Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure.
Ontology highlight
ABSTRACT:
SUBMITTER: Verweij N
PROVIDER: S-EPMC5459820 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
Publications
Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure.
Verweij Niek N Eppinga Ruben N RN Hagemeijer Yanick Y van der Harst Pim P
Scientific reports 20170605 1
Coronary artery disease (CAD) is the major cause of morbidity and mortality in the world. Identification of novel genetic determinants may provide new opportunities for developing innovative strategies to predict, prevent and treat CAD. Therefore, we meta-analyzed independent genetic variants passing P <× 10<sup>-5</sup> in CARDIoGRAMplusC4D with novel data made available by UK Biobank. Of the 161 genetic variants studied, 71 reached genome wide significance (p < 5 × 10<sup>-8</sup>) including 1 ...[more]
Similar Datasets
Project description:Background Perioperative atrial fibrillation (POAF) is common in patients undergoing cardiac surgery. Conflicting evidence exists whether patients with POAF after cardiac surgery have an increased long-term risk of stroke and other adverse events. Methods and Results We prospectively followed for up to 5 years 4624 patients without prior atrial fibrillation who underwent coronary artery bypass grafting in an international study. POAF was defined as atrial fibrillation that occurred during the initial hospitalization for surgery, lasted for ≥5 minutes, and required treatment. Outcomes assessed were a composite of death, nonfatal myocardial infarction or nonfatal stroke, and its individual components. Median age was 67 years, and 778 (16.8%) had an episode of POAF. The incidence of the composite outcome was 6.84 and 4.10 per 100 patient-years in patients with and without POAF, and the incidence of stroke was 0.75 versus 0.45, respectively. The adjusted hazard ratios (aHRs) were 1.36 (95% CI, 1.16-1.59) for the composite outcome; 1.33 (95% CI, 1.10-1.61) for death; 1.58 (95% CI, 1.23-2.02) for myocardial infarction, and 1.27 (95% CI, 0.81-2.00) for stroke. In a landmark analysis excluding events of the initial hospital admission, the aHRs were 1.26 (95% CI, 1.03-1.54) for the composite outcome, 1.28 (95% CI, 1.03-1.59) for death, 1.70 (95% CI, 0.86-3.36) for myocardial infarction, and 1.07 (95% CI, 0.59-1.93) for stroke. At hospital discharge, 10.7% and 1.4% of patients with and without POAF received oral anticoagulation, respectively. Conclusions Patients with POAF after cardiac surgery had an increased long-term risk of adverse outcomes, mainly death and myocardial infarction. The risk of stroke was low and not increased in patients with POAF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00463294.
| S-EPMC8477852 | biostudies-literature
Project description:Background The CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke or TIA [transient ischemic attack], vascular disease, age 65 to 74 years, sex category female; 2 indicates 2 points, otherwise 1 point) scoring system is recommended to guide decisions on oral anticoagulation therapy for stroke prevention in patients with nonsurgery atrial fibrillation. A score ≥1 in men and ≥2 in women, corresponding to an annual stroke risk exceeding 1%, warrants long-term oral anticoagulation provided the bleeding risk is acceptable. However, in patients with new-onset postoperative atrial fibrillation, the optimal risk stratification method is unknown. The aim of this study was therefore to evaluate the CHA2DS2-VASc scoring system for estimating the 1-year ischemic stroke risk in patients with new-onset postoperative atrial fibrillation after coronary artery bypass grafting. Methods and Results All patients with new-onset postoperative atrial fibrillation and without oral anticoagulation after first-time isolated coronary artery bypass grafting performed in Sweden during 2007 to 2017 were eligible for this registry-based observational cohort study. The 1-year ischemic stroke rate at each step of the CHA2DS2-VASc score was estimated using a Kaplan-Meier estimator. Of the 6368 patients included (mean age, 69.9 years; 81% men), >97% were treated with antiplatelet drugs. There were 147 ischemic strokes during the first year of follow-up. The ischemic stroke rate at 1 year was 0.3%, 0.7%, and 1.5% in patients with CHA2DS2-VASc scores of 1, 2, and 3, respectively, and ≥2.3% in patients with a score ≥4. A sensitivity analysis, with the inclusion of patients on anticoagulants, was performed and supported the primary results. Conclusions Patients with new-onset atrial fibrillation after coronary artery bypass grafting and a CHA2DS2-VASc score <3 have such a low 1-year risk for ischemic stroke that oral anticoagulation therapy should probably be avoided.
