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OBJECTIVE - Phenome-wide association studies (PheWAS) scan across billing codes in the electronic health record (EHR) and re-purpose clinical EHR data for research. In this study, we examined whether PheWAS could function as an EHR-based discovery tool for systemic lupus erythematosus (SLE) and identified novel clinical associations in male versus female patients with SLE.
METHODS - We used a de-identified version of the Vanderbilt University Medical Center EHR, which includes more than 2.8 million subjects. We performed EHR-based PheWAS to compare SLE patients with age-, sex-, and race-matched control subjects and to compare male SLE patients with female SLE patients, controlling for multiple testing using a false discovery rate (FDR) P value of 0.05.
RESULTS - We identified 1,097 patients with SLE and 5,735 matched control subjects. In a comparison of patients with SLE and matched controls, SLE patients were shown to be more likely to have International Classification of Diseases, Ninth Revision codes related to the SLE disease criteria. In the PheWAS of male versus female SLE patients, with adjustment for age and race, male patients were shown to be more likely to have atrial fibrillation (odds ratio 4.50, false discovery rate P = 3.23 × 10 ). Chart review confirmed atrial fibrillation, with the majority of patients developing atrial fibrillation after the SLE diagnosis and having multiple risk factors for atrial fibrillation. After adjustment for age, sex, race, and coronary artery disease, SLE disease status was shown to be significantly associated with atrial fibrillation (P = 0.002).
CONCLUSION - Using PheWAS to compare male and female patients with SLE, we identified a novel association of an increased incidence of atrial fibrillation in male patients. SLE disease status was shown to be independently associated with atrial fibrillation, even after adjustment for age, sex, race, and coronary artery disease. These results demonstrate the utility of PheWAS as an EHR-based discovery tool for SLE.
© 2018, American College of Rheumatology.
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). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10). 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.
BACKGROUND AND OBJECTIVES - The incidence of atrial fibrillation is high in ESRD, but limited data are available on the incidence of atrial fibrillation across a broad range of kidney function. Thus, we examined the association of eGFR and urine albumin-to-creatinine ratio with risk of incident atrial fibrillation.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - We meta-analyzed three prospective cohorts: the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Cox regression models were performed examining the association of eGFR and urine albumin-to-creatinine ratio with incident atrial fibrillation adjusting for demographics and comorbidity. In additional analyses, we adjusted for measures of subclinical cardiovascular disease (by electrocardiogram and cardiac imaging) and interim heart failure and myocardial infarction events.
RESULTS - In the meta-analyzed study population of 16,769 participants without prevalent atrial fibrillation, across categories of decreasing eGFR (eGFR>90 [reference], 60-89, 45-59, 30-44, and <30 ml/min per 1.73 m), there was a stepwise increase in the adjusted risk of incident atrial fibrillation: hazard ratios (95% confidence intervals) were 1.00, 1.09 (0.97 to 1.24), 1.17 (1.00 to 1.38), 1.59 (1.28 to 1.98), and 2.03 (1.40 to 2.96), respectively. There was a stepwise increase in the adjusted risk of incident atrial fibrillation across categories of increasing urine albumin-to-creatinine ratio (urine albumin-to-creatinine ratio <15 [reference], 15-29, 30-299, and ≥300 mg/g): hazard ratios (95% confidence intervals) were 1.00, 1.04 (0.83 to 1.30), 1.47 (1.20 to 1.79), and 1.76 (1.18 to 2.62), respectively. The associations were consistent after adjustment for subclinical cardiovascular disease measures and interim heart failure and myocardial infarction events.
CONCLUSIONS - In this meta-analysis of three cohorts, reduced eGFR and elevated urine albumin-to-creatinine ratio were significantly associated with greater risk of incident atrial fibrillation, highlighting the need for further studies to understand mechanisms linking kidney disease with atrial fibrillation.
Copyright © 2017 by the American Society of Nephrology.
