000169151 001__ 169151
000169151 005__ 20260220162133.0
000169151 0247_ $$2doi$$a10.1016/j.jacl.2025.11.017
000169151 0248_ $$2sideral$$a148240
000169151 037__ $$aART-2025-148240
000169151 041__ $$aeng
000169151 100__ $$0(orcid)0000-0003-1028-8581$$aGracia-Rubio, Irene$$uUniversidad de Zaragoza
000169151 245__ $$aSequencing and functional characterization of SCARB1 variants in subjects with extreme HDL cholesterol levels
000169151 260__ $$c2025
000169151 5060_ $$aAccess copy available to the general public$$fUnrestricted
000169151 5203_ $$aBACKGROUND
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.
000169151 536__ $$9info:eu-repo/grantAgreement/ES/ISCIII/PT17-0015-0039
000169151 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000169151 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000169151 700__ $$aBenito-Vicente, Asier
000169151 700__ $$0(orcid)0000-0002-9647-0108$$aLamiquiz-Moneo, Itziar$$uUniversidad de Zaragoza
000169151 700__ $$aBea, Ana María
000169151 700__ $$aMarco-Benedí, Victoria$$uUniversidad de Zaragoza
000169151 700__ $$aCabrera-Antón, Endika
000169151 700__ $$aMartín, César
000169151 700__ $$0(orcid)0000-0001-7043-0952$$aCiveira, Fernando$$uUniversidad de Zaragoza
000169151 700__ $$aCenarro, Ana
000169151 7102_ $$11003$$2027$$aUniversidad de Zaragoza$$bDpto. Anatom.Histolog.Humanas$$cArea Anatom.Embriol.Humana
000169151 7102_ $$11007$$2610$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cArea Medicina
000169151 773__ $$g(2025), [13 pp.]$$pJournal of Clinical Lipidology$$tJournal of Clinical Lipidology$$x1933-2874
000169151 8564_ $$s1560510$$uhttps://zaguan.unizar.es/record/169151/files/texto_completo.pdf$$yVersión publicada
000169151 8564_ $$s2260863$$uhttps://zaguan.unizar.es/record/169151/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000169151 909CO $$ooai:zaguan.unizar.es:169151$$particulos$$pdriver
000169151 951__ $$a2026-02-20-14:53:58
000169151 980__ $$aARTICLE