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.

中文翻译：

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LDLR、APOB 和 PCSK9 中罕见的遗传变异与主动脉瓣狭窄有关。


背景 尽管提出 LDL-C （低密度脂蛋白胆固醇） 在主动脉瓣狭窄 （AS） 中的因果关系，但降脂治疗的随机对照试验未能预防严重的 AS。我们旨在评估 LDL（低密度脂蛋白）代谢的 3 个临床重要基因 （LDLR、APOB 和 PCSK9） 的蛋白质破坏变异介导的 LDL-C 水平终生改变对 AS 和通过主动脉瓣的峰值速度的影响。方法 我们使用了来自英国生物样本库 （UKB） 和 All of Us 的测序数据和电子健康记录以及来自 UKB 的磁共振成像数据。我们使用功能丧失转录本效应估计器 （LOFTEE） 和 AlphaMissense 算法确定了预测的蛋白质破坏变异，并评估了它们与 LDL-C 和主动脉瓣峰值速度的关联 （UK Biobank），以及诊断的 AS 和主动脉瓣置换术 （UK Biobank 和 All of Us）。结果：我们在 UKB 中纳入了 421 049 名无关参与者 （5621 名 AS） 和 195 519 名无关参与者 （1087 名 AS） 在我们所有人中。LDLR 中蛋白质破坏变异的携带者平均 LDL-C 较高 （UKB：+42.6 mg/dL;P=4.4e-237）和 AS 风险更高（荟萃分析：比值比，3.52 [95% CI，2.39-5.20];P=2.3e-10）和主动脉瓣置换术（meta分析：比值比，3.78 [95% CI，2.26-6.32];P=4.0e-7）。APOB 或 PCSK9 中蛋白破坏变异的携带者平均 LDL-C 较低 （UKB： -32.3 mg/dL;P<5e-324）和 AS 风险较低（荟萃分析：比值比，0.49 [95% CI，0.31-0.75];P=0.001）和主动脉瓣置换术（meta分析：比值比，0.54 [95% CI，0.30-0.97];P = 0.04）。 在 57 371 名 UKB 成像子研究参与者中，LDLR 中蛋白质破坏变异携带者通过主动脉瓣的峰值速度更高（+12.2 cm/s;P=1.6e-5）和 PCSK9 中蛋白质破坏变体携带者更低 （-6.9 cm/s;P=0.022）。结论 赋予终生较高或较低 LDL-C 水平的罕见遗传变异分别与 AS 风险的显着增加和降低有关。早期和持续的降脂治疗可能会减缓或预防 AS 的发生。