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1.
Circ Res ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31691645

RESUMO

Rationale: Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in TTN and early-onset AF. Objective: We sought to determine the contribution of rare and common genetic variation to AF risk in the general population. Methods and Results: The UK Biobank is a population-based study of 500,000 individuals including a subset with genome-wide genotyping and exome sequencing. In this case-control study, we included AF cases and controls of genetically determined white-European ancestry; analyses were performed using a logistic mixed-effects model adjusting for age, sex, the first 4 principal components of ancestry, empirical relationships and case-control imbalance. An exome wide, gene-based burden analysis was performed to examine the relationship between AF and rare, high-confidence LOF variants in genes with {greater than or equal to} 10 LOF carriers. A polygenic risk score (PRS) for AF was estimated using the LDpred algorithm. We then compared the contribution of AF PRS and LOF variants to AF risk. The study included 1,546 AF cases and 41,593 controls. In an analysis of 9,099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene, TTN (OR 2.71, P=2.50x10-8). The association with AF was more significant (OR 6.15, P=3.26x10-14) when restricting to LOF variants located in exons highly expressed in cardiac tissue (TTNLOF). Overall, 0.44% of individuals carried TTNLOF variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF PRS, only 9.3% had AF. In contrast, an AF PRS explained 4.7% of the variance in AF susceptibility, while TTNLOF variants only accounted for 0.2%. Conclusions: Both monogenic and polygenic factors contribute to AF risk in the general population. While monogenic TTNLOF variants confer a substantial AF penetrance, polygenic risk explains a larger proportion of genetic susceptibility to AF.

2.
Circulation ; 2018 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-30586722

RESUMO

BACKGROUND: Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. METHODS: We defined all-cause HF among 488010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30201). RESULTS: We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci ( P<1×10-6), the majority linked to upstream HF risk factors, ie, coronary artery disease ( CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation ( PITX2). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy ( BAG3, CLCNKA-ZBTB17). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated BAG3 as a disease susceptibility gene for NICM (loss-offunction variant carrier frequency=0.01%; odds ratio,12.03; P=3.62×10-5). CONCLUSIONS: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction.

3.
JAMA ; 320(22): 2354-2364, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30535219

RESUMO

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main Outcomes and Measures: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10-3. Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01). Conclusions and Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.


Assuntos
Fibrilação Atrial/genética , Conectina/genética , Mutação com Perda de Função , Adulto , Idade de Início , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Controle de Qualidade
4.
J Gen Intern Med ; 33(12): 2070-2077, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30076573

RESUMO

BACKGROUND: Oral anticoagulants reduce the risk of stroke in patients with atrial fibrillation. However, many patients with atrial fibrillation at elevated stroke risk are not treated with oral anticoagulants. OBJECTIVE: To test whether electronic notifications sent to primary care physicians increase the proportion of ambulatory patients prescribed oral anticoagulants. DESIGN: Randomized controlled trial conducted from February to May 2017 within 18 practices in an academic primary care network. PARTICIPANTS: Primary care physicians (n = 175) and their patients with atrial fibrillation, at elevated stroke risk, and not prescribed oral anticoagulants. INTERVENTION: Patients of each physician were randomized to the notification or usual care arm. Physicians received baseline email notifications and up to three reminders with patient information, educational material and primary care guidelines for anticoagulation management, and surveys in the notification arm. MAIN MEASURES: The primary outcome was the proportion of patients prescribed oral anticoagulants at 3 months in the notification (n = 972) vs. usual care (n = 1364) arms, compared using logistic regression with clustering by physician. Secondary measures included survey-based physician assessment of reasons why patients were not prescribed oral anticoagulants and how primary care physicians might be influenced by the notification. KEY RESULTS: Over 3 months, a small proportion of patients were newly prescribed oral anticoagulants with no significant difference in the notification (3.9%, 95% CI 2.8-5.3%) and usual care (3.2%, 95% CI 2.4-4.2%) arms (p = 0.37). The most common, non-exclusive reasons why patients were not on oral anticoagulants included atrial fibrillation was transient (30%) or paroxysmal (12%), patient/family declined (22%), high bleeding risk (20%), fall risk (19%), and frailty (10%). For 95% of patients, physicians stated they would not change their management after reviewing the alert. CONCLUSIONS: Electronic physician notification did not increase anticoagulation in patients with atrial fibrillation at elevated stroke risk. Primary care physicians did not prescribe anticoagulants because they perceived the bleeding risk was too high or stroke risk was too low. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02950285.

