IMPORTANCEAlthough rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity.OBJECTIVES To assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations. DESIGN, SETTING, AND PARTICIPANTSIn this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged Յ66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes.

Atrial fibrillation (AF) is the most prevalent cardiac rhythm disorder worldwide but the underlying genetic and molecular mechanisms and the response to therapies is not fully understood. Despite a greater burden of AF risk factors in Hispanics/Latinos the prevalence of AF remains low. Over the last decade, genome-wide association studies have identified numerous AF susceptibility loci in mostly whites of European descent. The goal of this study was to determine if the top 9 single nucleotide polymorphisms (SNPs) associated with AF in patients of European descent also increase susceptibility to AF in Hispanics/Latinos. AF cases were prospectively enrolled in the University of Illinois at Chicago (UIC) AF Registry and control subjects were identified from the UIC Cohort of Patients, Family and Friends. AF cases and controls were genotyped for 9 AF risk SNPs at chromosome 1q21: rs13376333, rs6666258; chr1q24: rs3903239; chr4q25: rs2200733; rs10033464; chr10q22: rs10824026; chr14q23: rs1152591; chr16q22: rs2106261 and rs7193343. The study sample consisted of 713 Hispanic/Latino subjects including 103 AF cases and 610 controls. Among the 8 AF risk SNPs genotyped, only rs10033464 SNP at chromosome (chr) 4q25 (near PITX2) was significantly associated with development of AF after multiple risk factor adjustment and multiple testing (adj. odds ratio [OR] 2.27, 95% confidence interval [CI] 1.31–3.94; P = 3.3 x 10−3). Furthermore, the association remained significant when the analysis was restricted to Hispanics of Mexican descent (adj. OR 2.32, 95% CI 1.35–3.99; P = 0.002. We confirm for the first time the association between a chromosome 4q25 SNP and increased susceptibility to AF in Hispanics/Latinos. While the underlying molecular mechanisms by which the chr4q25 SNP modulates AF risk remains unclear, this study supports a genetic basis for non-familial AF in patients of Hispanic descent.

IMPORTANCEThe association between obesity, an established risk factor for atrial fibrillation (AF), and response to antiarrhythmic drugs (AADs) remains unclear.OBJECTIVE To test the hypothesis that obesity differentially mediates response to AADs in patients with symptomatic AF and in mice with diet-induced obesity (DIO) and pacing induced AF. DESIGN, SETTING, AND PARTICIPANTSAn observational cohort study was conducted including 311 patients enrolled in a clinical-genetic registry. Mice fed a high-fat diet for 10 weeks were also evaluated. The study was conducted from January 1, 2018, to June 2, 2019.MAIN OUTCOMES AND MEASURES Symptomatic response was defined as continuation of the same AAD for at least 3 months. Nonresponse was defined as discontinuation of the AAD within 3 months of initiation because of poor symptomatic control of AF necessitating alternative rhythm control therapy. Outcome measures in DIO mice were pacing-induced AF and suppression of AF after 2 weeks of treatment with flecainide acetate or sotalol hydrochloride.RESULTS A total of 311 patients (mean [SD] age, 65 [12] years; 120 women [38.6%]) met the entry criteria and were treated with a class I or III AAD for symptomatic AF. Nonresponse to class I AADs in patients with obesity was less than in those without obesity (30% [obese] vs 6% [nonobese]; difference, 0.24; 95% CI, 0.11-0.37; P = .001). Both groups had similar symptomatic response to a potassium channel blocker AAD. On multivariate analysis, obesity, AAD class (class I vs III AAD [obese] odds ratio [OR], 4.54; 95% Wald CI, 1.84-11.20; P = .001), female vs male sex (OR, 2.31; 95% Wald CI, 1.07-4.99; P = .03), and hyperthyroidism (OR, 4.95; 95% Wald CI, 1.23-20.00; P = .02) were significant indicators of the probability of failure to respond to AADs. Pacing induced AF in 100% of DIO mice vs 30% (P < .001) in controls. Furthermore, DIO mice showed a greater reduction in AF burden when treated with sotalol compared with flecainide (85% vs 25%; P < .01). CONCLUSIONS AND RELEVANCEResults suggest that obesity differentially mediates response to AADs in patients and in mice with AF, possibly reducing the therapeutic effectiveness of sodium channel blockers. These findings may have implications for the management of AF in patients with obesity.

Key Points Question What is the association of family history with the pathogenesis of early-onset atrial fibrillation in patients of African, European, and Hispanic descent? Findings In this cohort study of 664 patients, probands with early-onset atrial fibrillation were significantly more likely to have a family history of arrhythmia in first-degree relatives than patients with non–early-onset atrial fibrillation. Compared with European American probands, African American and Hispanic/Latino probands with early-onset atrial fibrillation were more likely to have a first-degree relative with arrhythmia. Meaning These findings support genetic predisposition to early-onset atrial fibrillation across individuals of European, African, and Hispanic/Latino descent and have important implications for identifying family members at risk for atrial fibrillation and sequencing candidate genes.

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