Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population.

IF 14.8 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Nay Aung, Hannah L Nicholls, C Anwar A Chahal, Mohammed Y Khanji, Elisa Rauseo, Sucharitha Chadalavada, Steffen E Petersen, Patricia B Munroe, Perry M Elliott, Luis R Lopes
{"title":"Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population.","authors":"Nay Aung, Hannah L Nicholls, C Anwar A Chahal, Mohammed Y Khanji, Elisa Rauseo, Sucharitha Chadalavada, Steffen E Petersen, Patricia B Munroe, Perry M Elliott, Luis R Lopes","doi":"10.1001/jamacardio.2024.2190","DOIUrl":null,"url":null,"abstract":"<p><strong>Importance: </strong>The population prevalence of cardiac transthyretin amyloidosis (ATTR) caused by pathogenic variation in the TTR gene (vATTR) is unknown.</p><p><strong>Objective: </strong>To estimate the population prevalence of disease-causing TTR variants and evaluate associated phenotypes and outcomes.</p><p><strong>Design, setting, and participants: </strong>This population-based cohort study analyzed UK Biobank (UKB) participants with whole-exome sequencing, electrocardiogram, and cardiovascular magnetic resonance data. Participants were enrolled from 2006 to 2010, with a median follow-up of 12 (IQR, 11-13) years (cutoff date for the analysis, March 12, 2024). Sixty-two candidate TTR variants were extracted based on rarity (minor allele frequency ≤0.0001) and/or previously described associations with amyloidosis if more frequent.</p><p><strong>Exposure: </strong>Carrier status for TTR variants.</p><p><strong>Main outcomes and measures: </strong>Associations of TTR carrier status with vATTR prevalence and cardiovascular imaging and electrocardiogram traits were explored using descriptive statistics. Associations between TTR carrier status and atrial fibrillation, conduction disease, heart failure, and all-cause mortality were evaluated using adjusted Cox proportional hazards models. Genotypic and diagnostic concordance was examined using International Statistical Classification of Diseases, Tenth Revision codes from the hospital record.</p><p><strong>Results: </strong>The overall cohort included 469 789 UKB participants (mean [SD] age, 56.5 [8.1] years; 54.2% female and 45.8% male). A likely pathogenic/pathogenic (LP/P) TTR variant was detected in 473 (0.1%) participants, with Val142Ile being the most prevalent (367 [77.6%]); 91 individuals (0.02%) were carriers of a variant of unknown significance . The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry. The LP/P variants were associated with higher left ventricular mass indexed to body surface area (β = 4.66; 95% CI, 1.87-7.44), and Val142Ile was associated with a longer PR interval (β = 18.34; 95% CI, 5.41-31.27). The LP/P carrier status was associated with a higher risk of heart failure (hazard ratio [HR], 2.68; 95% CI, 1.75-4.12) and conduction disease (HR, 1.88; 95% CI, 1.25-2.83). Higher all-cause mortality risk was observed for non-Val142Ile LP/P variants (HR, 1.98; 95% CI, 1.06-3.67). Thirteen participants (2.8%) with LP/P variants had diagnostic codes compatible with cardiac or neurologic amyloidosis. Variants of unknown significance were not associated with outcomes.</p><p><strong>Conclusions and relevance: </strong>This study found that approximately 1 in 1000 UKB participants were LP/P TTR variant carriers, exceeding previously reported prevalence. The findings emphasize the need for clinical vigilance in identifying individuals at risk of developing vATTR and associated poor outcomes.</p>","PeriodicalId":14657,"journal":{"name":"JAMA cardiology","volume":" ","pages":"964-972"},"PeriodicalIF":14.8000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11359106/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JAMA cardiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1001/jamacardio.2024.2190","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0

Abstract

Importance: The population prevalence of cardiac transthyretin amyloidosis (ATTR) caused by pathogenic variation in the TTR gene (vATTR) is unknown.

Objective: To estimate the population prevalence of disease-causing TTR variants and evaluate associated phenotypes and outcomes.

Design, setting, and participants: This population-based cohort study analyzed UK Biobank (UKB) participants with whole-exome sequencing, electrocardiogram, and cardiovascular magnetic resonance data. Participants were enrolled from 2006 to 2010, with a median follow-up of 12 (IQR, 11-13) years (cutoff date for the analysis, March 12, 2024). Sixty-two candidate TTR variants were extracted based on rarity (minor allele frequency ≤0.0001) and/or previously described associations with amyloidosis if more frequent.

Exposure: Carrier status for TTR variants.

Main outcomes and measures: Associations of TTR carrier status with vATTR prevalence and cardiovascular imaging and electrocardiogram traits were explored using descriptive statistics. Associations between TTR carrier status and atrial fibrillation, conduction disease, heart failure, and all-cause mortality were evaluated using adjusted Cox proportional hazards models. Genotypic and diagnostic concordance was examined using International Statistical Classification of Diseases, Tenth Revision codes from the hospital record.

