Cardiovascular Disease Initiative (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P.), Cambridge, MA.
Broad Institute of MIT and Harvard (J.T.R., S.J.J., S. Kany, X.W., S. Khurshid, P.T.E., J.P.P, A.N.S., S.F.F., M.M.), Cambridge, MA.
Circulation. 2024 Nov 26;150(22):1767-1780. doi: 10.1161/CIRCULATIONAHA.124.070982. Epub 2024 Sep 2.
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 (, , and ).
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).
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 had higher mean LDL-C (UKB: +42.6 mg/dL; =4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39-5.20]; =2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26-6.32]; =4.0e-7). Carriers of protein-disrupting variants in or had lower mean LDL-C (UKB: -32.3 mg/dL; <5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31-0.75]; =0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30-0.97]; =0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in (+12.2 cm/s; =1.6e-5) and lower in carriers of protein-disrupting variants in (-6.9 cm/s; =0.022).
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.
尽管 LDL-C（低密度脂蛋白胆固醇）在主动脉瓣狭窄（AS）中具有因果关系，但降脂治疗的随机对照试验未能预防严重的 AS。我们旨在评估通过 3 个临床意义重大的 LDL（低密度脂蛋白）代谢基因（ 、 和 ）中的蛋白破坏变异体介导的 LDL-C 水平终生变化对 AS 和主动脉瓣峰值速度的影响。
我们使用来自 UK Biobank（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 Loss Of Function Transcript Effect Estimator（LOFTEE）和 AlphaMissense 算法识别预测的蛋白破坏变异体，并评估它们与 LDL-C 和主动脉瓣峰值速度（UKB）的关联，以及诊断的 AS 和主动脉瓣置换（UKB 和 All of Us）。
我们在 UKB 中纳入了 421049 名无关参与者（5621 名患有 AS），在 All of Us 中纳入了 195519 名无关参与者（1087 名患有 AS）。携带 中蛋白破坏变异体的个体 LDL-C 平均值较高（UKB：+42.6mg/dL；=4.4e-237），患 AS（荟萃分析：比值比，3.52[95%CI，2.39-5.20]；=2.3e-10）和主动脉瓣置换（荟萃分析：比值比，3.78[95%CI，2.26-6.32]；=4.0e-7）的风险更高。携带 或 中蛋白破坏变异体的个体 LDL-C 平均值较低（UKB：-32.3mg/dL；<5e-324），患 AS（荟萃分析：比值比，0.49[95%CI，0.31-0.75]；=0.001）和主动脉瓣置换（荟萃分析：比值比，0.54[95%CI，0.30-0.97]；=0.04）的风险较低。在 57371 名 UKB 成像子研究参与者中，携带 中蛋白破坏变异体的个体主动脉瓣峰值速度较高（+12.2cm/s；=1.6e-5），携带 中蛋白破坏变异体的个体主动脉瓣峰值速度较低（-6.9cm/s；=0.022）。
终生 LDL-C 水平升高或降低的罕见遗传变异与 AS 风险的显著增加或降低相关。早期和持续的降脂治疗可能会减缓或预防 AS 的发展。
