Find en forsker – Københavns Universitet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Paolo Zanoni, Sumeet A Khetarpal, Daniel B Larach, William F Hancock-Cerutti, John S Millar, Marina Cuchel, Stephanie DerOhannessian, Anatol Kontush, Praveen Surendran, Danish Saleheen, Stella Trompet, J Wouter Jukema, Anton Jm de Craen, Panos Deloukas, Naveed Sattar, Ian Ford, Chris Packard, Abdullah al Shafi Majumder, Dewan S Alam, Emanuele Di Angelantonio & 32 andre Goncalo Abecasis, Rajiv Chowdhury, Jeanette Erdmann, Børge G Nordestgaard, Sune F Nielsen, Anne Tybjærg-Hansen, Ruth Frikke Schmidt, Kari Kuulasmaa, Dajiang J Liu, Markus Perola, Stefan Blankenberg, Veikko Salomaa, Satu Männistö, Philippe Amouyel, Dominique Arveiler, Jean Ferrières, Martina Müller-Nurasyid, Marco M Ferrario, Frank Kee, Cristen J Willer, Nilesh J Samani, Heribert Schunkert, Adam S Butterworth, Joanna M. M. Howson, Gina M Peloso, Nathan O Stitziel, John Danesh, Sekar Kathiresan, Daniel J Rader, CHD Exome+ Consortium, CARDIoGRAM Exome Consortium, Global Lipids Genetics Consortium

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).

OriginalsprogEngelsk
TidsskriftScience (New York, N.Y.)
Vol/bind351
Tidsskriftsnummer6278
Sider (fra-til)1166-71
Antal sider6
ISSN0036-8075
DOI
StatusUdgivet - 11 mar. 2016

ID: 177525379