Dataset Information

Genetic Basis of Early Onset Atrial Fibrillation in Patients without Risk Factors.

ABSTRACT:

Background

Atrial fibrillation (AF) is the most common arrhythmia and typically occurs in elderly patients with other cardiovascular and extracardiac diseases. However, up to 15% of AF develops without any related risk factors. Recently, the role of genetic factors has been highlighted in this particular form of AF.

Aims

The aims of this study were to determine the prevalence of pathogenic variants in early-onset AF in patients without known disease-related risk factors and to identify any structural cardiac abnormalities in these patients.

Materials and methods

We conducted exome sequencing and interpretation in 54 risk factor-free early-onset AF patients and further validated our findings in a similar AF patient cohort from the UK Biobank.

Results

Pathogenic/likely pathogenic variants were found in 13/54 (24%) patients. The variants were identified in cardiomyopathy-related and not arrhythmia-related genes. The majority of the identified variants were TTN gene truncating variants (TTNtvs) (9/13 (69%) patients). We also observed two TTNtvs founder variants in the analysed population-c.13696C>T p.(Gln4566Ter) and c.82240C>T p.(Arg27414Ter). Pathogenic/likely pathogenic variants were found in 9/107 (8%) individuals from an independent similar AF patient cohort from the UK Biobank. In correspondence with our Latvian patients, only variants in cardiomyopathy-associated genes were identified. In five (38%) of the thirteen Latvian patients with pathogenic/likely pathogenic variants, dilation of one or both ventricles was identified on a follow-up cardiac magnetic resonance scan.

Conclusions

We observed a high prevalence of pathogenic/likely pathogenic variants in cardiomyopathy-associated genes in patients with risk factor-free early-onset AF. Moreover, our follow-up imaging data indicate that these types of patients are at risk of developing ventricular dilation. Furthermore, we identified two TTNtvs founder variants in our Latvian study population.

SUBMITTER: Rudaka I

PROVIDER: S-EPMC10057774 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Genetic Basis of Early Onset Atrial Fibrillation in Patients without Risk Factors.

Rudaka Irina I Vilne Baiba B Isakova Jekaterina J Kalejs Oskars O Gailite Linda L Rots Dmitrijs D

Journal of cardiovascular development and disease 20230228 3

<h4>Background</h4>Atrial fibrillation (AF) is the most common arrhythmia and typically occurs in elderly patients with other cardiovascular and extracardiac diseases. However, up to 15% of AF develops without any related risk factors. Recently, the role of genetic factors has been highlighted in this particular form of AF.<h4>Aims</h4>The aims of this study were to determine the prevalence of pathogenic variants in early-onset AF in patients without known disease-related risk factors and to ide ...[more]

PMID: 36975868

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Project description:CONTEXT:Although the heritability of atrial fibrillation (AF) is established, the contribution of familial AF to predicting new-onset AF remains unknown. OBJECTIVE:To determine whether familial occurrence of AF is associated with new-onset AF beyond established risk factors. DESIGN, SETTING, AND PARTICIPANTS:The Framingham Heart Study, a prospective community-based cohort study started in 1948. Original and Offspring Cohort participants were aged at least 30 years, were free of AF at the baseline examination, and had at least 1 parent or sibling enrolled in the study. The 4421 participants in this analysis (mean age, 54 [SD, 13] years; 54% women) were followed up through December 31, 2007. MAIN OUTCOME MEASURES:Incremental predictive value of incorporating different features of familial AF (any familial AF, premature familial AF [onset ?65 years old], number of affected relatives, and youngest age of onset in a relative) into a risk model for new-onset AF. RESULTS:Across 11,971 examinations during the period 1968-2007, 440 participants developed AF. Familial AF occurred among 1185 participants (26.8%) and premature familial AF occurred among 351 participants (7.9%). Atrial fibrillation occurred more frequently among participants with familial AF than without familial AF (unadjusted absolute event rates of 5.8% and 3.1%, respectively). The association was not attenuated by adjustment for AF risk factors (multivariable-adjusted hazard ratio, 1.40; 95% confidence interval [CI], 1.13-1.74) or reported AF-related genetic variants. Among the different features of familial AF examined, premature familial AF was associated with improved discrimination beyond traditional risk factors to the greatest extent (traditional risk factors, C statistic, 0.842 [95% CI, 0.826-0.858]; premature familial AF, C statistic, 0.846 [95% CI, 0.831-0.862]; P = .004). Modest changes in integrated discrimination improvement were observed with premature familial AF (2.1%). Net reclassification improvement (assessed using 8-year risk thresholds of <5%, 5%-10%, and >10%) did not change significantly with premature familial AF (index statistic, 0.011; 95% CI, -0.021 to 0.042; P = .51), although categoryless net reclassification was improved (index statistic, 0.127; 95% CI, 0.064-0.189; P = .009). CONCLUSIONS:In this cohort, familial AF was associated with an increased risk of AF that was not attenuated by adjustment for AF risk factors including genetic variants. Assessment of premature familial AF was associated with a very slight increase in predictive accuracy compared with traditional risk factors.

