little evidence is available regarding the impact of genetic polymorphisms on the risk of stroke in patients with atrial fibrillation (AF). Angiotensin II plays a pathophysiologic role in prothrombotic atrial endocardial remodeling.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the effect of polymorphisms of renin-angiotensin system genes on the incidence of stroke in a prospective cohort of patients with AF.
  
  
  METHODS
  A total of 712 AF patients were longitudinally followed-up for 10.3 ± 2.7 years. Eight polymorphisms of renin-angiotensin system genes were genotyped.
  
  
  RESULTS
  Patients carrying the G-6 allele in the promoter of the angiotensinogen gene, which was associated with higher promoter activity, were more likely to develop stroke than were noncarriers (hazard ratio 2.54, 95% confidence interval [1.26-5.12], P = .009 after adjustment for CHADS2 score). G-6A polymorphism provides information additional to CHADS2 on stroke risk prediction (C-statistic 0.672 vs. 0.724, P = .039). In haplotype analysis, angiotensinogen gene promoter haplotypes containing -217G/-6G, which was associated with the highest promoter activity, were associated with an increased risk of stroke (P = .004). G-217/G-6 haplotype carriers were even more likely to develop stroke than were noncarriers (hazard ratio 2.78, 95% confidence interval 1.37-5.64, P = .003 after multivariable adjustment). In pharmacogenetic analysis, the increased risk of stroke in subjects carrying G-6 was eliminated by concomitant treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (P = .012 for interaction).
  
  
  CONCLUSIONS
  In addition to the CHADS2 score, angiotensinogen gene polymorphisms may be considered an additional genetic predictor of stroke in patients with AF. Genotyping of the angiotensinogen gene is helpful to determine which AF patients may benefit from treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
authors.forename: Chia-Ti
authors.initials: CT
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Lotung Poh-Ai hospital, Yilan, Taiwan.
authors.forename: Shu-Hsuan
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Department of Clinical Pathology, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
authors.forename: Jen-Kuang
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Lian-Yu
authors.initials: LY
authors.lastname: Lin
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Cho-Kai
authors.initials: CK
authors.lastname: Wu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chuen-Den
authors.initials: CD
authors.lastname: Tseng
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Lai
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: jueyhwang@ntu.edu.tw.
authors.forename: Juey-Jen
authors.initials: JJ
authors.lastname: Hwang
authors.affiliation: Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: futienc@ntuh.gov.tw.
authors.forename: Fu-Tien
authors.initials: FT
authors.lastname: Chiang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: jiunnlee@ntu.edu.tw.
authors.forename: Jiunn-Lee
authors.initials: JL
authors.lastname: Lin
mesh_terms: D000368:Aged; D000483:Alleles; D001281:Atrial Fibrillation / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005544:Forecasting; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012084:Renin-Angiotensin System / Q000235:genetics*; D012307:Risk Factors; D020521:Stroke / Q000209:etiology* / Q000235:genetics / Q000378:metabolism
chemical_list: D004247:DNA
keywords: Atrial fibrillation; Pharmacogenetics; Polymorphisms; Prospective; Renin–angiotensin system; Stroke