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Zanoni, P.* ; Khetarpal, S.A.* ; Larach, D.B.* ; Hancock-Cerutti, W.F.* ; Millar, J.S.* ; Cuchel, M.* ; Derohannessian, S.L.* ; Kontush, A.* ; Surendran, P.* ; Saleheen, D.* ; Trompet, S.* ; Jukema, J.W.* ; de Craen, A.J.* ; Deloukas, P.* ; Sattar, N.* ; Ford, I.* ; Packard, C.* ; Al Shafi Majumder, A.* ; Alam, D.S.* ; di Angelantonio, E.* ; Abecasis, G.* ; Chowdhury, R.* ; Erdmann, J.* ; Nørdestgaard, B.G.* ; Nielsen, S.F.* ; Tybjærg-Hansen, A.* ; Schmidt, R.F.* ; Kuulasmaa, K.* ; Liu, D.J.* ; Perola, M.* ; Blankenberg, S.* ; Salomaa, V.* ; Männistö, S.* ; Amouyel, P.* ; Arveiler, D.* ; Ferrieres, J.* ; Müller-Nurasyid, M. ; Ferrario, M.* ; Kee, F.* ; Willer, C.J.* ; Samani, N.* ; Schunkert, H.* ; Butterworth, A.S.* ; Howson, J.M.M.* ; Peloso, G.M.* ; Stitziel, N.O.* ; Danesh, J.* ; Kathiresan, S.* ; Rader, D.J.* ; CHD Exome Consortium (*) ; CARDIoGRAM Exome Consortium (*) ; Global Lipids Genetics Consortium (*)

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

Science 351, 1166-1671 (2016)

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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).

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords High-density-lipoprotein; Selective Lipid Uptake; I Sr-bi; Deficient Mice; Targeted Mutation; Transgenic Mice; Metabolism; Expression; Ester; Atherosclerosis

ISSN (print) / ISBN 0036-8075

e-ISSN 1095-9203

Journal Science

Quellenangaben Volume: 351, Issue: 6278, Pages: 1166-1671

Publisher American Association for the Advancement of Science (AAAS)

Publishing Place Washington

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology II (EPI2)