%0 Journal Article %J Nat Genet %D 2012 %T Meta-analysis identifies six new susceptibility loci for atrial fibrillation. %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Albert, Christine M %A Glazer, Nicole L %A Ritchie, Marylyn D %A Smith, Albert V %A Arking, Dan E %A Müller-Nurasyid, Martina %A Krijthe, Bouwe P %A Lubitz, Steven A %A Bis, Joshua C %A Chung, Mina K %A Dörr, Marcus %A Ozaki, Kouichi %A Roberts, Jason D %A Smith, J Gustav %A Pfeufer, Arne %A Sinner, Moritz F %A Lohman, Kurt %A Ding, Jingzhong %A Smith, Nicholas L %A Smith, Jonathan D %A Rienstra, Michiel %A Rice, Kenneth M %A Van Wagoner, David R %A Magnani, Jared W %A Wakili, Reza %A Clauss, Sebastian %A Rotter, Jerome I %A Steinbeck, Gerhard %A Launer, Lenore J %A Davies, Robert W %A Borkovich, Matthew %A Harris, Tamara B %A Lin, Honghuang %A Völker, Uwe %A Völzke, Henry %A Milan, David J %A Hofman, Albert %A Boerwinkle, Eric %A Chen, Lin Y %A Soliman, Elsayed Z %A Voight, Benjamin F %A Li, Guo %A Chakravarti, Aravinda %A Kubo, Michiaki %A Tedrow, Usha B %A Rose, Lynda M %A Ridker, Paul M %A Conen, David %A Tsunoda, Tatsuhiko %A Furukawa, Tetsushi %A Sotoodehnia, Nona %A Xu, Siyan %A Kamatani, Naoyuki %A Levy, Daniel %A Nakamura, Yusuke %A Parvez, Babar %A Mahida, Saagar %A Furie, Karen L %A Rosand, Jonathan %A Muhammad, Raafia %A Psaty, Bruce M %A Meitinger, Thomas %A Perz, Siegfried %A Wichmann, H-Erich %A Witteman, Jacqueline C M %A Kao, W H Linda %A Kathiresan, Sekar %A Roden, Dan M %A Uitterlinden, André G %A Rivadeneira, Fernando %A McKnight, Barbara %A Sjögren, Marketa %A Newman, Anne B %A Liu, Yongmei %A Gollob, Michael H %A Melander, Olle %A Tanaka, Toshihiro %A Stricker, Bruno H Ch %A Felix, Stephan B %A Alonso, Alvaro %A Darbar, Dawood %A Barnard, John %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Gudnason, Vilmundur %A Kääb, Stefan %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Atrial Fibrillation %K Child %K Child, Preschool %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Infant %K Infant, Newborn %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K Young Adult %X

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

%B Nat Genet %V 44 %P 670-5 %8 2012 Apr 29 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22544366?dopt=Abstract %R 10.1038/ng.2261 %0 Journal Article %J Circ Arrhythm Electrophysiol %D 2014 %T Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging. %A Roberts, Jason D %A Dewland, Thomas A %A Longoria, James %A Fitzpatrick, Annette L %A Ziv, Elad %A Hu, Donglei %A Lin, Jue %A Glidden, David V %A Psaty, Bruce M %A Burchard, Esteban G %A Blackburn, Elizabeth H %A Olgin, Jeffrey E %A Heckbert, Susan R %A Marcus, Gregory M %K Age Factors %K Aged %K Aging %K Atrial Fibrillation %K California %K Cardiac Surgical Procedures %K Cellular Senescence %K Cross-Sectional Studies %K Female %K Genetic Predisposition to Disease %K Humans %K Incidence %K Leukocytes %K Male %K Phenotype %K Polymorphism, Single Nucleotide %K Prospective Studies %K Risk Assessment %K Risk Factors %K Telomerase %K Telomere %K Time Factors %X

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 ± 0.20 versus 1.02 ± 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.