The first-in-class Bruton's tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation (AF) has been reported in 6-16% of ibrutinib patients. We pooled data from 1505 chronic lymphocytic leukemia and mantle cell lymphoma patients enrolled in four large, randomized, controlled studies to characterize AF with ibrutinib and its management. AF incidence was 6.5% [95% Confidence Interval (CI): 4.8, 8.5] for ibrutinib at 16.6-months 1.6% (95%CI: 0.8, 2.8) for comparator and 10.4% (95%CI: 8.4, 12.9) at the 36-month follow up; estimated cumulative incidence: 13.8% (95%CI: 11.2, 16.8). Ibrutinib treatment, prior history of AF and age 65 years or over were independent risk factors for AF. Multiple AF events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with AF did not discontinue ibrutinib, and more than half received common anticoagulant/antiplatelet medications on study. Low-grade bleeds were more frequent with ibrutinib, but serious bleeds were uncommon (ibrutinib, 2.9%; comparator, 2.0%). Although the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation ().
Copyright© 2017 Ferrata Storti Foundation.
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.
BACKGROUND - One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability.
METHODS AND RESULTS - We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; =0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; =0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; =0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16]).
CONCLUSIONS - The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.
© 2017 American Heart Association, Inc.
Obstructive sleep apnea (OSA) and single nucleotide polymorphisms (SNPs) at the 4q25 locus are associated with increased risk of atrial fibrillation (AF). Whether these associations are independent of traditional risk factors for AF remains unknown. Using billing code queries and manual chart review, we assembled a cohort of adults that underwent overnight polysomnography and at least 1 12-lead electrocardiogram. Case status was defined by electrocardiographic data in support of AF or documentation of AF by a staff cardiologist. Controls were defined by a lack of primary evidence of AF and absence of a diagnosis of AF in the medical record. OSA severity was categorized based on Apnea-Hypopnea Index. Genotyping for a key 4q25 SNP (rs2200733) was performed using the Sequenom platform. Logistic regression was used to test for associations of AF with OSA category and 4q25 SNP genotype while adjusting for age, gender, body mass index, ancestry, hypertension status, and heart failure status. The cohort consisted of 674 subjects (62 ± 13 years; 44% women), including 132 patients with AF. After adjustment for established risk factors, the association between AF and OSA severity was borderline significant (odds ratio 1.2, 95% CI 1.0 to 1.5). The association between AF and 4q25 SNP status remained significant in a fully adjusted model that included OSA severity (odds ratio 1.5, 95% CI 1.3 to 5.7). In conclusion, OSA severity and the chromosome 4q25 SNP genotype were associated with AF status independent of clinical risk factors. Knowledge of AF-related SNPs may enhance AF risk stratification for those undergoing polysomnography.
Copyright © 2017 Elsevier Inc. All rights reserved.
BACKGROUND - Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2), 1q21 (rs13376333 in KCNN3), and 16q22 (rs7193343 in ZFHX3) have consistently been associated with the risk of atrial fibrillation (AF). Single-center studies have shown that 4q25 risk alleles predict recurrence of AF after catheter ablation of AF. Here, we performed a meta-analysis to test the hypothesis that these 4 AF susceptibility SNPs modulate response to AF ablation.
METHODS AND RESULTS - Patients underwent de novo AF ablation between 2008 and 2012 at Vanderbilt University, the Heart Center Leipzig, and Massachusetts General Hospital. The primary outcome was 12-month recurrence, defined as an episode of AF, atrial flutter, or atrial tachycardia lasting >30 seconds after a 3-month blanking period. Multivariable analysis of the individual cohorts using a Cox proportional hazards model was performed. Summary statistics from the 3 centers were analyzed using fixed effects meta-analysis. A total of 991 patients were included (Vanderbilt University, 245; Heart Center Leipzig, 659; and Massachusetts General Hospital, 87). The overall single procedure 12-month recurrence rate was 42%. The overall risk allele frequency for these SNPs ranged from 12% to 35%. Using a dominant genetic model, the 4q25 SNP, rs2200733, predicted a 1.4-fold increased risk of recurrence (adjusted hazard ratio,1.3 [95% confidence intervals, 1.1-1.6]; P=0.011). The remaining SNPs, rs10033464 (4q25), rs13376333 (1q21), and rs7193343 (16q22) were not significantly associated with recurrence.