| S-EPMC9238552 | biostudies-literature
Project description:ImportanceNew-onset postoperative atrial fibrillation (POAF) is a common complication of coronary artery bypass graft (CABG) surgery. However, the long-term risk of thromboembolism in patients who develop POAF after CABG surgery remains unknown. In addition, information on stroke prophylaxis in this setting is lacking.ObjectiveTo examine stroke prophylaxis and the long-term risk of thromboembolism in patients with new-onset POAF after first-time isolated CABG surgery compared with patients with nonsurgical, nonvalvular atrial fibrillation (NVAF).Design, setting, and participantsThis cohort study used data from a clinical cardiac surgery database and Danish nationwide registries to identify patients undergoing first-time isolated CABG surgery who developed new-onset POAF from January 1, 2000, through June 30, 2015. These patients were matched by age, sex, CHA2DS2-VASc score, and year of diagnosis to patients with nonsurgical NVAF in a 1 to 4 ratio. Data analysis was completed from February 2017 to January 2018.Main outcomes and measuresThe proportion of patients initiating oral anticoagulation therapy within 30 days and the rates of thromboembolism.ResultsA total of 2108 patients who developed POAF after CABG surgery were matched with 8432 patients with NVAF. In the full population of 10 540 patients, the median (interquartile range) age was 69.2 (63.7-74.7) years; 8675 patients (82.3%) were men. Oral anticoagulation therapy was initiated within 30 days postdischarge in 175 patients with POAF (8.4%) and 3549 patients with NVAF (42.9%). The risk of thromboembolism was lower in the POAF group than in the NVAF group (18.3 vs 29.7 events per 1000 person-years; adjusted hazard ratio [HR], 0.67; 95% CI, 0.55-0.81; P < .001). Anticoagulation therapy during follow-up was associated with a lower risk of thromboembolic events in both patients with POAF (adjusted HR, 0.55; 95% CI, 0.32-0.95; P = .03) and NVAF (adjusted HR, 0.59; 95% CI, 0.51-0.68; P < .001) compared with patients who did not receive any anticoagulation therapy. Further, the risk of thromboembolism was not significantly higher in patients with POAF compared with those who did not develop POAF after CABG surgery (adjusted HR, 1.11; 95% CI, 0.94-1.32; P < .24).Conclusions and relevanceNew-onset POAF in patients who had undergone CABG surgery was associated with a lower long-term thromboembolic risk than that of patients who had NVAF. These data do not support the notion that new-onset POAF should be regarded as equivalent to primary NVAF in terms of long-term thromboembolic risk.
| S-EPMC5875315 | biostudies-literature
Project description:Background The clinical significance of fibrillatory wave on electrocardiography during atrial fibrillation (AF) is poorly understood. The aim of the current study was to explore the association of fine fibrillatory wave with heart failure (HF) in AF. Methods and Results The current study enrolled 2442 patients with AF whose baseline ECG during AF rhythm was available from a community-based prospective survey, the Fushimi AF Registry. The impact of fine fibrillatory wave, defined as the amplitude of fibrillatory waves <0.1 mV, on the primary composite HF end point (a composite of hospitalization attributable to HF or cardiac death) was examined. Fine fibrillatory wave was observed in 589 patients (24.1%). Patients with fine fibrillatory wave were older, and had a higher prevalence of sustained AF, preexisting HF, and larger left atrial diameter than those with coarse fibrillatory wave. During the median follow-up duration of 5.9 years, the cumulative incidence of the primary composite HF end point was significantly higher in patients with fine fibrillatory wave than in those with coarse fibrillatory wave (5.3% versus 3.6% per patient-year, log-rank P<0.001). The higher risk associated with fine fibrillatory wave was consistent even for individual components of the primary composite HF end point. On multivariable analysis, fine fibrillatory wave became an independent predictor for the primary composite HF end point (hazard ratio, 1.31; 95% CI, 1.07-1.61; P=0.01). Conclusions Compared with coarse fibrillatory wave, fine fibrillatory wave was more prevalent in patients with a larger left atrial diameter or those with sustained AF and was independently associated with a higher risk of HF events. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000005834.