5.
Am Heart J ; 200: 24-31, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29898845

RESUMO

BACKGROUND: Many patients with atrial fibrillation (AF) and elevated stroke risk are not prescribed oral anticoagulation (OAC) despite evidence of benefit. Identification of factors associated with OAC non-prescription could lead to improvements in care. METHODS AND RESULTS: Using NCDR PINNACLE, a United States-based ambulatory cardiology registry, we examined factors associated with OAC non-prescription in patients with non-valvular AF at elevated stroke risk (CHA2DS2-VASc ≥2) between January 5, 2008 and December 31, 2014. Among 674,841 patients, 57% were treated with OAC (67% of whom were treated with warfarin). OAC prescription varied widely (28%-75%) across preselected strata of age, stroke risk (CHA2DS2-VASc), and bleeding risk (HAS-BLED), generally indicating that older patients at high stroke and low bleeding risk are commonly treated with OAC. Other factors associated with OAC non-prescription included reversible AF etiology; female sex; liver, renal, or vascular disease; and physician versus non-physician provider. Antiplatelet use was common (57%) and associated with the greatest risk of OAC non-prescription (odds ratio [OR] 4.44, 95% confidence interval [CI] 4.39-4.49). CONCLUSIONS: In this registry of AF patients, older patients at elevated stroke and low bleeding risk were commonly treated with OAC. However, a variety of factors were associated with OAC non-prescription. Specifically, antiplatelet use was prevalent and associated with the highest likelihood of OAC non-prescription. Future studies are warranted to understand provider and patient rationale that may underlie observed associations with OAC non-prescription.

6.
Thromb Res ; 168: 53-59, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29902632

RESUMO

INTRODUCTION: Data from epidemiological studies and clinical trials suggest an influence of dietary and circulating polyunsaturated fatty acids (PUFAs) on the hemostasis profile. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) related to plasma PUFAs levels. We aimed to investigate whether the SNPs related to plasma PUFAs levels were also associated with plasma levels of hemostatic variables. MATERIALS AND METHODS: We tested the associations between 9 PUFA-related SNPs and 6 hemostatic variables in 9035 European Americans (EAs) and 2702 African Americans (AAs) in the Atherosclerosis Risk in Communities (ARIC) Study. We then conducted a replication study by looking-up our novel observed associations in three published GWAS for hemostatic factors in different EA populations. RESULTS: We observed a novel linoleic acid-related locus at the JMJD1C region associated with factor VII activity (FVIIc): rs10740118 and rs1935, Beta (p) = -1.31 (1 × 10-3) and 1.37 (5 × 10-4) in EAs, respectively, and - 1.24 (5 × 10-4) and 1.28 (3 × 10-4) in meta-analysis of EAs and AAs of ARIC. This novel association was replicated in two of three independent EA populations (p = 0.01 and 0.03 in meta-analyses). We confirmed previously reported associations at the docosapentaenoic acid-related GCKR locus with protein C and FVIIc and at JMJD1C with fibrinogen. Adjustment for plasma PUFAs did not abolish the associations between these loci and hemostatic variables. CONCLUSIONS: Our study identified a novel association for FVIIc at JMJD1C, a histone demethylase that plays a role in DNA repair and possibly transcription regulation and RNA processing.


Assuntos
Ácidos Graxos Ômega-3/genética , Ácidos Graxos Insaturados/genética , Pleiotropia Genética/genética , Variação Genética/genética , Feminino , Hemostáticos , Humanos , Masculino , Pessoa de Meia-Idade
7.
Circ Arrhythm Electrophysiol ; 11(7): e006273, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29954742

