Stroke and bleeding risk in atrial fibrillation with CHA2DS2-VASC risk score of one: the Norwegian AFNOR study.

BACKGROUND AND AIMS: The benefit of oral anticoagulant (OAC) therapy in atrial fibrillation (AF) and intermediate stroke risk is debated. In a nationwide Norwegian cohort with a non-sex CHA2DS2-VASc risk score of one, this study aimed to investigate (i) stroke and bleeding risk in AF patients with and without OAC treatment, and (ii) the risk of stroke in non-anticoagulated individuals with and without AF. METHODS: A total of 1 118 762 individuals including 34 460 AF patients were followed during 2011-18 until ischaemic stroke, intracranial haemorrhage, increased CHA2DS2-VASc score, or study end. One-year incidence rates (IRs) were calculated as events per 100 person-years (%/py). Cox regression models provided adjusted hazard ratios (aHRs [95% confidence intervals]). RESULTS: Among AF patients, the ischaemic stroke IR was 0.51%/py in OAC users and 1.05%/py in non-users (aHR 0.47 [0.37-0.59]). Intracranial haemorrhage IR was 0.28%/py in OAC users and 0.19%/py in non-users (aHR 1.23 [0.88-1.72]). Oral anticoagulant use was associated with an increased risk of major bleeding (aHR 1.37 [1.16-1.63]) but lower risk of the combined outcome of ischaemic stroke, major bleeding, and mortality (aHR 0.57 [0.51-0.63]). Non-anticoagulated individuals with AF had higher risk of ischaemic stroke compared to non-AF individuals with the same risk profile (aHR 2.47 [2.17-2.81]). CONCLUSIONS: In AF patients at intermediate risk of stroke, OAC use was associated with overall favourable clinical outcomes. Non-anticoagulated AF patients had higher risk of ischaemic stroke compared to the general population without AF with the same risk profile.

Genetic variants on chromosomes 7p31 and 12p12 are associated with abnormal atrial electrical activation in patients with early-onset lone atrial fibrillation.

BACKGROUND: Abnormal P-wave morphology (PWM) has been associated with a history of atrial fibrillation (AF) in earlier studies. Although lone AF is believed to have substantial genetic basis, studies on associations between single nucleotide polymorphisms (SNP) linked to lone AF and PWM have not been reported. We aimed to assess whether SNPs previously associated with lone AF (rs2200733, rs13376333, rs3807989, and rs11047543) are also linked to P-wave abnormalities. METHODS: Four SNPs were studied in 176 unrelated individuals with early-onset lone AF (age at onset <50 years), median age 38 years (19-63 years), 149 men. Using sinus rhythm ECG, orthogonal PWM was classified as Type 1-positive in leads X and Y and negative in lead Z, Type 2-positive in leads X and Y and biphasic (-/+) in lead Z, Type 3-positive in lead X and biphasic in lead Y (+/-), and the remaining as atypical. RESULTS: Two SNPs were found to be significantly associated with altered P-wave morphology distribution: rs3807989 near the gene CAV1/CAV2 and rs11047543 near the gene SOX5. Both SNPs were associated with a higher risk of non-Type 1 P-wave morphology (rs3807989: OR = 4.8, 95% CI = 2.3-10.2, p < 0.001; rs11047543: OR = 4.7, 95% CI = 1.1-20.5, p = 0.04). No association was observed for rs2200733 and rs13376333. CONCLUSION: In this study, the two variants rs3807989 and rs11047543, previously associated with PR interval and lone AF, were associated with altered P-wave morphology distribution in patients with early-onset lone AF. These findings suggest that common genetic variants may modify atrial conduction properties.

Whole Exome Sequencing in Atrial Fibrillation.

Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

Systematic screening for atrial fibrillation in a 65-year-old population with risk factors for stroke: data from the Akershus Cardiac Examination 1950 study.

