| Title: | Population-Level Prevalence of Rare Variants Associated With Atrial Fibrillation and its Impact on Patient Outcomes |
| Journal: | JACC Clinical Electrophysiology |
| Published: | 18 Jan 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36669898/ |
| DOI: | https://doi.org/10.1016/j.jacep.2022.11.022 |
Publication 10969
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Abstract
BACKGROUND: Whole exome sequencing may identify rare pathogenic/likely pathogenic variants (LPVs) that are linked to atrial fibrillation (AF). The impact of LPVs associated with AF on a population level on outcomes is unclear.</p>
OBJECTIVES: This study sought to examine the association of LPVs with AF and their impact on clinical outcomes using the UK Biobank, a national repository of participants with available whole exome sequencing data.</p>
METHODS: A total of 200,631 individuals in the UK Biobank were studied. Incident and prevalent AF, comorbidities, and outcomes were identified using self-reported assessments and hospital stay operative, and death registry records. LPVs were determined using arrhythmia and cardiomyopathy gene panels with LOFTEE and ClinVar to predict variants of functional significance.</p>
RESULTS: Compared with control subjects, there was a modestly increased prevalence of LPVs among 9,585 patients with AF (2.0% vs 1.7%, respectively; P = 0.01). Among those with prevalent AF at <45 years of age, 4.2% were LPV carriers. LPVs in TTN and PKP2 were associated with AF with adjusted odds ratios of 2.69 (95% CI: 1.57-4.61) and 2.69 (95% CI: 1.54-4.68), respectively. There was no significant difference in combined ischemic stroke, heart failure hospitalization, and mortality among patients who have AF with and without LPVs (25.1% vs 23.8%; P = 0.49). Among participants with AF and available cardiac magnetic resonance imaging data, LPV carriers had lower left ventricular ejection fractions than non-LPV carriers (42% vs 52%; P = 0.027).</p>
CONCLUSIONS: Patients with AF had a modestly increased prevalence of LPVs. Among reference arrhythmia and cardiomyopathy genes, the contribution of rare variants to AF risk at a population level is modest and its impact on outcomes appears to be limited, despite an association of LPVs with reduced left ventricular ejection fraction among patients with AF.</p>
10 Authors
- Manjinder S Kandola
- Scott Kulm
- Luke K Kim
- Steven M Markowitz
- Christopher F Liu
- George Thomas
- James E Ip
- Bruce B Lerman
- Olivier Elemento
- Jim W Cheung
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