RESUMO

BACKGROUND: The frequency of cardiac rhythm abnormalities and their risk factors in community-dwelling adults are not well characterized. METHODS: We determined the frequency of rhythm abnormalities in the UK Biobank, a national prospective cohort. We tested associations between risk factors and incident rhythm abnormalities using multivariable proportional hazards regression. RESULTS: Of 502 627 adults (median age, 58 years [interquartile range, 13]; 54.4% women), 2.35% had a baseline rhythm abnormality. The prevalence increased with age with 4.84% of individuals aged 65 to 73 years affected. During 3 368 332 person-years of follow-up, 15 906 new rhythm abnormalities were detected (4.72 per 1000 person-years; 95% confidence interval [CI]: 4.65-4.80). Atrial fibrillation (3.11 per 1000 person-years; 95% CI: 3.05-3.17), bradyarrhythmias (0.89 per 1000 person-years; 95% CI: 0.86-0.92), and conduction system diseases (1.06 per 1000 person-years; 95% CI: 1.02-1.09) were more common than supraventricular (0.51 per 1000 person-years; 95% CI: 0.48-0.53) and ventricular arrhythmias (0.57 per 1000 person-years; 95% CI: 0.55-0.60). Older age (hazard ratio [HR]: 2.35 per 10-year increase; 95% CI: 2.29-2.41; P<0.01), male sex (HR: 1.83; 95% CI: 1.76-1.89; P<0.01), hypertension (HR: 1.49; 95% CI: 1.44-1.54; P<0.01), chronic kidney disease (HR: 1.95; 95% CI: 1.67-2.27; P<0.01), and heart failure (HR: 1.99; 95% CI: 1.76-2.26; P<0.01) were associated with new rhythm abnormalities. CONCLUSIONS: The frequency of rhythm abnormalities in middle-aged to older community-dwelling adults is substantial. Atrial fibrillation, bradyarrhythmias, and conduction system diseases account for most rhythm conditions.

8.
Nat Genet ; 50(9): 1225-1233, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29892015

RESUMO

Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

9.
Circ Genom Precis Med ; 11(5): e002037, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29748316

RESUMO

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2×10-6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9×10-11) and SCN5A (P=1.1×10-7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

10.
BMJ ; 361: k1453, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29699974

RESUMO

OBJECTIVE: To examine the association between risk factor burdens-categorized as optimal, borderline, or elevated-and the lifetime risk of atrial fibrillation. DESIGN: Community based cohort study. SETTING: Longitudinal data from the Framingham Heart Study. PARTICIPANTS: Individuals free of atrial fibrillation at index ages 55, 65, and 75 years were assessed. Smoking, alcohol consumption, body mass index, blood pressure, diabetes, and history of heart failure or myocardial infarction were assessed as being optimal (that is, all risk factors were optimal), borderline (presence of borderline risk factors and absence of any elevated risk factor), or elevated (presence of at least one elevated risk factor) at index age. MAIN OUTCOME MEASURE: Lifetime risk of atrial fibrillation at index age up to 95 years, accounting for the competing risk of death. RESULTS: At index age 55 years, the study sample comprised 5338 participants (2531 (47.4%) men). In this group, 247 (4.6%) had an optimal risk profile, 1415 (26.5%) had a borderline risk profile, and 3676 (68.9%) an elevated risk profile. The prevalence of elevated risk factors increased gradually when the index ages rose. For index age of 55 years, the lifetime risk of atrial fibrillation was 37.0% (95% confidence interval 34.3% to 39.6%). The lifetime risk of atrial fibrillation was 23.4% (12.8% to 34.5%) with an optimal risk profile, 33.4% (27.9% to 38.9%) with a borderline risk profile, and 38.4% (35.5% to 41.4%) with an elevated risk profile. Overall, participants with at least one elevated risk factor were associated with at least 37.8% lifetime risk of atrial fibrillation. The gradient in lifetime risk across risk factor burden was similar at index ages 65 and 75 years. CONCLUSIONS: Regardless of index ages at 55, 65, or 75 years, an optimal risk factor profile was associated with a lifetime risk of atrial fibrillation of about one in five; this risk rose to more than one in three a third in individuals with at least one elevated risk factor.


