To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5), or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an 'atrial cardiomyopathy', either during fetal heart development or as a response to stress in the adult heart.

No abstract

Background— Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, Na V 1.5, plays a pivotal role in setting the conduction velocity and the initial depolarization of the cardiac myocytes. We hypothesized that early-onset lone AF was associated with genetic variation in SCN5A . Methods and Results— The coding sequence of SCN5A was sequenced in 192 patients with early-onset lone AF. Eight nonsynonymous mutations (T220I, R340Q, T1304M, F1596I, R1626H, D1819N, R1897W, and V1951M) and 2 rare variants (S216L in 2 patients and F2004L) were identified. Of 11 genopositive probands, 6 (3.2% of the total population) had a variant previously associated with long QT syndrome type 3 (LQTS3). The prevalence of LQTS3-associated variants in the patients with lone AF was much higher than expected, compared with the prevalence in recent exome data (minor allele frequency, 1.6% versus 0.3%; P =0.003), mainly representing the general population. The functional effects of the mutations were analyzed by whole cell patch clamp in HEK293 cells; for 5 of the mutations previously associated with LQTS3, patch-clamp experiments showed an increased sustained sodium current, suggesting a mechanistic overlap between LQTS3 and early-onset lone AF. In 9 of 10 identified mutations and rare variants, we observed compromised biophysical properties affecting the transient peak current. Conclusions— In a cohort of patients with early-onset lone AF, we identified a high prevalence of SCN5A mutations previously associated with LQTS3. Functional investigations of the mutations revealed both compromised transient peak current and increased sustained current.

We aimed to study whether visit-to-visit variability of glycated hemoglobin A 1c (HbA 1c) is associated with incident major adverse cardiovascular events (MACE), all-cause mortality, and type 2 diabetes in people without diabetes. RESEARCH DESIGN AND METHODS We included primary care patients with no history of diabetes or cardiovascular disease and with three annual HbA 1c measurements within normal range (<6.5% [48 mmol/mol]). For each individual, we measured the HbA 1c variability as the SD of the residuals obtained from a linear regression on the three HbA 1c measurements. From the linear regression, we also obtained the estimated index HbA 1c (intercept) and the trend over time (slope). Follow-up began at the date of the third measurement. Associations between HbA 1c variability and outcome were analyzed using Cox regression, adjusted for traditional risk factors, intercept, and trend and reported as hazard ratio per SD increase in variability (HR SD). RESULTS In total, 6,756 individuals were included. During a median follow-up time of 6.3 years, 996 developed MACE, 856 died, and 1,267 developed type 2 diabetes. We found a significant association between increasing HbA 1c variability and incident MACE (HR SD 1.09 [95% CI 1.03-1.15]) and all-cause mortality (HR SD 1.13 [95% CI 1.07-1.20]), whereas there were no associations with type 2 diabetes (HR SD 1.00 [95% CI 0.95-1.05]). We calculated 5-year absolute risks of MACE and all-cause mortality and found clinically relevant differences across several age, sex, comorbidity, and HbA 1c variability-defined subgroups. CONCLUSIONS In a primary care population free of diabetes and cardiovascular disease, high HbA 1c variability was associated with increased risks of MACE and all-cause mortality. Type 2 diabetes is an important risk factor for major adverse cardiovascular events (MACE) and premature death from cardiovascular causes (1,2). Glycated hemoglobin A 1c (HbA 1c) is a readily available and highly reproducible biomarker that reflects the 3-month average plasma glucose concentration; it can be measured in the nonfasting state, and a value $6.5% (48 mmol/mol) is considered diagnostic for diabetes (3).