心房颤动与心肌病相关的基因变异

IF 14.8 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JAMA cardiology Pub Date : 2025-04-30 DOI:10.1001/jamacardio.2025.0460

Leonoor F J M Wijdeveld,Ezimamaka Ajufo,Saketh P Challa,Joel T Rämö,Xin Wang,Shinwan Kany,Jennifer L Halford,Lu-Chen Weng,Seung Hoan Choi,Krishna G Aragam,J Peter van Tintelen,Bianca J J M Brundel,Sean J Jurgens,Patrick T Ellinor

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引用次数: 0

摘要

房颤（AF）是一种常见的病态心律失常，其患者更有可能携带与遗传性心肌病相关的罕见基因变异。先前对房颤罕见致病变异的研究依赖于小规模的医院转诊人群，并且对临床结果的了解仍然有限。目的评估AF患者心肌病相关致病性或可能致病性（CMP- plp）遗传变异的患病率和预后意义。设计、环境和参与者在2项前瞻性队列研究中，评估了AF和早发性AF患者群体中CMP- plp变异的患病率。评估了携带CMP- plp变异与AF诊断后发生心肌病或心力衰竭（CMP/HF）风险之间的关系。最后，评估CMP-PLP变异、临床风险和多基因风险的共同作用。本研究纳入了2项大型纵向队列研究，即英国生物银行（UKB）（数据2006-2023）和我们所有人研究计划（AllofUs）（2018-2022）。UKB和AllofUs队列分别包含393 768和193 232名不相关的基因型参与者。ExposuresCMP-PLP变体。主要结果和测量方法：AF诊断后CMP- plp变异的患病率和发生CMP/HF的风险。结果在UKB队列中，32 281名参与者（8%）患有房颤(平均[SD]年龄62岁；20 男性459人[63.4%])。在AllofUs队列中，11， 901名参与者（6%）患有房颤(平均[SD]年龄，67岁；男性6576人[55.3%])。与生物库人群相比，CMP-PLP变异在AF患者中的流行率是前者的两倍(UKB, 2.04%；95% ci, 1.89%-2.20%；AllofUs, 2.52%;95% CI, 2.25%-2.82%)， 45岁前发病的房颤患病率为5倍(UKB, 4.99%；95% ci, 3.07%-7.91%；AllofUs, 4.66%;3.40% - -6.32%)。房颤患者CMP/HF的累积发病率（18%）高于无房颤患者（3%）。然而，在没有CMP/HF病史的AF患者中(UKB, 20 226；携带CMP- plp变异的AllofUs， 8330)与发生CMP/HF的1.6倍风险相关（荟萃分析，95% CI, 1.32-1.90）。最后，CMP- plp变异、多基因评分和临床危险因素是CMP/HF的独立估计值。该队列研究的结果表明，CMP- plp变异在早发性房颤患者中非常普遍。携带CMP- plp变异的房颤患者未来发生CMP/HF的风险增加，与临床和多基因风险无关。这些结果表明，房颤患者的基因检测可以识别出发生CMP/HF的高风险个体。

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Cardiomyopathy-Associated Gene Variants in Atrial Fibrillation.

Importance Patients with atrial fibrillation (AF), a common morbid arrhythmia, are more likely to carry rare genetic variants associated with inherited cardiomyopathies. Prior studies on rare pathogenic variants in AF relied on small, hospital referral populations, and knowledge on clinical outcomes remains limited. Objective To evaluate the prevalence and prognostic implications of cardiomyopathy-associated pathogenic or likely pathogenic (CMP-PLP) genetic variants in patients with AF. Design, Setting, and Participants In 2 prospective cohort studies, the prevalence of CMP-PLP variants was assessed in the population of patients with AF and early-onset AF. The association between carrying a CMP-PLP variant and the risk of incident cardiomyopathy or heart failure (CMP/HF) after AF diagnosis was evaluated. Finally, the joint contributions of CMP-PLP variants, clinical risk, and polygenic risk were assessed. Included in this study were 2 large longitudinal cohort studies, the UK Biobank (UKB) (data 2006-2023) and the All of Us Research Program (AllofUs) (2018-2022). The UKB and AllofUs cohorts, respectively, contained 393 768 and 193 232 unrelated genotyped participants. Exposures CMP-PLP variants. Main Outcomes and Measures Prevalence of CMP-PLP variants and risk of incident CMP/HF after AF diagnosis. Results In the UKB cohort, 32 281 participants (8%) had AF (mean [SD] age, 62 [6] years; 20 459 male [63.4%]). In the AllofUs cohort, 11 901 participants (6%) had AF (mean [SD] age, 67 [12] years; 6576 male [55.3%]). Compared with the biobank populations, CMP-PLP variants were twice as prevalent in patients with AF (UKB, 2.04%; 95% CI, 1.89%-2.20%; AllofUs, 2.52%; 95% CI, 2.25%-2.82%) and 5 times as prevalent in AF with onset before age 45 years (UKB, 4.99%; 95% CI, 3.07%-7.91%; AllofUs, 4.66%; 3.40%-6.32%). Cumulative incidence of CMP/HF was high in patients with AF (18%) compared with patients without AF (3%). Still, among patients with AF without prior CMP/HF (UKB, 20 226; AllofUs, 8330), carrying a CMP-PLP variant was associated with 1.6-fold risk of incident CMP/HF (meta-analysis, 95% CI, 1.32-1.90). Finally, CMP-PLP variants, a polygenic score, and clinical risk factors were independent estimators of CMP/HF. Conclusions and Relevance Results of this cohort study suggest that the prevalence of CMP-PLP variants was substantial in patients with early-onset AF. Patients with AF carrying a CMP-PLP variant had an associated increased risk of future CMP/HF, independent of clinical and polygenic risk. These results indicate that genetic testing in patients with AF may identify individuals at higher risk for developing CMP/HF.

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来源期刊

JAMA cardiology Medicine-Cardiology and Cardiovascular Medicine

CiteScore

45.80

自引率

1.70%

发文量

264

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