Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation - 12/05/16

Doi : 10.1016/j.ahj.2016.02.002

Jason D. Roberts, MD ^a, Thomas A. Dewland, MD ^a, David V. Glidden, PhD ^b, Thomas J. Hoffmann, PhD ^b,^c, Dan E. Arking, PhD ^d, Lin Y. Chen, MD, MS ^e, Bruce M. Psaty, MD, PhD ^f,^g,^h, Jeffrey E. Olgin, MD ^a, Alvaro Alonso, MD, PhD ⁱ, Susan R. Heckbert, MD, PhD ^f,^h,^j, Gregory M. Marcus, MD, MAS ^a,^{^⁎}
^a Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, CA
^b Departments of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA
^c Institute for Human Genetics, University of California San Francisco, San Francisco, CA
^d McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
^e Department of Medicine, Cardiovascular Division, University of Minnesota, Minneapolis, MN
^f Cardiovascular Health Research Unit, University of Washington, Seattle, WA
^g Departments of Medicine and Health Services, University of Washington, Seattle, WA
^h Group Health Research Institute, Group Health, Seattle, WA
ⁱ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN
^j Department of Epidemiology, University of Washington, Seattle, WA

^⁎Reprint requests: Gregory M. Marcus, MD, MAS, 500 Parnassus Ave, MUE 434, San Francisco, CA 94143-1354.500 Parnassus Ave, MUE 434San FranciscoCA94143-1354

Résumé

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.

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Vol 175

P. 9-17 - mai 2016 Retour au numéro

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Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation - 12/05/16

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