| S-EPMC9075419 | biostudies-literature
Project description:BACKGROUND:Genome-wide association studies have identified multiple loci associated with coronary artery disease and myocardial infarction, but only a few of these loci are current targets for on-market medications. To identify drugs suitable for repurposing and their targets, we created 2 unique pipelines integrating public data on 49 coronary artery disease/myocardial infarction-genome-wide association studies loci, drug-gene interactions, side effects, and chemical interactions. METHODS:We first used publicly available genome-wide association studies results on all phenotypes to predict relevant side effects, identified drug-gene interactions, and prioritized candidates for repurposing among existing drugs. Second, we prioritized gene product targets by calculating a druggability score to estimate how accessible pockets of coronary artery disease/myocardial infarction-associated gene products are, then used again the genome-wide association studies results to predict side effects, excluded loci with widespread cross-tissue expression to avoid housekeeping and genes involved in vital processes and accordingly ranked the remaining gene products. RESULTS:These pipelines ultimately led to 3 suggestions for drug repurposing: pentolinium, adenosine triphosphate, and riociguat (to target CHRNB4, ACSS2, and GUCY1A3, respectively); and 3 proteins for drug development: LMOD1 (leiomodin 1), HIP1 (huntingtin-interacting protein 1), and PPP2R3A (protein phosphatase 2, regulatory subunit b-double prime, ?). Most current therapies for coronary artery disease/myocardial infarction treatment were also rediscovered. CONCLUSIONS:Integration of genomic and pharmacological data may prove beneficial for drug repurposing and development, as evidence from our pipelines suggests.
| S-EPMC6205215 | biostudies-literature
Project description:Obesity has been identified as a risk factor for postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG). However, no studies have addressed the influence of race on this association. A total of 13,594 patients undergoing first-time, isolated CABG without preoperative AF between 1992 and 2011 were included in our study. The association between body mass index and POAF was compared by race. Relative risk and 95% CIs were computed using maximum likelihood log-binomial regression. Increasing levels of body mass index were associated with higher POAF risk after CABG in black but not white patients (pinteraction = 0.0009).
| S-EPMC4799751 | biostudies-literature
Project description:BackgroundPostoperative atrial fibrillation (pAF) after coronary artery bypass grafting is a common complication. Whether pAF is associated with an increased risk of cerebrovascular accident (CVA) remains uncertain. We investigated the association between pAF and long-term risk of CVA by performing a post hoc analysis of 10-year outcomes of the ART (Arterial Revascularization Trial).MethodsFor the present analysis, among patients enrolled in the ART (n=3102), we excluded those who did not undergo surgery (n=25), had a history of atrial fibrillation (n=45), or had no information on the incidence of pAF (n=9). The final population consisted of 3023 patients, of whom 734 (24.3%) developed pAF with the remaining 2289 maintaining sinus rhythm. Competing risk and Cox regression analyses were used to investigate the association between pAF and the risk of CVA.ResultsAt 10 years, the cumulative incidence of CVA was 6.3% (4.6%-8.1%) versus 3.7% (2.9%-4.5%) in patients with pAF and sinus rhythm, respectively. pAF was an independent predictor of CVA at 10 years (hazard ratio, 1.53 [95% CI, 1.06-2.23]; P=0.025) even when CVAs that occurred during the index admission were excluded from the analysis (hazard ratio, 1.47 [95% 1.02-2.11]; P=0.04).ConclusionsPatients with pAF after coronary artery bypass grafting are at higher risk of CVA. These findings challenge the notion that pAF is a benign complication.