Assuntos
Fibrilação Atrial/epidemiologia , Complicações do Diabetes/epidemiologia , Hipertensão/epidemiologia , Fatores Etários , Idoso , Fibrilação Atrial/etiologia , Feminino , Inquéritos Epidemiológicos , Humanos , Hipertensão/complicações , Estilo de Vida , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
PLoS One ; 13(4): e0195719, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29649275

RESUMO

Studies have reported that higher circulating levels of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol and lower of high-density lipoprotein (HDL) cholesterol may be associated with increased risk of abdominal aortic aneurysm (AAA). Whether dyslipidemia causes AAA is still unclear and is potentially testable using a Mendelian randomization (MR) approach. We investigated the associations between blood lipids and AAA using two-sample MR analysis with SNP-lipids association estimates from a published genome-wide association study of blood lipids (n = 188,577) and SNP-AAA association estimates from European Americans (EAs) of the Atherosclerosis Risk in Communities (ARIC) study (n = 8,793). We used inverse variance weighted (IVW) MR as the primary method and MR-Egger regression and weighted median MR estimation as sensitivity analyses. Over a median of 22.7 years of follow-up, 338 of 8,793 ARIC participants experienced incident clinical AAA. Using the IVW method, we observed positive associations of plasma LDL cholesterol and TC with the risk of AAA (odds ratio (OR) = 1.55, P = 0.02 for LDL cholesterol and OR = 1.61, P = 0.01 for TC per 1 standard deviation of lipid increment). Using the MR-Egger regression and weighted median methods, we were able to validate the association of AAA risk with TC, although the associations were less consistent for LDL cholesterol due to wider confidence intervals. Triglycerides and HDL cholesterol were not associated with AAA in any of the MR methods. Assuming instrumental variable assumptions are satisfied, our finding suggests that higher plasma TC and LDL cholesterol are causally associated with the increased risk of AAA in EAs.


Assuntos
Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/genética , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/etiologia , Causalidade , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/genética , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangue
12.
Circulation ; 137(10): 1027-1038, 2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29129827

RESUMO

BACKGROUND: The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown. METHODS: We estimated the lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of ≈1000 AF-associated single-nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes mellitus, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk. RESULTS: Among 4606 participants without AF at 55 years of age, 580 developed incident AF (median follow-up, 9.4 years; 25th-75th percentile, 4.4-14.3 years). The lifetime risk of AF >55 years of age was 37.1% and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at 55 years of age, those in low-polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval, 15.4-9.1), whereas those in high-risk tertiles had a risk of 48.2% (95% confidence interval, 41.3-55.1). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition (P<0.001). CONCLUSIONS: In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible and together with clinical risk factor burden explains a substantial gradient in long-term AF risk.

13.
Circ Cardiovasc Genet ; 10(6)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29237688

RESUMO

BACKGROUND: Previous reports have implicated multiple genetic loci associated with AF, but the contributions of genome-wide variation to AF susceptibility have not been quantified. METHODS AND RESULTS: We assessed the contribution of genome-wide single-nucleotide polymorphism variation to AF risk (single-nucleotide polymorphism heritability, h2g ) using data from 120 286 unrelated individuals of European ancestry (2987 with AF) in the population-based UK Biobank. We ascertained AF based on self-report, medical record billing codes, procedure codes, and death records. We estimated h2g using a variance components method with variants having a minor allele frequency ≥1%. We evaluated h2g in age, sex, and genomic strata of interest. The h2g for AF was 22.1% (95% confidence interval, 15.6%-28.5%) and was similar for early- versus older-onset AF (≤65 versus >65 years of age), as well as for men and women. The proportion of AF variance explained by genetic variation was mainly accounted for by common (minor allele frequency, ≥5%) variants (20.4%; 95% confidence interval, 15.1%-25.6%). Only 6.4% (95% confidence interval, 5.1%-7.7%) of AF variance was attributed to variation within known AF susceptibility, cardiac arrhythmia, and cardiomyopathy gene regions. CONCLUSIONS: Genetic variation contributes substantially to AF risk. The risk for AF conferred by genomic variation is similar to that observed for several other cardiovascular diseases. Established AF loci only explain a moderate proportion of disease risk, suggesting that further genetic discovery, with an emphasis on common variation, is warranted to understand the causal genetic basis of AF.