Project description:ObjectiveAtrial fibrillation frequently develops in patients with sepsis and is associated with increased morbidity and mortality. Unfortunately, risk factors for new-onset atrial fibrillation in sepsis have not been clearly elucidated. Clarification of the risk factors for atrial fibrillation during sepsis may improve our understanding of the mechanisms of arrhythmia development and help guide clinical practice.Data sourcesMedline, Embase, Web of Science, and Cochrane CENTRAL.Study selectionWe conducted a systematic review and meta-analysis to identify risk factors for new-onset atrial fibrillation during sepsis.Data extractionWe extracted the adjusted odds ratio for each risk factor associated with new-onset atrial fibrillation during sepsis. For risk factors present in more than one study, we calculated pooled odds ratios (meta-analysis). We classified risk factors according to type and quantified the factor effect sizes. We then compared sepsis-associated atrial fibrillation risk factors with risk factors for community-associated atrial fibrillation.Data synthesisForty-four factors were examined as possible risk factors for new-onset atrial fibrillation in sepsis, 18 of which were included in meta-analyses. Risk factors for new-onset atrial fibrillation included demographic factors, comorbid conditions, and most strongly, sepsis-related factors. Sepsis-related factors with a greater than 50% change in odds of new-onset atrial fibrillation included corticosteroid use, right heart catheterization, fungal infection, vasopressor use, and a mean arterial pressure target of 80-85 mm Hg. Several cardiovascular conditions that are known risk factors for community-associated atrial fibrillation were not identified as risk factors for new-onset atrial fibrillation in sepsis.ConclusionsOur study shows that risk factors for new-onset atrial fibrillation during sepsis are mainly factors that are associated with the acute sepsis event and are not synonymous with risk factors for community-associated atrial fibrillation. Our results provide targets for future studies focused on atrial fibrillation prevention and have implications for several key areas in the management of patients with sepsis such as glucocorticoid administration, vasopressor selection, and blood pressure targets.

Project description:ImportanceAtrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with different epidemiological and pathophysiological processes for women vs men and a poorer prognosis for women. Further investigation of sex-specific risk factors associated with AF development in women is warranted.ObjectiveTo investigate the linear and potential nonlinear associations between sex-specific risk factors and the risk of new-onset AF in women.Design, setting, and participantsThis population-based cohort study obtained data from the 2006 to 2010 UK Biobank study, a cohort of more than 500 000 participants aged 40 to 69 years. Participants were women without AF and history of hysterectomy and/or bilateral oophorectomy at baseline. Median follow-up period for AF onset was 11.6 years, and follow-up ended on October 3, 2020.ExposuresSelf-reported, sex-specific risk factors, including age at menarche, history of irregular menstrual cycle, menopause status, age at menopause, years after menopause, age at first live birth, years after last birth, history of spontaneous miscarriages, history of stillbirths, number of live births, and total reproductive years.Main outcomes and measuresThe primary outcome was new-onset AF, which was defined by the use of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code I48.ResultsA total of 235 191 women (mean [SD] age, 55.7 [8.1] years) were included in the present study. During follow-up, 4629 (2.0%) women experienced new-onset AF. In multivariable-adjusted models, history of irregular menstrual cycle was associated with higher AF risk (hazard ratio [HR], 1.34; 95% CI, 1.01-1.79). Both early menarche (age 7-11 years; HR, 1.10 [95% CI, 1.00-1.21]) and late menarche (age 13-18 years; HR, 1.08 [95% CI, 1.00-1.17]) were associated with AF incidence. Early menopause (age 35-44 years; HR, 1.24 [95% CI, 1.10-1.39]) and delayed menopause (age ≥60 years; HR, 1.34 [95% CI, 1.10-1.78]) were associated with higher risk of AF. Compared with women with 1 to 2 live births, those with 0 live births (HR, 1.13; 95% CI, 1.04-1.24) or 7 or more live births (HR, 1.67; 95% CI, 1.03-2.70) both had significantly higher AF risk.Conclusions and relevanceResults of this study suggest that irregular menstrual cycles, nulliparity, and multiparity were associated with higher risk of new-onset AF among women. The results highlight the importance of taking into account the reproductive history of women in devising screening strategies for AF prevention.

Project description: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.ObjectivesTo 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 ≤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.ExposuresRare and novel variants categorized as pathogenic or likely pathogenic.Main outcomes and measuresThe prevalence of rare and novel pathogenic variants in African American and Hispanic/Latinx probands with early-onset AF and genotype-phenotype associations.ResultsAmong 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 relevanceIn 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.

Dataset Information

Genetic Basis of Early Onset Atrial Fibrillation in Patients without Risk Factors.

Background

Aims

Materials and methods

Results

Conclusions

Publications

Genetic Basis of Early Onset Atrial Fibrillation in Patients without Risk Factors.

Similar Datasets

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