Aims: To investigate the yield of screening for atrial fibrillation (AF) in a cohort of 65-year-old individuals from the general population with additional risk factors for stroke. Methods and results: We invited participants with additional risk factors for stroke (CHA2DS2-VASc score ≥2 for men or ≥ 3 for women) without previously known AF from a population-based study in Norway to participate in a 2-week screening for AF. Screening was performed by one-lead 'thumb electrocardiography (ECG)' recordings of 30 s twice daily or when the participants experienced symptoms. In total, 1742 (47.0%) participants of the Akershus Cardiac Examination (ACE) 1950 study had at least one additional risk factor for stroke. Of these, 123 cases reported a history of AF and 101 (5.8%) cases were ECG validated. Eight [0.5%, 95% confidence interval (CI) 0.2-0.9] new AF cases were diagnosed by 12-lead ECG at baseline, and 10 additional participants were diagnosed with AF before screening commenced. We invited all 1601 participants who met the inclusion criteria for screening, of which 1510 (94.3%) participants were included (44% women and 56% men). The screening revealed AF in 13 (0.9%, 95% CI 0.5-1.5) participants. The total prevalence of ECG-validated AF after screening among the 65-year-olds with risk factors for stroke was 7.6% (95% CI 6.4-8.9), in men 10.0% (95% CI 8.2-12.0), and in women 4.3% (95% CI 3.0-6.1) (P < 0.001). Conclusion: In a group of 1510 well-characterized 65-year-olds with risk factors for stroke, 2-week intermittent ECG screening identified undiagnosed AF in 0.9%. The total prevalence of AF was 7.6%.

A comparison of the CHARGE-AF and the CHA2DS2-VASc risk scores for prediction of atrial fibrillation in the Framingham Heart Study.

BACKGROUND: Atrial fibrillation (AF) affects more than 33 million individuals worldwide and increases risks of stroke, heart failure, and death. The CHARGE-AF risk score was developed to predict incident AF in three American cohorts and it was validated in two European cohorts. The CHA2DS2-VASc risk score was derived to predict risk of stroke, peripheral embolism, and pulmonary embolism in individuals with AF, but it has been increasingly used for AF risk prediction. We compared CHARGE-AF risk score versus CHA2DS2-VASc risk score for incident AF risk in a community-based cohort. METHODS AND RESULTS: We studied Framingham Heart Study participants aged 46 to 94 years without prevalent AF and with complete covariates. We predicted AF risk using Fine-Gray proportional sub-distribution hazards regression. We used the Wald χ(2) statistic for model fit, C-statistic for discrimination, and Hosmer-Lemeshow (HL) χ(2) statistic for calibration. We included 9722 observations (mean age 63.9 ± 10.6 years, 56% women) from 4548 unique individuals: 752 (16.5%) developed incident AF and 793 (17.4%) died. The mean CHARGE-AF score was 12.0 ± 1.2 and the sub-distribution hazard ratio (sHR) for AF per unit increment was 2.15 (95% CI, 99-131%; P < .0001). The mean CHA2DS2-VASc score was 2.0 ± 1.5 and the sHR for AF per unit increment was 1.43 (95% CI, 37%-51%; P < .0001). The CHARGE-AF model had better fit than CHA2DS2-VASc (Wald χ(2) = 403 vs 209, both with 1 df), improved discrimination (C-statistic = 0.75, 95% CI, 0.73-0.76 vs C-statistic = 0.71, 95% CI, 0.69-0.73), and better calibration (HL χ(2) = 5.6, P = .69 vs HL χ(2) = 28.5, P < .0001). CONCLUSION: The CHARGE-AF risk score performed better than the CHA2DS2-VASc risk score at predicting AF in a community-based cohort.

Genetics of atrial fibrillation: from families to genomes.

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and the prevalence is increasing. The disease confers an increased risk of severe complications such as heart failure, stroke and death, yet the treatment options available are insufficient. AF can develop secondary to other diseases, but there is also evidence of a heritable component. The molecular basis for the heritability of AF has been explored in depth over the past decade. Rare variants have been identified in ion channels, transcription factors and a wide range of other genes. More recently, common variant analyses have identified 14 genetic loci associated with AF. Thus, the genetics of AF is complex and heterogeneous. In this review, we describe the common and rare variants identified for AF, the potential clinical implications of these variants and the future directions in this field. Increasing our understanding of the pathophysiology of AF will aid the development of new and improved treatment strategies and risk prediction of AF, the first steps toward a more individualized treatment of the arrhythmia.

