Repository logo
 
Publication

The Functional Landscape Of Coding Variation In The Familial Hypercholesterolemia Gene LDLR

2025-10-30Journal article Restricted access
Simple item page
datacite.subject.fosCiências Médicas
dc.contributor.authorTabet, Daniel R.
dc.contributor.authorCoté, Atina G.
dc.contributor.authorLancaster, Megan C.
dc.contributor.authorWeile, Jochen
dc.contributor.authorRayhan, Ashyad
dc.contributor.authorFotiadou, Iosifina
dc.contributor.authorKishore, Nishka
dc.contributor.authorLi, Roujia
dc.contributor.authorKuang, Da
dc.contributor.authorKnapp, Jennifer J.
dc.contributor.authorCarrero, Carmela Serio
dc.contributor.authorTaverniti, Olivia
dc.contributor.authorAxakova, Anna
dc.contributor.authorCastelli, Jack M. P.
dc.contributor.authorIslam, Mohammad Majharul
dc.contributor.authorSowlati-Hashjin, Shahin
dc.contributor.authorGandhi, Aanshi
dc.contributor.authorMaaieh, Ranim
dc.contributor.authorGarton, Michael
dc.contributor.authorMatreyek, Kenneth
dc.contributor.authorFowler, Douglas M.
dc.contributor.authorBourbon, Mafalda
dc.contributor.authorPfisterer, Simon G.
dc.contributor.authorGlazer, Andrew M.
dc.contributor.authorKroncke, Brett M.
dc.contributor.authorParikh, Victoria N.
dc.contributor.authorAshley, Euan A.
dc.contributor.authorKnowles, Joshua W.
dc.contributor.authorClaussnitzer, Melina
dc.contributor.authorCirulli, Elizabeth T.
dc.contributor.authorHegele, Robert A.
dc.contributor.authorRoden, Dan M.
dc.contributor.authorMacRae, Calum A.
dc.contributor.authorRoth, Frederick P.
dc.date.accessioned2025-12-03T18:36:10Z
dc.date.available2025-12-03T18:36:10Z
dc.date.issued2025-10-30
dc.description.abstractVariants in the familial hypercholesterolemia gene -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 missense variants, limiting interventions that reduce disease burden. Here, we tested the impact of ~17,000 (nearly all possible) 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.eng
dc.description.sponsorshipFunding: R01HL164675 (to F.P.R., D.M.R., E.A.A., C.A.M., V.N.P., A.M.G., and B.M.K.) The One Brave Idea Initiative (jointly funded by the American Heart Association, Verily Life Sciences LLC, and Astra-Zeneca, Inc. with additional support from Quest Diagnostics) (to C.A.M. and F.P.R.). Canada Foundation for Innovation (to F.P.R.). Canadian Institutes of Health Research Foundation Grant FDN159926 (to F.P.R.). The Canada Excellence Research Chairs Program (to F.P.R.). University of Toronto Precision Medicine Initiative (PRiME) Fellowship PRMF2022 (to D.R.T.) National Human Genome Research Institute of the National Institutes of Health Center of Excellence in Genomic Science Initiative RM1HG010461 (to D.M.F. and F.P.R.). NHGRI Impact of Genomic Variation on Function Initiative UM1HG019189 (to F.P.R.). EU Horizon RIA: 101155885-2, FH-EARLY (to M.B. and S.G.P.). La Caixa Foundation (LCF/PR/HP23/52330032) (to M.B. and S.G.P.). NIH from R01DK106236, P30 DK116074 (to the Stanford Diabetes Research Center), R01DK116750, R01DK137889, R01DK120565 (to J.W.K), and NHGRI K08HG014001 (to M.C.L.) The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA#: AO 16037; Federally Qualified Health Centers: HHSN 26320160085U; Data and Research Center; 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; OT2 OD025276.
dc.identifier.citationScience. 2025 Oct 30:eady7186. doi: 10.1126/science.ady7186. Online ahead of print
dc.identifier.doi10.1126/science.ady7186
dc.identifier.eissn1095-9203
dc.identifier.issn0036-8075
dc.identifier.pmid41166440
dc.identifier.urihttp://hdl.handle.net/10400.18/10636
dc.language.isoeng
dc.peerreviewedyes
dc.publisherAmerican Association for the Advancement of Science
dc.relation101155885-2
dc.relation.hasversionhttps://www.science.org/doi/10.1126/science.ady7186
dc.rights.uriN/A
dc.subjectFamilial Hypercholesterolemia
dc.subjectLDLR
dc.subjectCholesterol
dc.subjectDoenças Cardio e Cérebro-Vasculares
dc.subjectColesterol
dc.titleThe Functional Landscape Of Coding Variation In The Familial Hypercholesterolemia Gene LDLReng
dc.typejournal article
dcterms.referenceshttps://www.science.org/doi/suppl/10.1126/science.ady7186/suppl_file/science.ady7186_sm.pdf
dcterms.referenceshttps://www.science.org/doi/suppl/10.1126/science.ady7186/suppl_file/science.ady7186_mdar_reproducibility_checklist.pdf
dcterms.referenceshttps://www.science.org/doi/suppl/10.1126/science.ady7186/suppl_file/science.ady7186_data_s1_to_s8.zip
dspace.entity.typePublication
oaire.citation.titleScience
oaire.citation.volumeeady7186
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
2025. The functional landscape of coding variation in the FH gene LDLR.pdf
Size:
8.78 MB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
4.03 KB
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

DPSPDNT - Artigos em revistas internacionais
INSA - Artigos em revistas internacionais