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Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . 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. This large, multi-ethnic genome-wide association study identifies 97 loci significantly associated with atrial fibrillation. These loci are enriched for genes involved in cardiac development, electrophysiology, structure and contractile function.

Warfarin is the most widely used oral anticoagulant worldwide, but serious bleeding complications are common. We tested whether genetic variants can identify patients who are at increased risk of bleeding with warfarin and, consequently, those who would derive a greater safety benefit with a direct oral anticoagulant rather than warfarin. ENGAGE AF-TIMI 48 was a randomised, double-blind trial in which patients with atrial fibrillation were assigned to warfarin to achieve a target international normalised ratio of 2·0–3·0, or to higher-dose (60 mg) or lower-dose (30 mg) edoxaban once daily. A subgroup of patients was included in a prespecified genetic analysis and genotyped for variants in CYP2C9 and VKORC1. The results were used to create three genotype functional bins (normal, sensitive, and highly sensitive responders to warfarin). This trial is registered with ClinicalTrials.gov, number NCT00781391. 14 348 patients were included in the genetic analysis. Of 4833 taking warfarin, 2982 (61·7%) were classified as normal responders, 1711 (35·4%) as sensitive responders, and 140 (2·9%) as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent greater proportions of time over-anticoagulated in the first 90 days of treatment (median 2·2%, IQR 0–20·2; 8·4%, 0–25·8; and 18·3%, 0–32·6; ptrend<0·0001) and had increased risks of bleeding with warfarin (sensitive responders hazard ratio 1·31, 95% CI 1·05–1·64, p=0·0179; highly sensitive responders 2·66, 1·69–4·19, p<0·0001). Genotype added independent information beyond clinical risk scoring. During the first 90 days, when compared with warfarin, treatment with edoxaban reduced bleeding more so in sensitive and highly sensitive responders than in normal responders (higher-dose edoxaban pinteraction=0·0066; lower-dose edoxaban pinteraction=0·0036). After 90 days, the reduction in bleeding risk with edoxaban versus warfarin was similarly beneficial across genotypes. CYP2C9 and VKORC1 genotypes identify patients who are more likely to experience early bleeding with warfarin and who derive a greater early safety benefit from edoxaban compared with warfarin. Daiichi Sankyo.

Clopidogrel must be metabolized to an active form to be effective. Cytochrome P-450 variants resulting in slow metabolism may reduce clinical efficacy. This study in patients with acute coronary syndromes or atrial fibrillation did not confirm diminished efficacy in those with slow metabolism. Clopidogrel, when added to aspirin, reduces the rate of major vascular events among patients with acute coronary syndromes and atrial fibrillation. 1 , 2 Recent reports suggest that certain common genetic variants, involving the hepatic cytochrome P-450 system, that are involved in the conversion of clopidogrel to its active metabolite are associated with an increased rate of recurrent cardiovascular events, implying that the benefits of clopidogrel may be attenuated in patients with these genetic variants. Specifically, in patients who are carriers of a loss-of-function CYP2C19 allele (including the *2 and *3 alleles), the conversion of clopidogrel to its active metabolite may be . . .

Abstract Context Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not. Objective To test whether genetically determined variation in normal range thyroid function is causally associated with the risk of stroke and coronary artery disease (CAD) and investigate via which pathways these relations may be mediated. Design, Setting, and Participants Mendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto’s thyroiditis and Graves’ disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used. Main Outcome Measures Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels. Results A 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto’s thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; P = 0.026), which was mainly mediated via body mass index. Conclusion These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke, and CAD. We identify variation in normal range thyroid function and Hashimoto’s thyroiditis as risk factors for stroke and CAD, respectively.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. Low serum albumin level is linked to the emergence of many cardiovascular diseases, including AF. In this study, we aim to characterize the nature and magnitude of the prospective association between serum albumin and incident AF in the Atherosclerosis Risk in Communities (ARIC) Study and investigate any causal relevance to the association between them. ARIC Study is a population-based, prospective, cohort study of cardiovascular risk factors in four US communities, initially consisting of 15,792 participants, aged 45–64 years, recruited between 1987 and 1989 (visit 1). The final sample size was 12,833 in this study. Baseline (visit 1) characteristics were compared between groups using one-way ANOVA test, Chi square test, or Kruskal–Wallis test as appropriate. We used multivariable Cox’ hazard regression models to assess the association between albumin and incident AF. Two-sample Mendelian randomization (MR) based on publicly available summary-level data from genome-wide association studies was used to estimate the causal influence of the serum albumin and incident AF. During a median follow-up of 25.1 years, 2259 (17.6%) participants developed incident AF. After multiple adjustment, serum albumin was inversely associated with incidence of AF [HR = 0.90, 95% CI 0.86–0.94, per SD (0.27 g/dL) increase; HR = 0.80, 95% CI 0.71–0.91, Q4 vs. Q1]. In MR analysis, we detected no evidence for a causal relation between serum albumin level and AF in inverse-variance weighted (IVW) method (odds ratio: 0.996, 95% CI 0.980–1.012, per 1 g/dL increase of albumin; P  = 0.620) without evidence of heterogeneity between estimates from individual SNPs ( P heterogeneity  = 0.981 [MR-Egger] and P heterogeneity  = 0.860 [IVW]) nor pleiotropy effect ( P pleiotropy  = 0.193). The serum albumin level is independently inverse associated with incident AF in a linear pattern. However, MR analyses did not support a causal role of serum albumin in the etiology of AF.