Genetic variation in KCNA5: impact on the atrial-specific potassium current IKur in patients with lone atrial fibrillation.

AIMS: Genetic factors may be important in the development of atrial fibrillation (AF) in the young. KCNA5 encodes the potassium channel α-subunit KV1.5, which underlies the voltage-gated atrial-specific potassium current IKur. KCNAB2 encodes KVß2, a ß-subunit of KV1.5, which increases IKur. Three studies have identified loss-of-function mutations in KCNA5 in patients with idiopathic AF. We hypothesized that early-onset lone AF is associated with high prevalence of genetic variants in KCNA5 and KCNAB2. METHODS AND RESULTS: The coding sequences of KCNA5 and KCNAB2 were sequenced in 307 patients with mean age of 33 years at the onset of lone AF, and in 216 healthy controls. We identified six novel non-synonymous mutations [E48G, Y155C, A305T (twice), D322H, D469E, and P488S] in KCNA5 in seven patients. None were present in controls. We identified a significantly higher frequency of rare deleterious variants in KCNA5 in the patients than in controls. The mutations were analysed with confocal microscopy and whole-cell patch-clamp techniques. The mutant proteins Y155C, D469E, and P488S displayed decreased surface expression and loss-of-function in patch-clamp studies, whereas E48G, A305T, and D322H showed preserved surface expression and gain-of-function for KV1.5. CONCLUSION: This study is the first to present gain-of-function mutations in KCNA5 in patients with early-onset lone AF. We identified three gain-of-function and three loss-of-function mutations. We report a high prevalence of variants in KCNA5 in these patients. This supports the hypothesis that both increased and decreased potassium currents enhance AF susceptibility.

Loss of Cardiac Splicing Regulator RBM20 Is Associated With Early-Onset Atrial Fibrillation.

We showed an association between atrial fibrillation and rare loss-of-function (LOF) variants in the cardiac splicing regulator RBM20 in 2 independent cohorts. In a rat model with loss of RBM20, we demonstrated altered splicing of sarcomere genes (NEXN, TTN, TPM1, MYOM1, and LDB3), and differential expression in key cardiac genes. We identified altered sarcomere and mitochondrial structure on electron microscopy imaging and found compromised mitochondrial function. Finally, we demonstrated that 3 novel LOF variants in RBM20, identified in patients with atrial fibrillation, lead to significantly reduced splicing activity. Our results implicate alternative splicing as a novel proarrhythmic mechanism in the atria.

Atrial Fibrillation Genetics Update: Toward Clinical Implementation.

Atrial fibrillation (AF) is the most common heart rhythm disorder worldwide and may have serious cardiovascular health consequences. AF is associated with increased risk of stroke, dementia, heart failure, and death. There are several known robust, clinical risk predictors for AF, such as male sex, increasing age, and hypertension; however, during the last couple of decades, a substantive genetic component has also been established. Over the last 10 years, the discovery of novel AF-related genetic variants has accelerated, increasing our understanding of mechanisms behind AF. Current studies are focusing on mapping the polygenic structure of AF, improving risk prediction, therapeutic development, and patient-specific management. Nevertheless, it is still difficult for clinicians to interpret the role of genetics in AF prediction and management. Here, we provide an overview of relevant topics within the genetics of AF and attempt to provide some guidance on how to interpret genetic advances and their implementation into clinical decision-making.

Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study.

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear. Objective: To evaluate the potential direct involvement of thyroid traits on AF. Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry. Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data. Main Outcomes and Measures: Prevalent and incident AF. Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045). Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

Multi-ethnic genome-wide association study for atrial fibrillation.

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.

Atrial fibrillation in women: treatment.

Sex-specific differences in the epidemiology, pathophysiology, presentation, prognosis, and treatment of atrial fibrillation (AF) are increasingly recognized. Women with AF generally experience worse symptoms, poorer quality of life, and have higher risk of stroke and death than men with AF. Effective treatment of the arrhythmia in women is critical to reduce the rate of adverse events. We review the current evidence on sex-specific differences in the utilization and outcomes of treatments for AF, including rate-control and rhythm-control strategies, and stroke-prevention therapy. In addition, we provide a critical evaluation of potential disparities and biases in health-care use that might be associated with differences in the outcomes between women and men. We underscore current knowledge gaps that need to be addressed in future studies to improve the management of AF in women. In particular, we suggest several strategies to produce high-quality evidence from randomized clinical trials for women with AF.