CONCLUSIONS - Among the 3 genetic loci most strongly associated with AF, the chromosome 4q25 SNP rs2200733 is significantly associated with recurrence of atrial arrhythmias after catheter ablation for AF.
© 2015 American Heart Association, Inc.
BACKGROUND - Postoperative atrial fibrillation (PoAF) is common after coronary artery bypass grafting. We previously showed that atrial fibrillation susceptibility single nucleotide polymorphisms (SNPs) at the chromosome 4q25 locus are associated with PoAF. Here, we tested the hypothesis that a combined clinical and genetic model incorporating atrial fibrillation risk SNPs would be superior to a clinical-only model.
METHODS AND RESULTS - We developed and externally validated clinical and clinical/genetic risk models for PoAF. The discovery and validation cohorts included 556 and 1164 patients, respectively. Clinical variables previously associated with PoAF and 13 SNPs at loci associated with atrial fibrillation in genome-wide association studies were considered. PoAF occurred in 30% and 29% of patients in the discovery and validation cohorts, respectively. In the discovery cohort, a logistic regression model with clinical factors had good discrimination, with an area under the receiver operator characteristic curve of 0.76. The addition of 10 SNPs to the clinical model did not improve discrimination (area under receiver operator characteristic curve, 0.78; P=0.14 for difference between the 2 models). In the validation cohort, the clinical model had good discrimination (area under the receiver operator characteristic curve, 0.69) and addition of genetic variables resulted in a marginal improvement in discrimination (area under receiver operator characteristic curve, 0.72; P<0.0001).
CONCLUSIONS - We developed and validated a model for the prediction of PoAF containing common clinical variables. Addition of atrial fibrillation susceptibility SNPs did not improve model performance. Tools to accurately predict PoAF are needed to risk stratify patients undergoing coronary artery bypass grafting and identify candidates for prophylactic therapies.
© 2015 American Heart Association, Inc.
The efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in preventing recurrence of atrial fibrillation (AF) is controversial and their effects on inflammation and oxidative stress in this population are not known. This study examined the effects of high-dose marine n-3 PUFAs added to conventional therapy on the recurrence of AF and on markers of inflammation and oxidative stress. Patients with paroxysmal or persistent AF were randomized to n-3 PUFAs (4 g/day; n = 126) or placebo (n = 64) in a 2:1 ratio in a prospective, double-blind, placebo-controlled, parallel group study. The primary outcome was time to recurrence of AF. Secondary outcomes were changes in biomarkers of inflammation (serum interleukin [IL]-6, IL-8, IL-10, tissue necrosis factor alpha, monocyte chemoattractant protein-1, and vascular endothelial growth factor), N-terminal-pro-brain-type natriuretic peptide, and oxidative stress (urinary F2-isoprostanes). AF recurred in 74 patients (58.7%) randomized to n-3 PUFAs and in 30 patients (46.9%) who received placebo; time to recurrence of AF did not differ significantly in the 2 groups (hazard ratio 1.20; 95% confidence interval 0.76 to 1.90, adjusted p = 0.438). Compared with placebo, n-3 PUFAs did not result in clinically meaningful changes in concentrations of inflammatory markers, N-terminal-pro-brain-type natriuretic peptide or F2-isoprostanes. In conclusion, in patients with paroxysmal or persistent AF, treatment with n-3 PUFAs 4 g/day did not reduce the recurrence of AF, nor was it associated with clinically important effects on concentrations of markers of inflammation and oxidative stress. (Clinical trial registration number, NCT 00552084.).
Copyright © 2015 Elsevier Inc. All rights reserved.