169151 20260220162133.0 doi 10.1016/j.jacl.2025.11.017 sideral 148240 ART-2025-148240 eng Gracia-Rubio, Irene Universidad de Zaragoza (orcid)0000-0003-1028-8581 Sequencing and functional characterization of SCARB1 variants in subjects with extreme HDL cholesterol levels 2025 BACKGROUND Rare variants in SCARB1, which encodes the high-density lipoprotein (HDL) receptor scavenger receptor class B type 1 (SR-B1), are hypothesized to drive unexplained extreme levels of plasma HDL cholesterol (HDL-C). OBJECTIVE We sequenced and phenotypically correlated SCARB1 by analyzing individuals with extreme HDL-C levels and characterizing the functional consequences of rare identified variants. METHODS SCARB1 was Sanger-sequenced in 96 unrelated participants with extreme HDL-C levels. Clinical, biochemical, and anthropometric data were compared between groups. Bioinformatic tools were used to predict the functional impact of all detected variants. Familial analyses of predicted damaging in silico or not previously described variants was assessed, and HDL uptake was quantified by flow cytometry in HEK293 cells expressing rare SCARB1 variants showing a suggestive pattern of familial segregation. RESULTS Compared with the high-HDL-C group, low-HDL-C subjects exhibited lower low-density lipoprotein cholesterol and total cholesterol but higher triglycerides, higher body mass index, and a greater frequency of atherosclerotic cardiovascular disease events. Twenty-five SCARB1 variants were identified; 4 of them, c.-177G>T, p.(Thr118Ser), c.843-982G>A and p.(Thr378Met), were predicted to be deleterious. The missense changes p.(Thr118Ser) and p.(Thr378Met) showed a suggestive pattern of segregation with high HDL-C in available pedigrees. Cells expressing p.(Thr378Met) SCARB1 variant showed a reduction in HDL uptake vs wild-type. CONCLUSION Rare predicted damaging in silico variant in SCARB1, p.(Thr378Met), impairs SR-B1-mediated HDL uptake and associates with high HDL-C levels, highlighting SCARB1 as a candidate gene for genetic screening in dyslipidemic patients. Access copy available to the general public Unrestricted info:eu-repo/grantAgreement/ES/ISCIII/PT17-0015-0039 info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Benito-Vicente, Asier Lamiquiz-Moneo, Itziar Universidad de Zaragoza (orcid)0000-0002-9647-0108 Bea, Ana María Marco-Benedí, Victoria Universidad de Zaragoza Cabrera-Antón, Endika Martín, César Civeira, Fernando Universidad de Zaragoza (orcid)0000-0001-7043-0952 Cenarro, Ana 1003 027 Universidad de Zaragoza Dpto. Anatom.Histolog.Humanas Area Anatom.Embriol.Humana 1007 610 Universidad de Zaragoza Dpto. Medicina, Psiqu. y Derm. Area Medicina (2025), [13 pp.] Journal of Clinical Lipidology Journal of Clinical Lipidology 1933-2874 1560510 http://zaguan.unizar.es/record/169151/files/texto_completo.pdf Versión publicada 2260863 http://zaguan.unizar.es/record/169151/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:169151 articulos driver 2026-02-20-14:53:58 ARTICLE