Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium
Siland, J E; Geelhoed, B; Roselli, C; Wang, B; Lin, H J; Weiss, S; Trompet, S; van den Berg, M E; Soliman, E Z; Chen, L Y; Ford, I; Jukema, J W; Macfarlane, P W; Kornej, J; Lin, H; Lunetta, K L; Kavousi, M; Kors, J A; Ikram, M A; Guo, X; Yao, J; Dörr, M; Felix, S B; Völker, U; Sotoodehnia, N; Arking, D E; Stricker, B H; Heckbert, S R; Lubitz, S A; Benjamin, E J; Alonso, A; Ellinor, P T; van der Harst, P; Rienstra, M
(2022) PLoS ONE, volume 17, issue 5, pp. 1 - 13
(Article)
Abstract
BACKGROUND: Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and
... read more
incident AF. METHOD AND RESULTS: Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65-75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94-0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. CONCLUSIONS: For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.
show less
Download/Full Text
Keywords: Aged, Atrial Fibrillation, Electrocardiography, Female, Heart Rate/genetics, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Random Allocation, Risk Factors, Journal Article, Meta-Analysis
ISSN: 1932-6203
Publisher: Public Library of Science
Note: Funding Information: The Atherosclerosis Risk in Communities study has been funded in whole or in part with funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Service (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I, R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C). Additional support for this analysis was provided by NHLBI grant K24HL148521 and American Heart Association grant 16EIA26410001. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract nos. N01-HC-25195, HHSN268201500001I, and 75N92019D00031). Dr. Kornej was supported by Marie Sklodowska-Curie Actions under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 838259). Dr. Benjamin is supported by NIH NHLBI grants R01HL092577 and 1R01HL128914 and American Heart Association 18SFRN34110082. Dr. Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Dr. Lubitz receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb / Pfizer, Bayer AG, and Blackstone Life Sciences. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. PREVEND is supported by the Dutch Kidney Foundation (grant E0.13) and the Netherlands Heart Foundation (grant NHS2010B280). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Funding Information: ConsortiumforHealthyAginggrant050-060-810). TheRotterdamStudyissupportedbytheErasmus UniversityMedicalCenterandErasmusUniversity, Rotterdam;TheNetherlandsOrganisationfor ScientificResearch(NWO);TheNetherlands OrganisationforHealthResearchandDevelopment (ZonMw);theResearchInstituteforDiseasesin theElderly(RIDE);TheNetherlandsGenomics Initiative(NGI);theMinistryofEducation,Culture andScience;theMinistryofHealth,Welfareand Sports;theEuropeanCommission(DGXII);and theMunicipalityofRotterdam.Thecontributionof inhabitants,generalpractitionersandpharmacists oftheOmmoorddistricttotheRotterdamStudyis gratefullyacknowledged.TheStudyofHealthin Pomerania(SHIP)issupportedbytheGerman FederalMinistryofEducationandResearch (Bundesministeriumfu ¨r Bildungund Forschung (BMBF);grants01ZZ9603,01ZZ0103,and 01ZZ0403)andtheGermanResearchFoundation (DeutscheForschungsgemeinschaft(DFG);grant GR1912/5-1).SHIPispartoftheCommunity MedicineResearchnet(CMR)oftheUniversityof GreifswaldwhichisfundedbytheBMBFaswellas theMinistryforEducation,ScienceandCultureand theMinistryofLabor,EqualOpportunities,and SocialAffairsoftheFederalStateofMecklenburg-WestPomerania.TheCMRencompassesseveral researchprojectsthatsharedatafromSHIP. Genome-widedatahavebeensupportedbyajoint grantfromSiemensHealthcare,Erlangen, GermanyandtheFederalStateofMecklenburg-WestPomerania.TheAFGenconsortiumis supportedbyR01HL128914and2R01HL092577 andAmericanHeartAssociationgrant 18SFRN34110082.Thefundershadnorolein studydesign,datacollectionandanalysis,decision topublish,orpreparationofthemanuscript. Publisher Copyright: Copyright: © 2022 Siland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
(Peer reviewed)