Assuntos
Fibrilação Atrial/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido
14.
Circ Cardiovasc Genet ; 10(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28974514

RESUMO

BACKGROUND: Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor PRRX1 could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility. METHODS AND RESULTS: We sequenced a ≈158 kb region encompassing PRRX1 in 962 individuals with and without AF. We identified a broad region of association with AF at the 1q24 locus. Using in silico prediction and functional validation, we identified an enhancer that interacts with the promoter of PRRX1 in cells of cardiac lineage. Within this enhancer, we identified a single-nucleotide polymorphism, rs577676, which alters enhancer activity in a mouse atrial cell line and in embryonic zebrafish and differentially regulates PRRX1 expression in human left atria. We found that suppression of PRRX1 in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF. CONCLUSIONS: We have identified a functional genetic variant that alters PRRX1 expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.


Assuntos
Potenciais de Ação/genética , Fibrilação Atrial , Proteínas de Homeodomínio , Células-Tronco Embrionárias Humanas/metabolismo , Miócitos Cardíacos/metabolismo , Polimorfismo de Nucleotídeo Único , Animais , Animais Geneticamente Modificados , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Linhagem Celular , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Células-Tronco Embrionárias Humanas/patologia , Humanos , Camundongos , Miócitos Cardíacos/patologia , Peixe-Zebra
15.
Sci Rep ; 7(1): 11303, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28900195

RESUMO

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

16.
Am J Cardiol ; 120(8): 1316-1321, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28823487

RESUMO

Oral anticoagulation (OAC) is effective yet reportedly underutilized for stroke prevention in atrial fibrillation (AF). Factors associated with delayed OAC after incident AF are unknown. Using a large electronic medical record, we identified incident episodes of AF diagnosed in 2006 to 2014 using a validated algorithm. Among patients with a Congestive heart failure, Hypertension, Age, Diabetes, and Stroke (CHADS2) score ≥1 started on OAC within 1 year, we examined baseline characteristics at AF diagnosis and their association with time to OAC using multivariable Cox proportional hazards modeling. Of 4,388 patients with incident AF and CHADS2 score ≥1 who were started on OAC within 1 year, the mean age was 72.6, and 41% were women. Median time to OAC was 5 days (interquartile range 1 to 43), and most patients received warfarin (86.3%). Among patients without prevalent stroke, 98 strokes (2.2% of the sample) occurred between AF diagnosis and OAC initiation. In multivariable analyses, several factors were associated with delayed OAC including female gender (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.01 to 1.15), absence of hypertension (HR 1.15, 95% CI 1.03 to 1.27), previous fall (HR 1.53, 95% CI 1.08 to 2.17), and chronic kidney disease (HR 1.12, 95% CI 1.04 to 1.21). Among women, OAC prescription at 1, 3, and 6 months was 70.0%, 81.7%, and 89.5%, respectively, whereas for men, OAC prescription was 73.4%, 84.0%, and 91.5%, respectively. Most patients with new AF and elevated stroke risk started on OAC receive it within 1 week, although the promptness of initiation varies. The stroke rate is substantial in the period between AF diagnosis and OAC initiation. Interventions targeting identified risk factors for delayed OAC may result in improved outcomes.


Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/complicações , Medição de Risco , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Idoso , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Incidência , Masculino , Massachusetts/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Fatores de Tempo
17.
Circ Cardiovasc Genet ; 10(4)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28794112

RESUMO

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies. METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction. CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.


Assuntos
Eletrocardiografia , Loci Gênicos , Estudo de Associação Genômica Ampla , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Caveolina 1/genética , Caveolina 2/genética , Genótipo , Átrios do Coração/metabolismo , Humanos , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Proteínas com Domínio T/genética
19.
Stroke ; 48(6): 1451-1456, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28468926

RESUMO

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes. METHODS: We examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds. RESULTS: There were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association (P=6×10-4) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at P<1×10-3 in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest P=1.2×10-9, 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes. CONCLUSIONS: Comprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses.


Assuntos
Fibrilação Atrial/genética , Isquemia Encefálica/genética , Embolia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Acidente Vascular Cerebral/genética , Estudos de Casos e Controles , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Reino Unido
20.
Nat Genet ; 49(6): 946-952, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28416818

RESUMO

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.


Assuntos
Fibrilação Atrial/genética , Loci Gênicos , Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
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