该课题组研究人员测试了大约17,000种（几乎所有可能的）LDLR错义编码变体对LDLR细胞表面丰度和LDL摄取的影响，得到了序列功能图，这些图概括了已知的生物化学，提供了功能见解，并为解释临床变异提供了证据。在前瞻性人类队列中，功能评分与高脂血症表型相关，并增强多基因评分以改善风险推断，强调这种抵抗加速家族性高胆固醇血症诊断和改善患者预后的潜力。
据介绍，家族性高胆固醇血症基因ldlr的变异——心血管疾病最重要的遗传驱动因素——可提高循环低密度脂蛋白（LDL）胆固醇浓度，增加过早动脉粥样硬化的风险。临床上遇到的近一半LDLR错义变异缺乏明确的分类，限制了减轻疾病负担的干预措施。
附：英文原文
Title: The functional landscape of coding variation in the familial hypercholesterolemia gene LDLR
Author: Daniel R Tabet, Atina G Coté, Megan C Lancaster, Jochen Weile, Ashyad Rayhan, Iosifina Fotiadou, Nishka Kishore, Roujia Li, Da Kuang, Jennifer J. Knapp, Carmela Serio Carrero, Olivia Taverniti, Anna Axakova, Jack M.P. Castelli, Mohammad Majharul Islam, Shahin Sowlati-Hashjin, Aanshi Gandhi, Ranim Maaieh, Michael Garton, Kenneth Matreyek, Douglas M Fowler, Mafalda Bourbon, Simon G. Pfisterer, Andrew M. Glazer, Brett M Kroncke, Victoria N. Parikh, Euan A. Ashley, Joshua W. Knowles, Melina Claussnitzer, Elizabeth T. Cirulli, Robert A. Hegele, Dan M. Roden, Calum A. MacRae, Frederick P. Roth
Issue&Volume: 2025-10-30
Abstract: Variants in the familial hypercholesterolemia gene LDLR—the most important genetic driver of cardiovascular disease—can raise circulating low-density lipoprotein (LDL) cholesterol concentrations and increase the risk of premature atherosclerosis. Definitive classifications are lacking for nearly half of clinically encountered LDLR missense variants, limiting interventions that reduce disease burden. Here, we tested the impact of ~17,000 (nearly all possible) LDLR missense coding variants on both LDLR cell-surface abundance and LDL uptake, yielding sequence–function maps that recapitulate known biochemistry, offer functional insights, and provide evidence for interpreting clinical variants. Functional scores correlated with hyperlipidemia phenotypes in prospective human cohorts and augmented polygenic scores to improve risk inference, highlighting the potential of this resource to accelerate familial hypercholesterolemia diagnosis and improve patient outcomes.
DOI: ady7186
Source: https://www.science.org/doi/10.1126/science.ady7186