Association of Rare Genetic Variants and Early-Onset Atrial Fibrillation in Ethnic Minority Individuals.

Importance: Although 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 Participants: In this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged ≤66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes. Recruitment took place from July 1, 2015, to June 30, 2019. Data were analyzed from February 1 to February 28, 2020. Exposures: Rare and novel variants categorized as pathogenic or likely pathogenic. Main Outcomes and Measures: The prevalence of rare and novel pathogenic variants in African American and Hispanic/Latinx probands with early-onset AF and genotype-phenotype associations. Results: Among 227 probands with early-onset AF, mean (SD) age at onset of AF was 51.0 (9.9) years, 132 probands (58.1%) were men, 148 (65.2%) were African American, and 79 (34.8%) were Hispanic/Latinx. A family history of AF was verified in 24 probands with early-onset AF (10.6%). Sequencing 60 candidate genes identified 53 (23 rare and 30 novel) variants with 16 of the 227 (7.0%) probands harboring likely pathogenic (43.8%) or pathogenic (56.2%) variants, with most loss-of-function variants in TTN, the gene encoding the sarcomeric protein titin (46.7%). In 6 families with more than 2 affected members, variants of unknown significance in sodium channel (SCN10A), potassium channel (KCNE5), sarcomeric proteins (MYH6 and TTN), and atrial natriuretic peptide (NPPA) cosegregated with AF. Conclusions and Relevance: In this study, likely pathogenic and pathogenic variants were identified, with most loss-of-function variants in TTN, that increase susceptibility to early-onset AF in African American and Hispanic/Latinx individuals. These findings provide further understanding toward molecular phenotyping of AF and suggest novel mechanism-based therapeutic approaches for this common arrhythmia in ethnic minority groups.

Association Between Obesity-Mediated Atrial Fibrillation and Therapy With Sodium Channel Blocker Antiarrhythmic Drugs.

Importance: The 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 Participants: An 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 Relevance: Results 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.

Genetic modulation of atrial fibrillation risk in a Hispanic/Latino cohort.

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.

Association Between Family History and Early-Onset Atrial Fibrillation Across Racial and Ethnic Groups.

Importance: There is a genetic predisposition to early-onset atrial fibrillation (EOAF) in European American individuals. However, the role of family history in the pathogenesis of EOAF in racial and ethnic minorities remains unclear. Objective: To determine whether probands with EOAF across racial and ethnic groups have a higher rate of AF in first-degree family members than racially and ethnically matched control patients with non-early-onset AF (non-EOAF). Design, Setting, and Participants: In this cohort study, patients prospectively enrolled in a clinical and genetic biorepository were administered baseline questionnaires that included questions about family history of AF. Early-onset AF was defined as AF occurring in probands aged 60 years or younger in the absence of structural heart disease. All other forms were categorized as non-EOAF. Recruitment took place from July 2015 to December 2017. Analysis was performed in January 2018. Main Outcomes and Measures: Primary analysis of reported family history of AF in first-degree relatives with sensitivity analysis restricted to those in whom a family history was confirmed by medical record review and electrocardiogram. Results: Of 664 patients enrolled (mean [SD] age, 62 [12] years; 407 [61%] male), 267 (40%) were European American; 258 (39%), African American; and 139 (21%), Hispanic/Latino. There was a family history of AF in 36 probands with EOAF (49%) compared with 128 patients with non-EOAF (22%) (difference, 27%; 95% CI, 14%-40%; P < .001). On multivariable analysis, the adjusted odds of a proband with EOAF who was of African descent (odds ratio [OR], 2.69; 95% CI, 1.06-6.91; P < .001) or Hispanic descent (OR, 9.25; 95% CI, 2.37-36.23; P = .002) having a first-degree relative with AF were greater than those of European descent (OR, 2.51; 95% CI, 1.29-4.87; P = .006). Overall, probands with EOAF were more likely to have a first-degree relative with AF compared with patients with non-EOAF (adjusted OR, 3.02; 95% CI, 1.82-4.95; P < .001) across the 3 racial and ethnic groups. Atrial fibrillation in a first-degree family member was confirmed in 32% of probands with EOAF vs 11% of those with non-EOAF (difference, 21%; 95% CI, 11%-33%; P < .001). Furthermore, African American (28% vs 5%; difference, 23%; 95% CI, 4%-43%; P = .001), European American (35% vs 20%; difference, 15%; 95% CI, 1%-30%; P = .03), and Hispanic/Latino (30% vs 5%; difference, 25%; 95% CI, 4%-54%; P = .02) probands with EOAF were more likely to have a first-degree relative with confirmed AF vs racially and ethnically matched control patients with non-EOAF. The positive and negative predictive values for a family history of confirmed AF were both 89%. Conclusions and Relevance: Probands of African or Hispanic/Latino descent with EOAF were more likely to have a first-degree relative with AF when compared with European American individuals. These findings support genetic predisposition to EOAF across all 3 races.