| S-EPMC7845484 | biostudies-literature
Project description:Patients with atrial fibrillation affected by an acute coronary syndrome have indications for oral anticoagulation and dual antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate receptor inhibitor after coronary artery stenting. The concurrent use of all 3 agents, termed triple oral antithrombotic therapy, significantly increases the risk of bleeding. To date, there is a lack of evidence on the proper combination and duration of anticoagulant and antiplatelet agents in patients with indications for both therapies. As such, care has been guided by expert opinion, and there is wide variation in clinician practice. In this review, the latest evidence on the risks and benefits of triple oral antithrombotic therapy in patients with atrial fibrillation after coronary artery stenting is summarized. We discuss the clinical risk scores useful in guiding the prediction of stroke, bleeding, and stent thrombosis. Additionally, we highlight where additional evidence is needed to determine the proper balance of anticoagulant and antiplatelet agents in this patient population.
| S-EPMC6649565 | biostudies-literature
Project description:Several studies have shown an overlap between genes involved in the pathophysiological mechanisms of atrial fibrillation (AF) and Brugada Syndrome (BrS). We investigated whether three single-nucleotide polymorphisms (SNPs) (rs11708996; G>C located intronic to SCN5A, rs10428132; T>G located in SCN10A, and rs9388451; T>C located downstream to HEY2) at loci associated with BrS in a recent genome-wide association study (GWAS) also were associated with AF. A total of 657 patients diagnosed with AF and a control group comprising 741 individuals free of AF were included. The three SNPs were genotyped using TaqMan assays. The frequencies of risk alleles in the AF population and the control population were compared in two-by-two models. One variant, rs10428132 at SCN10A, was associated with a statistically significant decreased risk of AF (odds ratio (OR)=0.77, P=0.001). A meta-analysis was performed by enriching the control population with allele frequencies from controls in the recently published BrS GWAS (2230 alleles). In this meta-analysis, both rs10428132 at SCN10A (OR=0.73, P=5.7 × 10(-6)) and rs11708996 at SCN5A (OR=0.80, P=0.02) showed a statistically significant decreased risk of AF. When assessing the additive effect of the three loci, we found that the risk of AF decreased in a dose-responsive manner with increasing numbers of risk alleles (OR=0.50, P=0.001 for individuals carrying ?4 risk alleles vs ?1 allele). In conclusion, the prevalence of three risk alleles previously associated with BrS was lower in AF patients than in patients free of AF, suggesting a protective role of these loci in developing AF.
| S-EPMC4231412 | biostudies-literature
Project description:Atrial fibrillation (AF), defined by disorganized atrial cardiac rhythm, is the most prevalent cardiac arrhythmia worldwide. Recent genetic studies have highlighted a major heritable component and identified numerous loci associated with AF risk, including the cardiogenic transcription factor genes TBX5, GATA4, and NKX2-5. We report that Tbx5 and Gata4 interact with opposite signs for atrial rhythm controls compared with cardiac development. Using mouse genetics, we found that AF pathophysiology caused by Tbx5 haploinsufficiency, including atrial arrhythmia susceptibility, prolonged action potential duration, and ectopic cardiomyocyte depolarizations, were all rescued by Gata4 haploinsufficiency. In contrast, Nkx2-5 haploinsufficiency showed no combinatorial effect. The molecular basis of the TBX5/GATA4 interaction included normalization of intra-cardiomyocyte calcium flux and expression of calcium channel genes Atp2a2 and Ryr2. Furthermore, GATA4 and TBX5 showed antagonistic interactions on an Ryr2 enhancer. Atrial rhythm instability caused by Tbx5 haploinsufficiency was rescued by a decreased dose of phospholamban, a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, consistent with a role for decreased sarcoplasmic reticulum calcium flux in Tbx5-dependent AF susceptibility. This work defines a link between Tbx5 dose, sarcoplasmic reticulum calcium flux, and AF propensity. The unexpected interactions between Tbx5 and Gata4 in atrial rhythm control suggest that evaluating specific interactions between genetic risk loci will be necessary for ascertaining personalized risk from genetic association data.
| S-EPMC6819107 | biostudies-literature