Background Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual’s genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. Methods First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a population of one million Europeans in total. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. Results The two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mmHg [OR] 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease. Conclusions The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF.

Abstract Context A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms. Objective Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk. Methods We used 2-sample mendelian randomization (MR) to test associations between TSH-associated single-nucleotide variations and 16 candidate mediators. We then performed multivariable mendelian randomization (MVMR) to test for a significant attenuation of the genetic association between TSH and AF, after adjusting for each mediator significantly associated with TSH. Results Four candidate mediators (free thyroxine, systolic blood pressure, heart rate, and height) were significantly inversely associated with genetically predicted TSH after adjusting for multiple testing. In MVMR analyses, adjusting for height significantly decreased the magnitude of the association between TSH and AF from –0.12 (SE 0.02) occurrences of AF per SD change in height to –0.06 (0.02) (P = .005). Adjusting for the other candidate mediators did not significantly attenuate the association. Conclusion The genetic association between TSH and increased AF risk is mediated, in part, by taller stature. Thus, some genetic mechanisms underlying TSH variability may contribute to AF risk through mechanisms determining height occurring early in life that differ from those driven by thyroid hormone–level elevations in later life.

A prolonged PR interval predicts atrial fibrillation (AF) recurrence after catheter ablation. We investigated the causal association between the PR interval and AF clinical recurrence by a Mendelian randomization. We prospectively included 1722 patients with AF (73.2% male, 58.6 ± 10.8 years old, 71.3% paroxysmal AF) who underwent catheter ablation into a genome-wide association study (GWAS). We searched for the genetic associations between the PR interval and AF recurrence by analyzing 44 single nucleotide polymorphisms (SNPs) already known to be associated with the PR interval, and investigated the Mendelian randomization. Based on the quartile analysis, the highest quartile of the PR interval was associated with an increased risk of AF recurrence compared with the lowest quartile (Hazard ratio (HR) = 1.91, 95% CI = 1.51–2.42, P = 8.41 × 10−8) during 35.7 ± 28.5 months of follow-up. Among 44 SNPs known to be associated with the PR interval, two SNPs had significant associations with the PR interval (P < 0.001 for each SNP). CAV1 (HR = 1.15, 95% CI = 1.02–1.31, P = 0.024) was associated with clinical recurrence of AF. A Mendelian randomization analysis demonstrated a significant association with CAV1 (HR = 1.04, 95% CI = 1.01–1.07, P = 0.006). A prolonged PR interval was a risk factor for an AF recurrence, and the PR interval had a potentially causal association with an AF clinical recurrence after catheter ablation at the genetic level.

Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non-selective beta-blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized trials. The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded “seamless” phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred. GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.govNCT01970501).

We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per quality-adjusted life-year (QALY) gained by pharmacogenetic-guided warfarin dosing versus standard treatment over a lifetime horizon. Incremental lifetime costs were £26 and 382 Swedish kronor (SEK) and incremental QALYs were 0.0039 and 0.0015 in the United Kingdom and Sweden, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were £6 702 and 253 848 SEK per QALY gained. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 93% of the simulations in the United Kingdom and below 500 000 SEK in 67% of the simulations in Sweden. Our data suggest that pharmacogenetic-guided dosing of warfarin is a cost-effective strategy to improve outcomes of patients with AF treated with warfarin in the United Kingdom and in Sweden.