@article {6594, title = {Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.}, journal = {Circ Arrhythm Electrophysiol}, volume = {7}, year = {2014}, month = {2014 Dec}, pages = {1026-32}, abstract = {

BACKGROUND: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.

METHODS AND RESULTS: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95\% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95\% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 {\textpm} 0.20 versus 1.02 {\textpm} 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.

CONCLUSIONS: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.

}, keywords = {Age Factors, Aged, Aging, Atrial Fibrillation, California, Cardiac Surgical Procedures, Cellular Senescence, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Humans, Incidence, Leukocytes, Male, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Risk Factors, Telomerase, Telomere, Time Factors}, issn = {1941-3084}, doi = {10.1161/CIRCEP.114.001781}, author = {Roberts, Jason D and Dewland, Thomas A and Longoria, James and Fitzpatrick, Annette L and Ziv, Elad and Hu, Donglei and Lin, Jue and Glidden, David V and Psaty, Bruce M and Burchard, Esteban G and Blackburn, Elizabeth H and Olgin, Jeffrey E and Heckbert, Susan R and Marcus, Gregory M} } @article {7165, title = {Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals.}, journal = {JAMA Cardiol}, volume = {1}, year = {2016}, month = {2016 Jul 1}, pages = {442-50}, abstract = {

IMPORTANCE: White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors.

OBJECTIVES: To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon.

DESIGN, SETTING, AND PARTICIPANTS: Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015.

MAIN OUTCOMES AND MEASURES: Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data.

RESULTS: A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4\%; 95\% CI, 2.9\%-29.9\%) and ARIC (31.7\%; 95\% CI, 16.0\%-53.0\%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified.

CONCLUSIONS AND RELEVANCE: The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2016.1185}, author = {Roberts, Jason D and Hu, Donglei and Heckbert, Susan R and Alonso, Alvaro and Dewland, Thomas A and Vittinghoff, Eric and Liu, Yongmei and Psaty, Bruce M and Olgin, Jeffrey E and Magnani, Jared W and Huntsman, Scott and Burchard, Esteban G and Arking, Dan E and Bibbins-Domingo, Kirsten and Harris, Tamara B and Perez, Marco V and Ziv, Elad and Marcus, Gregory M} } @article {7166, title = {Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.}, journal = {Am Heart J}, volume = {175}, year = {2016}, month = {2016 May}, pages = {9-17}, 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.

}, issn = {1097-6744}, doi = {10.1016/j.ahj.2016.02.002}, author = {Roberts, Jason D and Dewland, Thomas A and Glidden, David V and Hoffmann, Thomas J and Arking, Dan E and Chen, Lin Y and Psaty, Bruce M and Olgin, Jeffrey E and Alonso, Alvaro and Heckbert, Susan R and Marcus, Gregory M} } @article {7787, title = {Sleep characteristics that predict atrial fibrillation.}, journal = {Heart Rhythm}, volume = {15}, year = {2018}, month = {2018 Sep}, pages = {1289-1295}, abstract = {

BACKGROUND: The relationship between sleep disruption, independent of obstructive sleep apnea (OSA), and atrial fibrillation (AF) is unknown.

OBJECTIVE: The purpose of this study was to determine whether poor sleep itself is a risk factor for AF.

METHODS: We first performed an analysis of participants in the Health eHeart Study and validated those findings in the longitudinal Cardiovascular Health Study, including a subset of patients undergoing polysomnography. To determine whether the observed relationships readily translated to medical practice, we examined 2005-2009 data from the California Healthcare Cost and Utilization Project.

RESULTS: Among 4553 Health eHeart participants, the 526 with AF exhibited more frequent nighttime awakening (odd ratio [OR] 1.47; 95\% confidence interval [CI] 1.14-1.89; P = .003). In 5703 Cardiovascular Health Study participants followed for a median 11.6 years, frequent nighttime awakening predicted a 33\% greater risk of AF (hazard ratio [HR] 1.33; 95\% CI 1.17-1.51; P <.001). In patients with polysomnography (N = 1127), every standard deviation percentage decrease in rapid eye movement (REM) sleep was associated with a 18\% higher risk of developing AF (HR 1.18; 95\% CI 1.00-1.38; P = .047). Among 14,330,651 California residents followed for a median 3.9 years, an insomnia diagnosis predicted a 36\% increased risk of new AF (HR 1.36; 95\% CI 1.30-1.42; P <.001).

CONCLUSION: Sleep disruption consistently predicted AF before and after adjustment for OSA and other potential confounders across several different populations. Sleep quality itself may be important in the pathogenesis of AF, potentially representing a novel target for prevention.

}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2018.05.008}, author = {Christensen, Matthew A and Dixit, Shalini and Dewland, Thomas A and Whitman, Isaac R and Nah, Gregory and Vittinghoff, Eric and Mukamal, Kenneth J and Redline, Susan and Robbins, John A and Newman, Anne B and Patel, Sanjay R and Magnani, Jared W and Psaty, Bruce M and Olgin, Jeffrey E and Pletcher, Mark J and Heckbert, Susan R and Marcus, Gregory M} }