| Title: | The functional landscape of coding variation in the familial hypercholesterolemia gene LDLR |
| Journal: | Science |
| Published: | 19 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41166440/ |
| DOI: | https://doi.org/10.1126/science.ady7186 |
| URL: | https://pmc.ncbi.nlm.nih.gov/articles/PMC12726852/ |
Publication 17696
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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. We tested the impact of ~17,000 (nearly all possible) LDLR 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.</p>
7 Keywords
- Cholesterol, LDL
- Genetic Code
- Humans
- Hyperlipoproteinemia Type II
- Multifactorial Inheritance
- Mutation, Missense
- Receptors, LDL
34 Authors
- 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 S Carrero
- Olivia Taverniti
- Anna Axakova
- Jack M P Castelli
- Mohammad M 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
1 Application
| Application ID | Title |
|---|---|
| 51135 | Evaluating the impact of computational and experimental measures of rare variant deleteriousness on burden-based association testing |
Enabling scientific discoveries that improve human health