Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation

Am Heart J. 2016 May:175:9-17. doi: 10.1016/j.ahj.2016.02.002. Epub 2016 Feb 13.


Background: Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier status of 9 AF-associated SNPs on the efficacy of RAS inhibition for the primary prevention of AF.

Methods: We performed SNP-RAS inhibitor interaction testing with unadjusted and adjusted Cox proportional hazards models using a discovery (Cardiovascular Health Study) and a replication (Atherosclerosis Risk in Communities) cohort. Additive genetic models were used for the SNP analyses, and 2-tailed P values <.05 were considered statistically significant.

Results: Among 2,796 Cardiovascular Health Study participants, none of the 9 a priori identified candidate SNPs exhibited a significant SNP-drug interaction. Two of the 9 SNPs, rs2106261 (16q22) and rs6666258 (1q21), revealed interaction relationships that neared statistical significance (with point estimates in the same direction for angiotensin-converting enzyme inhibitor only and angiotensin II receptor blocker only analyses), but neither association could be replicated among 8,604 participants in Atherosclerosis Risk in Communities.

Conclusions: Our study failed to identify AF-associated SNP genetic subtypes of AF that derive increased benefit from upstream RAS inhibition for AF prevention. Future studies should continue to investigate the impact of genotype on the response to AF treatment strategies in an effort to develop personalized approaches to therapy and prevention.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Angiotensin Receptor Antagonists / pharmacology*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Atrial Fibrillation* / epidemiology
  • Atrial Fibrillation* / genetics
  • Atrial Fibrillation* / prevention & control
  • Female
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Male
  • Pharmacogenomic Testing
  • Polymorphism, Single Nucleotide
  • Primary Prevention / methods
  • Proportional Hazards Models
  • Renin-Angiotensin System* / drug effects
  • Renin-Angiotensin System* / genetics
  • Treatment Outcome
  • United States / epidemiology


  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors

Grants and funding