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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #341881
Research Project: Genomics, Nutrition, and Health

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 disease

Author
item ZANONI, PAOLO - UNIVERSITY OF PENNSYLVANIA
item KHETARPAL, SUMEET - UNIVERSITY OF PENNSYLVANIA
item LARACH, DANIEL - UNIVERSITY OF PENNSYLVANIA
item HANCOCK-CERUTTI, WILLIAM - UNIVERSITY OF PENNSYLVANIA
item MILLAR, JOHN - UNIVERSITY OF PENNSYLVANIA
item CUCHEL, MARINA - UNIVERSITY OF PENNSYLVANIA
item DEROHANNESSIAN, STEPHANIE - UNIVERSITY OF PENNSYLVANIA
item KONTUSH, ANATOL - PIERRE AND MARIE CURIE UNIVERSITY
item SURENDRAN, PRAVEN - UNIVERSITY OF CAMBRIDGE
item SALEHEEN, DANISH - UNIVERSITY OF CAMBRIDGE
item TROMPET, STELLA - LEIDEN UNIVERSITY MEDICAL CENTER
item JUKEMA, J WOUTER - LEIDEN UNIVERSITY MEDICAL CENTER
item DE CRAEN, ANTON - LEIDEN UNIVERSITY MEDICAL CENTER
item DELOUKAS, PANOS - WELLCOME TRUST SANGER INSTITUTE
item SATTAR, NAVEED - UNIVERSITY OF GLASGOW
item FORD, IAN - UNIVERSITY OF GLASGOW
item PACKARD, CHRIS - GLASGOW CLINICAL RESEARCH FACILITY
item MAJUMDER, ABDULLAH - NATIONAL INSTITUTE OF CARDIOVASCULAR DISEASES
item ALAM, DEWAN - YORK UNIVERSITY
item ANGELANTONIO, EMANUELE - UNIVERSITY OF CAMBRIDGE
item ABECASIS, GONCALO - UNIVERSITY OF MICHIGAN
item CHOWDHURY, RAJIV - UNIVERSITY OF CAMBRIDGE
item ERDMANN, JEANETTE - UNIVERSITY OF LUBECK
item NORDESTGAARD, BOERGE - COPENHAGEN UNIVERSITY
item NIELSEN, SUNE - COPENHAGEN UNIVERSITY
item TYBJAERG-HANSEN, ANNE - UNIVERSITY OF COPENHAGEN
item SCHMIDT, RUTH - COPENHAGEN UNIVERSITY
item KUULASMAA, KARI - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item LIU, DAJIANG - PENNSYLVANIA STATE UNIVERSITY
item PEROLA, MARKUS - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item BLANKENBERG, STEFAN - UNIVERSITY HEART CENTER HAMBURG
item SALOMAA, VEIKKO - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item MANNISTO, SATU - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item AMOUYEL, PHILIPPE - INSTITUT PASTEUR - FRANCE
item ARVEILER, DOMINIQUE - UNIVERSITÉ DE STRASBOURG: ACCUEIL
item FERRIERES, JEAN - TOULOUSE UNIVERSITY HOSPITAL
item MULLER-NURASYID, MARTINA - HELMHOLTZ CENTRE FOR ENVIRONMENTAL RESEARCH
item FERRARIO, MARCO - UNIVERSITY OF INSUBRIA
item KEE, FRANK - QUEENS UNIVERSITY - UNITED KINGDOM
item WILLER, CRISTEN - UNIVERSITY OF MICHIGAN
item SAMANI, NILESH - UNIVERSITY OF LEICESTER
item SCHUNKERT, HERIBERT - TECHNISCHE UNIVERSITAT MUNCHEN
item BUTTERWORTH, ADAM - UNIVERSITY OF CAMBRIDGE
item HOWSON, JOANNA - UNIVERSITY OF CAMBRIDGE
item PELOSO, GINA - MASSACHUSETTS GENERAL HOSPITAL
item STITZIEL, NATHAN - WASHINGTON UNIVERSITY
item DANESH, JOHN - UNIVERSITY OF CAMBRIDGE
item KATHIRESAN, SEKAR - MASSACHUSETTS GENERAL HOSPITAL
item RADER, DANIEL - UNIVERSITY OF PENNSYLVANIA
item 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).