Results: The overall cohort included 469 789 UKB participants (mean [SD] age, 56.5 [8.1] years; 54.2% female and 45.8% male). A likely pathogenic/pathogenic (LP/P) TTR variant was detected in 473 (0.1%) participants, with Val142Ile being the most prevalent (367 [77.6%]); 91 individuals (0.02%) were carriers of a variant of unknown significance . The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry. The LP/P variants were associated with higher left ventricular mass indexed to body surface area (β = 4.66; 95% CI, 1.87-7.44), and Val142Ile was associated with a longer PR interval (β = 18.34; 95% CI, 5.41-31.27). The LP/P carrier status was associated with a higher risk of heart failure (hazard ratio [HR], 2.68; 95% CI, 1.75-4.12) and conduction disease (HR, 1.88; 95% CI, 1.25-2.83). Higher all-cause mortality risk was observed for non-Val142Ile LP/P variants (HR, 1.98; 95% CI, 1.06-3.67). Thirteen participants (2.8%) with LP/P variants had diagnostic codes compatible with cardiac or neurologic amyloidosis. Variants of unknown significance were not associated with outcomes.

Conclusions and relevance: This study found that approximately 1 in 1000 UKB participants were LP/P TTR variant carriers, exceeding previously reported prevalence. The findings emphasize the need for clinical vigilance in identifying individuals at risk of developing vATTR and associated poor outcomes.

英国生物库人群中转铁蛋白变异体的患病率、心脏表型和预后。
重要性:由 TTR 基因致病变异(vATTR)引起的心脏转甲状腺素淀粉样变性病(ATTR)的人群患病率尚不清楚:估计致病TTR变异的人群患病率,并评估相关表型和结果:这项基于人群的队列研究分析了英国生物库(UKB)参与者的全外显子组测序、心电图和心血管磁共振数据。参与者于2006年至2010年期间入组,中位随访时间为12(IQR,11-13)年(分析截止日期为2024年3月12日)。根据稀有性(小等位基因频率≤0.0001)和/或先前描述的与淀粉样变性的关联(如果更常见),提取了62个候选TTR变体:主要结果和测量:采用描述性统计方法探讨 TTR 携带者状态与 vATTR 患病率、心血管成像和心电图特征之间的关联。使用调整后的 Cox 比例危险模型评估了 TTR 携带者状态与心房颤动、传导疾病、心力衰竭和全因死亡率之间的关系。使用医院记录中的国际疾病统计分类第十版代码对基因型和诊断的一致性进行了检查:总体队列包括 469 789 名 UKB 参与者(平均 [SD] 年龄为 56.5 [8.1] 岁;54.2% 为女性,45.8% 为男性)。473名参与者(0.1%)检测到可能致病/致病(LP/P)的TTR变异,其中Val142Ile最为普遍(367人[77.6%]);91人(0.02%)为意义不明的变异携带者。在欧洲血统的参与者中,LP/P变异体的总体流行率为0.02%(444 243人中有105人),在非洲血统的参与者中,LP/P变异体的流行率为4.3%(7533人中有321人)。LP/P变异与体表面积指数较高的左心室质量相关(β = 4.66;95% CI,1.87-7.44),Val142Ile与较长的PR间期相关(β = 18.34;95% CI,5.41-31.27)。LP/P 携带者与较高的心力衰竭风险(危险比 [HR],2.68;95% CI,1.75-4.12)和传导疾病风险(HR,1.88;95% CI,1.25-2.83)相关。非Val142Ile LP/P变异体的全因死亡风险更高(HR,1.98;95% CI,1.06-3.67)。13名患有LP/P变异的参与者(2.8%)的诊断代码与心脏或神经系统淀粉样变性相符。意义不明的变异与结果无关:本研究发现,约每 1000 名 UKB 参与者中就有 1 人是 LP/P TTR 变异携带者,超过了之前报道的患病率。研究结果强调,临床上需要提高警惕,识别有可能患上 vATTR 和相关不良预后的个体。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
JAMA cardiology
JAMA cardiology Medicine-Cardiology and Cardiovascular Medicine
CiteScore
45.80
自引率
1.70%
发文量
264
期刊介绍: JAMA Cardiology, an international peer-reviewed journal, serves as the premier publication for clinical investigators, clinicians, and trainees in cardiovascular medicine worldwide. As a member of the JAMA Network, it aligns with a consortium of peer-reviewed general medical and specialty publications. Published online weekly, every Wednesday, and in 12 print/online issues annually, JAMA Cardiology attracts over 4.3 million annual article views and downloads. Research articles become freely accessible online 12 months post-publication without any author fees. Moreover, the online version is readily accessible to institutions in developing countries through the World Health Organization's HINARI program. Positioned at the intersection of clinical investigation, actionable clinical science, and clinical practice, JAMA Cardiology prioritizes traditional and evolving cardiovascular medicine, alongside evidence-based health policy. It places particular emphasis on health equity, especially when grounded in original science, as a top editorial priority.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信