Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
Details
State: Public
Version: Final published version
Serval ID
serval:BIB_D3E3C31EE25E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
Journal
Science (New York, N.Y.)
Working group(s)
CHD Exome+ Consortium, CARDIoGRAM Exome Consortium, Global Lipids Genetics Consortium
Contributor(s)
Watson S., Schmidt E.M., Sengupta S., Gustafsson S., Kanoni S., Ganna A., Chen J., Buchkovich M.L., Mora S., Beckmann J.S., Bragg-Gresham J.L., Chang H.Y., Demirkan A., Den Hertog H.M., Do R., Donnelly L.A., Ehret G.B., Esko T., Feitosa M.F., Ferreira T., Fischer K., Fontanillas P., Fraser R.M., Freitag D.F., Gurdasani D., Heikkilä K., Hyppönen E., Isaacs A., Jackson A.U., Johansson Å., Johnson T., Kaakinen M., Kettunen J., Kleber M.E., Li X., Luan J., Lyytikäinen L.P., Magnusson P.K., Mangino M., Mihailov E., Montasser M.E., Nolte I.M., O'Connell J.R., Palmer C.D., Petersen A.K., Sanna S., Saxena R., Service S.K., Shah S., Shungin D., Sidore C., Song C., Strawbridge R.J., Surakka I., Tanaka T., Teslovich T.M., Thorleifsson G., Van den Herik E.G., Voight B.F., Volcik K.A., Waite L.L., Wong A., Wu Y., Zhang W., Absher D., Asiki G., Barroso I., Been L.F., Bolton J.L., Bonnycastle L.L., Brambilla P., Burnett M.S., Cesana G., Dimitriou M., Doney A.S., Döring A., Elliott P., Epstein S.E., Eyjolfsson G.I., Gigante B., Goodarzi M.O., Grallert H., Gravito M.L., Groves C.J., Hallmans G., Hartikainen A.L., Hayward C., Hernandez D., Hicks A.A., Holm H., Hung Y.J., Illig T., Jones M.R., Kaleebu P., Kastelein J.J., Khaw K.T., Kim E., Klopp N., Komulainen P., Kumari M., Langenberg C., Lehtimäki T., Lin S.Y., Lindström J., Loos R.J., Mach F., McArdle W.L., Meisinger C., Mitchell B.D., Müller G., Nagaraja R., Narisu N., Nieminen T.V., Nsubuga R.N., Olafsson I., Ong K.K., Palotie A., Papamarkou T., Pomilla C., Pouta A., Reilly M.P., Ridker P.M., Rivadeneira F., Rudan I., Ruokonen A., Scharnagl H., Seeley J., Silander K., Stancáková A., Stirrups K., Swift A.J., Tiret L., Uitterlinden A.G., van Pelt L.J., Vedantam S., Wainwright N., Wijmenga C., Wild S.H., Willemsen G., Wilsgaard T., Wilson J.F., Young E.H., Zhao J.H., Adair L.S., Arveiler D., Assimes T.L., Bandinelli S., Bennett F., Bochud M., Boehm B.O., Boomsma D.I., Borecki I.B., Bornstein S.R., Bovet P., Burnier M., Campbell H., Chakravarti A., Chambers J.C., Chen Y.D., Collins F.S., Cooper R.S., Dedoussis G., de Faire U., Feranil A.B., Ferrucci L., Freimer N.B., Gieger C., Groop L.C., Gudnason V., Gyllensten U., Hamsten A., Harris T.B., Hingorani A., Hirschhorn J.N., Hofman A., Hovingh G.K., Hsiung C.A., Humphries S.E., Hunt S.C., Hveem K., Iribarren C., Järvelin M.R., Jula A., Kähönen M., Kaprio J., Kesäniemi A., Kivimaki M., Kooner J.S., Koudstaal P.J., Krauss R.M., Kuh D., Kuusisto J., Kyvik K.O., Laakso M., Lakka T.A., Lind L., Lindgren C.M., Martin N.G., März W., McCarthy M.I., McKenzie C.A., Meneton P., Metspalu A., Moilanen L., Morris A.D., Munroe P.B., Njølstad I., Pedersen N.L., Power C., Pramstaller P.P., Price J.F., Psaty B.M., Quertermous T., Rauramaa R., Salomaa V., Sanghera D.K., Saramies J., Schwarz P.E., Sheu W.H., Shuldiner A.R., Siegbahn A., Spector T.D., Stefansson K., Strachan D.P., Tayo B.O., Tremoli E., Tuomilehto J., Uusitupa M., van Duijn C.M., Vollenweider P., Wallentin L., Wareham N.J., Whitfield J.B., Wolffenbuttel B.H., Ordovas J.M., Boerwinkle E., Palmer C.N., Thorsteinsdottir U., Chasman D.I., Rotter J.I., Franks P.W., Riatti S., Cupples L.A., Sandhu M.S., Rich S.S., Boehnke M., Deloukas P., Mohlke K.L., Ingelsson E., Gu D., Roberts R., Watkins H., Blankenberg S., Clarke R., Collins R., Kim B.J., McPherson R., Nieminen M.S., O'Donnell C., Schreiber S., Siegbahn A., Zalloua P.A.
ISSN
1095-9203 (Electronic)
ISSN-L
0036-8075
Publication state
Published
Issued date
11/03/2016
Volume
351
Number
6278
Pages
1166-1171
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).
Keywords
Aged, Amino Acid Substitution, Animals, Cholesterol, HDL/blood, Coronary Disease/blood, Coronary Disease/genetics, DNA Mutational Analysis, Female, Genetic Variation, Heterozygote, Homozygote, Humans, Leucine/genetics, Male, Mice, Middle Aged, Proline/genetics, Protein Processing, Post-Translational, Risk, Scavenger Receptors, Class B/genetics, Scavenger Receptors, Class B/metabolism
Pubmed
Create date
30/12/2016 11:03
Last modification date
20/08/2019 15:53
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