Rare Genetic Variants in LDLR, APOB, and PCSK9 Are Associated With Aortic Stenosis.

IF 35.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation Pub Date : 2024-11-26 Epub Date: 2024-09-02 DOI:10.1161/CIRCULATIONAHA.124.070982

Joel T Rämö, Sean J Jurgens, Shinwan Kany, Seung Hoan Choi, Xin Wang, Andrey N Smirnov, Samuel F Friedman, Mahnaz Maddah, Shaan Khurshid, Patrick T Ellinor, James P Pirruccello

{"title":"Rare Genetic Variants in LDLR, APOB, and PCSK9 Are Associated With Aortic Stenosis.","authors":"Joel T Rämö, Sean J Jurgens, Shinwan Kany, Seung Hoan Choi, Xin Wang, Andrey N Smirnov, Samuel F Friedman, Mahnaz Maddah, Shaan Khurshid, Patrick T Ellinor, James P Pirruccello","doi":"10.1161/CIRCULATIONAHA.124.070982","DOIUrl":null,"url":null,"abstract":"Background: Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism (LDLR, APOB, and PCSK9).Methods: We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us).Results: We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in LDLR had higher mean LDL-C (UKB: +42.6 mg/dL; P=4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39-5.20]; P=2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26-6.32]; P=4.0e-7). Carriers of protein-disrupting variants in APOB or PCSK9 had lower mean LDL-C (UKB: -32.3 mg/dL; P<5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31-0.75]; P=0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30-0.97]; P=0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in LDLR (+12.2 cm/s; P=1.6e-5) and lower in carriers of protein-disrupting variants in PCSK9 (-6.9 cm/s; P=0.022).Conclusions: Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development.","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"1767-1780"},"PeriodicalIF":35.5000,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCULATIONAHA.124.070982","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/2 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism (LDLR, APOB, and PCSK9).

Methods: We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us).

Results: We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in LDLR had higher mean LDL-C (UKB: +42.6 mg/dL; P=4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39-5.20]; P=2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26-6.32]; P=4.0e-7). Carriers of protein-disrupting variants in APOB or PCSK9 had lower mean LDL-C (UKB: -32.3 mg/dL; P<5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31-0.75]; P=0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30-0.97]; P=0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in LDLR (+12.2 cm/s; P=1.6e-5) and lower in carriers of protein-disrupting variants in PCSK9 (-6.9 cm/s; P=0.022).

Conclusions: Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development.

查看原文本刊更多论文

LDLR、APOB 和 PCSK9 的罕见遗传变异与主动脉狭窄有关。

背景：尽管低密度脂蛋白胆固醇（LDL-C）在主动脉瓣狭窄（AS）中被认为是因果关系，但降脂治疗的随机对照试验未能预防严重的主动脉瓣狭窄。我们的目的是评估由三个具有临床意义的低密度脂蛋白代谢基因（LDLR、APOB、PCSK9）中的蛋白干扰变异介导的低密度脂蛋白胆固醇水平终身改变对主动脉瓣狭窄和峰值速度的影响。研究方法我们利用英国生物库（UKB）和《我们所有人》的测序数据和电子健康记录以及英国生物库的磁共振成像数据。我们利用 LOFTEE 和 AlphaMissense 算法确定了预测的蛋白质干扰变异体，并评估了它们与低密度脂蛋白胆固醇和主动脉瓣峰值速度（UK Biobank）以及确诊的 AS 和主动脉瓣置换术（UK Biobank + All of Us）之间的关系。结果：我们在英国生物库中纳入了 421,049 名无关参与者（其中 5,621 人患有 AS），在 "我们所有人 "中纳入了 195,519 名无关参与者（其中 1,087 人患有 AS）。LDLR 蛋白质干扰变异携带者的平均 LDL-C 较高（UKB：+42.6 mg/dl，P=4.4e-237），患 AS（荟萃分析：比值比 [OR] =3.52 [95% CI 2.39-5.20]，P=2.3e-10）和主动脉瓣置换（荟萃分析：OR=3.78 [95% CI 2.26-6.32]，P=4.0e-7）的风险更大。APOB 或 PCSK9 蛋白质干扰变异携带者的平均低密度脂蛋白胆固醇含量较低（UKB：-32.3 mg/dl，PPCSK9：-6.9 cm/s，P=0.022）。结论罕见的基因变异可使LDL-C水平终生较高或较低，这分别与强直性脊柱炎风险的大幅增加和降低有关。早期和持续的降脂治疗可延缓或预防强直性脊柱炎的发生。

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

Circulation 医学-外周血管病

CiteScore

45.70

自引率

2.10%

发文量

1473

审稿时长

2 months

期刊介绍： Circulation is a platform that publishes a diverse range of content related to cardiovascular health and disease. This includes original research manuscripts, review articles, and other contributions spanning observational studies, clinical trials, epidemiology, health services, outcomes studies, and advancements in basic and translational research. The journal serves as a vital resource for professionals and researchers in the field of cardiovascular health, providing a comprehensive platform for disseminating knowledge and fostering advancements in the understanding and management of cardiovascular issues.