Identification of six new genetic loci associated with atrial fibrillation in the Japanese population.

Atrial fibrillation is the most common cardiac arrhythmia and leads to stroke. To investigate genetic loci associated with atrial fibrillation in the Japanese population, we performed a genome-wide association study (GWAS) that included 8,180 atrial fibrillation cases and 28,612 controls with follow-up in an additional 3,120 cases and 125,064 controls. We replicated previously reported loci and identified six new loci, near the KCND3, PPFIA4, SLC1A4-CEP68, HAND2, NEBL and SH3PXD2A genes. Five of the six new loci were specifically associated with atrial fibrillation in the Japanese population after comparing our data to those from individuals of European ancestry, suggesting that there might be different genetic factors affecting susceptibility across ancestry groups. Our study discovered variants in the HAND2, KCND3 and NEBL genes, which are relevant to atrial fibrillation susceptibility. The involvement of PPFIA4 and SH3PXD2A in axon guidance also suggested a role in disease pathogenesis. Our findings may contribute to a better understanding of atrial fibrillation susceptibility and pathogenesis.

Fifteen Genetic Loci Associated With the Electrocardiographic P Wave.

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.

Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.

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.

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

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.

Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis.

Atrial fibrillation (AF) is the most common sustained arrhythmia in women and men worldwide. During the past century, a range of risk factors has been associated with AF, severe complications from the arrhythmia have been identified, and its prevalence has been increasing steadily. Whereas evidence has accumulated regarding sex-specific differences in coronary heart disease and stroke, the differences between women and men with AF has received less attention. We review the current literature on sex-specific differences in the epidemiology of AF, including incidence, prevalence, risk factors, and genetics, and in the pathophysiology and the clinical presentation and prognosis of patients with this arrhythmia. We highlight current knowledge gaps and areas that warrant future research, which might advance understanding of variation in the risk factors and complications of AF, and ultimately aid more-tailored management of the arrhythmia.

Common and rare variants in SCN10A modulate the risk of atrial fibrillation.

BACKGROUND: Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r(2)=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. METHODS AND RESULTS: SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16-1.54]; P=2.3×10(-5)). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. CONCLUSIONS: The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.

Brugada syndrome risk loci seem protective against atrial fibrillation.

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.

Rare variants in GJA5 are associated with early-onset lone atrial fibrillation.

BACKGROUND: Genetic factors are believed to be important in early-onset lone atrial fibrillation (AF). The gene GJA5 encodes the gap-junction protein Cx40, which together with Cx43 is responsible for the electrical coupling of the atrial cardiomyocytes. The regulatory single nucleotide polymorphism rs10465885 in GJA5 was recently associated with early-onset lone AF (< 60 years) and was also found to be strongly associated with Cx40 messenger RNA levels. We hypothesized that this gene would have a strong effect in patients with a more selected phenotype, and that the findings regarding rs10465885 could be replicated in this group. METHODS: The coding region and flanking intron sequences of GJA5 were resequenced in 342 patients with onset of lone AF before the age of 50 (mean age at onset 34 ± 9 years), and in 216 controls. The single nucleotide polymorphism rs10465885 was genotyped in 342 patients and 534 control subjects and odds ratios were calculated for different genetic models. RESULTS: Genotyping of rs10465885 showed that the patients with early-onset lone AF were more likely to carry the A allele compared with controls (odds ratio = 1.30; P = 0.011). When resequencing GJA5, we identified the mutation A96S, previously associated with lone AF, which was not present in our control subjects or in any publicly available database or the National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI EVS; 10,758 alleles). CONCLUSIONS: We show a highly significant association between the A allele of rs10465885 and onset of lone AF before age 50. This opposes a previous study, wherein the G allele was found to be associated with AF, and makes it impossible to exclude that the associations are coincidental.