%B Circ Arrhythm Electrophysiol %V 7 %P 1026-32 %8 2014 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25381796?dopt=Abstract %R 10.1161/CIRCEP.114.001781 %0 Journal Article %J JAMA Cardiol %D 2016 %T Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals. %A Roberts, Jason D %A Hu, Donglei %A Heckbert, Susan R %A Alonso, Alvaro %A Dewland, Thomas A %A Vittinghoff, Eric %A Liu, Yongmei %A Psaty, Bruce M %A Olgin, Jeffrey E %A Magnani, Jared W %A Huntsman, Scott %A Burchard, Esteban G %A Arking, Dan E %A Bibbins-Domingo, Kirsten %A Harris, Tamara B %A Perez, Marco V %A Ziv, Elad %A Marcus, Gregory M %X

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.

%B JAMA Cardiol %V 1 %P 442-50 %8 2016 Jul 1 %G eng %N 4 %R 10.1001/jamacardio.2016.1185 %0 Journal Article %J Am Heart J %D 2016 %T Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation. %A Roberts, Jason D %A Dewland, Thomas A %A Glidden, David V %A Hoffmann, Thomas J %A Arking, Dan E %A Chen, Lin Y %A Psaty, Bruce M %A Olgin, Jeffrey E %A Alonso, Alvaro %A Heckbert, Susan R %A Marcus, Gregory M %X

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.

%B Am Heart J %V 175 %P 9-17 %8 2016 May %G eng %R 10.1016/j.ahj.2016.02.002 %0 Journal Article %J Sci Rep %D 2019 %T Alcohol consumption and leukocyte telomere length. %A Dixit, Shalini %A Whooley, Mary A %A Vittinghoff, Eric %A Roberts, Jason D %A Heckbert, Susan R %A Fitzpatrick, Annette L %A Lin, Jue %A Leung, Cindy %A Mukamal, Kenneth J %A Marcus, Gregory M %X

The relationship between alcohol consumption and mortality generally exhibits a U-shaped curve. The longevity observed with moderate alcohol consumption may be explained by other confounding factors, and, if such a relationship is present, the mechanism is not well understood. Indeed, the optimal amount of alcohol consumption for health has yet to be determined. Leukocyte telomere length is an emerging quantifiable marker of biological age and health, and a shorter telomere length is a predictor of increased mortality. Because leukocyte telomere length is a quantifiable and objectively measurable biomarker of aging, we sought to identify the amount of alcohol consumption associated with the longest telomere length and least telomere length attrition. Among over 2,000 participants from two distinct cohort studies, we found no pattern of alcohol consumption that was associated with longer telomere length or less telomere length attrition over time. Binge drinking may reduce telomere length. Using telomere length as a marker of age and health, these data fail to demonstrate any benefits of alcohol consumption, even when consumed in moderation.

%B Sci Rep %V 9 %P 1404 %8 2019 Feb 05 %G eng %N 1 %R 10.1038/s41598-019-38904-0 %0 Journal Article %J Circulation %D 2021 %T Epigenetic Age and the Risk of Incident Atrial Fibrillation. %A Roberts, Jason D %A Vittinghoff, Eric %A Lu, Ake T %A Alonso, Alvaro %A Wang, Biqi %A Sitlani, Colleen M %A Mohammadi-Shemirani, Pedrum %A Fornage, Myriam %A Kornej, Jelena %A Brody, Jennifer A %A Arking, Dan E %A Lin, Honghuang %A Heckbert, Susan R %A Prokic, Ivana %A Ghanbari, Mohsen %A Skanes, Allan C %A Bartz, Traci M %A Perez, Marco V %A Taylor, Kent D %A Lubitz, Steven A %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Pankow, James S %A Paré, Guillaume %A Sotoodehnia, Nona %A Benjamin, Emelia J %A Horvath, Steve %A Marcus, Gregory M %K Aged %K Aging %K Atrial Fibrillation %K DNA Methylation %K Epigenesis, Genetic %K Epigenomics %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Models, Cardiovascular %K Models, Genetic %X

BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.

METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.

RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.

CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

%B Circulation %V 144 %P 1899-1911 %8 2021 12 14 %G eng %N 24 %R 10.1161/CIRCULATIONAHA.121.056456