Location: Jean Mayer Human Nutrition Research Center On Aging
Title: Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart diseaseAuthor
ZANONI, PAOLO - University Of Pennsylvania | |
KHETARPAL, SUMEET - University Of Pennsylvania | |
LARACH, DANIEL - University Of Pennsylvania | |
HANCOCK-CERUTTI, WILLIAM - University Of Pennsylvania | |
MILLAR, JOHN - University Of Pennsylvania | |
CUCHEL, MARINA - University Of Pennsylvania | |
DEROHANNESSIAN, STEPHANIE - University Of Pennsylvania | |
KONTUSH, ANATOL - Pierre And Marie Curie University | |
SURENDRAN, PRAVEN - University Of Cambridge | |
SALEHEEN, DANISH - University Of Cambridge | |
TROMPET, STELLA - Leiden University Medical Center | |
JUKEMA, J WOUTER - Leiden University Medical Center | |
DE CRAEN, ANTON - Leiden University Medical Center | |
DELOUKAS, PANOS - Wellcome Trust Sanger Institute | |
SATTAR, NAVEED - University Of Glasgow | |
FORD, IAN - University Of Glasgow | |
PACKARD, CHRIS - Glasgow Clinical Research Facility | |
MAJUMDER, ABDULLAH - National Institute Of Cardiovascular Diseases | |
ALAM, DEWAN - York University | |
ANGELANTONIO, EMANUELE - University Of Cambridge | |
ABECASIS, GONCALO - University Of Michigan | |
CHOWDHURY, RAJIV - University Of Cambridge | |
ERDMANN, JEANETTE - University Of Lubeck | |
NORDESTGAARD, BOERGE - Copenhagen University | |
NIELSEN, SUNE - Copenhagen University | |
TYBJAERG-HANSEN, ANNE - University Of Copenhagen | |
SCHMIDT, RUTH - Copenhagen University | |
KUULASMAA, KARI - National Institute For Health And Welfare (HELSINKI) | |
LIU, DAJIANG - Pennsylvania State University | |
PEROLA, MARKUS - National Institute For Health And Welfare (HELSINKI) | |
BLANKENBERG, STEFAN - University Heart Center Hamburg | |
SALOMAA, VEIKKO - National Institute For Health And Welfare (HELSINKI) | |
MANNISTO, SATU - National Institute For Health And Welfare (HELSINKI) | |
AMOUYEL, PHILIPPE - Institut Pasteur - France | |
ARVEILER, DOMINIQUE - Université De Strasbourg: Accueil | |
FERRIERES, JEAN - Toulouse University Hospital | |
MULLER-NURASYID, MARTINA - Helmholtz Centre For Environmental Research | |
FERRARIO, MARCO - University Of Insubria | |
KEE, FRANK - Queens University - United Kingdom | |
WILLER, CRISTEN - University Of Michigan | |
SAMANI, NILESH - University Of Leicester | |
SCHUNKERT, HERIBERT - Technische Universitat Munchen | |
BUTTERWORTH, ADAM - University Of Cambridge | |
HOWSON, JOANNA - University Of Cambridge | |
PELOSO, GINA - Massachusetts General Hospital | |
STITZIEL, NATHAN - Washington University | |
DANESH, JOHN - University Of Cambridge | |
KATHIRESAN, SEKAR - Massachusetts General Hospital | |
RADER, DANIEL - University Of Pennsylvania | |
ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University |
Submitted to: Science
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 1/7/2016 Publication Date: 3/11/2016 Citation: Zanoni, P., Khetarpal, S.A., Larach, D.B., Hancock-Cerutti, W.F., Millar, J.S., Cuchel, M., Derohannessian, S., Kontush, A., Surendran, P., Saleheen, D., Trompet, S., Jukema, J., De Craen, A., Deloukas, P., Sattar, N., Ford, I., Packard, C., Majumder, A., Alam, D.S., Angelantonio, E.D., Abecasis, G., Chowdhury, R., Erdmann, J., Nordestgaard, B.G., Nielsen, S.F., Tybjaerg-Hansen, A., Schmidt, R.F., Kuulasmaa, K., Liu, D., Perola, M., Blankenberg, S., Salomaa, V., Mannisto, S., Amouyel, P., Arveiler, D., Ferrieres, J., Muller-Nurasyid, M., Ferrario, M., Kee, F., Willer, C.J., Samani, N., Schunkert, H., Butterworth, A.S., Howson, J.M., Peloso, G.M., Stitziel, N.O., Danesh, J., Kathiresan, S., Rader, D.J., Ordovas, J.M. 2016. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science. doi: 10.1126/science.aad3517. Interpretive Summary: Scavenger receptor BI is the major receptor for high-density lipoprotein cholesterol. In humans, high amounts of high-density lipoprotein cholesterol in plasma are associated with a lower risk of coronary heart disease. When mice are depleted of the Scarb1 gene that encodes scavenger receptor BI, they have markedly elevated high-density lipoprotein cholesterol levels but, paradoxically, increased atherosclerosis. The impact of scavenger receptor BI on high density lipoprotein metabolism and coronary heart disease risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma high density lipoprotein cholesterol levels, we identified one individual who had identical pairs of a genetic variant in the SCARB1 gene that resulted in loss of function of the receptor. This variant impairs processing of scavenger receptor BI and abolishes high density lipoprotein cholesterol uptake in several cell and animal models. Large population-based studies revealed that individuals who are carriers of this genetic variant have significantly increased levels of plasma high density lipoprotein cholesterol. Against the traditional dogma, these carriers of this genetic variant have elevated high density lipoprotein and an increased risk of coronary heart disease. Technical 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). |