Pulse lineResearch With Heart Logo

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

TitleImpact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.
Publication TypeJournal Article
Year of Publication2016
AuthorsRoberts JD, Dewland TA, Glidden DV, Hoffmann TJ, Arking DE, Chen LYee, Psaty BM, Olgin JE, Alonso A, Heckbert SR
Secondary AuthorsMarcus GM
JournalAm Heart J
Volume175
Pagination9-17
Date Published2016 05
ISSN1097-6744
KeywordsAged, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Atrial Fibrillation, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Pharmacogenomic Testing, Polymorphism, Single Nucleotide, Primary Prevention, Proportional Hazards Models, Renin-Angiotensin System, Treatment Outcome, United States
Abstract

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.

DOI10.1016/j.ahj.2016.02.002
Alternate JournalAm Heart J
PubMed ID27179719
PubMed Central IDPMC4873713
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
R01 HL080698 / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
R01 HL102214 / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States