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

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 De Craen; Panos Deloukas; Naveed Sattar; Ian Ford; Chris Packard; Abdullah Al Shafi Majumder; Dewan S. Alam; Emanuele Di Angelantonio; Goncalo Abecasis; Rajiv Chowdhury; Jeanette Erdmann; Børge G. Nordestgaard; Sune F. Nielsen; Anne Tybjærg-Hansen; Frikke Schmidt Ruth Frikke Schmidt; Kari Kuulasmaa; Dajiang J. Liu; Markus Perola; Stefan Blankenberg; Veikko Salomaa; Satu Männistö; Philippe Amouyel; Dominique Arveiler; Jean Ferrieres; Martina Möller-Nurasyid; Marco Ferrario; Frank Kee; Cristen J. Willer; Nilesh Samani; Heribert Schunkert; Adam S. Butterworth; Joanna M.M. Howson; Gina M. Peloso; Nathan O. Stitziel; John Danesh; Sekar Kathiresan; Daniel J. Rader

doi:10.1126/science.aad3517

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

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 De Craen, Panos Deloukas, Naveed Sattar, Ian Ford, Chris Packard, Abdullah Al Shafi Majumder, Dewan S. Alam, Emanuele Di AngelantonioGoncalo Abecasis, Rajiv Chowdhury, Jeanette Erdmann, Børge G. Nordestgaard, Sune F. Nielsen, Anne Tybjærg-Hansen, Frikke Schmidt Ruth Frikke Schmidt, Kari Kuulasmaa, Dajiang J. Liu, Markus Perola, Stefan Blankenberg, Veikko Salomaa, Satu Männistö, Philippe Amouyel, Dominique Arveiler, Jean Ferrieres, Martina Möller-Nurasyid, Marco Ferrario, Frank Kee, Cristen J. Willer, Nilesh Samani, Heribert Schunkert, Adam S. Butterworth, Joanna M.M. Howson, Gina M. Peloso, Nathan O. Stitziel, John Danesh, Sekar Kathiresan, Daniel J. Rader^*

^*Corresponding author for this work

114 Citations (Scopus)

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 lossof-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).

Original language	English
Journal	Science
Volume	351
Issue number	6278
Pages (from-to)	1166-1171
Number of pages	6
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.aad3517
Publication status	Published - 11.03.2016

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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., Wouter Jukema, J., De Craen, A., Deloukas, P., Sattar, N., Ford, I., Packard, C., Majumder, A. A. S., Alam, D. S., ... Rader, D. J. (2016). Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science, 351(6278), 1166-1171. https://doi.org/10.1126/science.aad3517

@article{d54b11ee2ba14ddfb38d7a20dc0d5c97,

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

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 lossof-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).",

author = "Paolo Zanoni and Khetarpal, {Sumeet A.} and Larach, {Daniel B.} and Hancock-Cerutti, {William F.} and Millar, {John S.} and Marina Cuchel and Stephanie DerOhannessian and Anatol Kontush and Praveen Surendran and Danish Saleheen and Stella Trompet and {Wouter Jukema}, J. and {De Craen}, Anton and Panos Deloukas and Naveed Sattar and Ian Ford and Chris Packard and Majumder, {Abdullah Al Shafi} and Alam, {Dewan S.} and {Di Angelantonio}, Emanuele and Goncalo Abecasis and Rajiv Chowdhury and Jeanette Erdmann and Nordestgaard, {B{\o}rge G.} and Nielsen, {Sune F.} and Anne Tybj{\ae}rg-Hansen and {Ruth Frikke Schmidt}, {Frikke Schmidt} and Kari Kuulasmaa and Liu, {Dajiang J.} and Markus Perola and Stefan Blankenberg and Veikko Salomaa and Satu M{\"a}nnist{\"o} and Philippe Amouyel and Dominique Arveiler and Jean Ferrieres and Martina M{\"o}ller-Nurasyid and Marco Ferrario and Frank Kee and Willer, {Cristen J.} and Nilesh Samani and Heribert Schunkert and Butterworth, {Adam S.} and Howson, {Joanna M.M.} and Peloso, {Gina M.} and Stitziel, {Nathan O.} and John Danesh and Sekar Kathiresan and Rader, {Daniel J.}",

year = "2016",

month = mar,

day = "11",

doi = "10.1126/science.aad3517",

language = "English",

volume = "351",

pages = "1166--1171",

journal = "Science",

issn = "0036-8075",

number = "6278",

}

Zanoni, P, Khetarpal, SA, Larach, DB, Hancock-Cerutti, WF, Millar, JS, Cuchel, M, DerOhannessian, S, Kontush, A, Surendran, P, Saleheen, D, Trompet, S, Wouter Jukema, J, De Craen, A, Deloukas, P, Sattar, N, Ford, I, Packard, C, Majumder, AAS, Alam, DS, Di Angelantonio, E, Abecasis, G, Chowdhury, R, Erdmann, J, Nordestgaard, BG, Nielsen, SF, Tybjærg-Hansen, A, Ruth Frikke Schmidt, FS, Kuulasmaa, K, Liu, DJ, Perola, M, Blankenberg, S, Salomaa, V, Männistö, S, Amouyel, P, Arveiler, D, Ferrieres, J, Möller-Nurasyid, M, Ferrario, M, Kee, F, Willer, CJ, Samani, N, Schunkert, H, Butterworth, AS, Howson, JMM, Peloso, GM, Stitziel, NO, Danesh, J, Kathiresan, S & Rader, DJ 2016, 'Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease', Science, vol. 351, no. 6278, pp. 1166-1171. https://doi.org/10.1126/science.aad3517

TY - JOUR

T1 - Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

AU - Zanoni, Paolo

AU - Khetarpal, Sumeet A.

AU - Larach, Daniel B.

AU - Hancock-Cerutti, William F.

AU - Millar, John S.

AU - Cuchel, Marina

AU - DerOhannessian, Stephanie

AU - Kontush, Anatol

AU - Surendran, Praveen

AU - Saleheen, Danish

AU - Trompet, Stella

AU - Wouter Jukema, J.

AU - De Craen, Anton

AU - Deloukas, Panos

AU - Sattar, Naveed

AU - Ford, Ian

AU - Packard, Chris

AU - Majumder, Abdullah Al Shafi

AU - Alam, Dewan S.

AU - Di Angelantonio, Emanuele

AU - Abecasis, Goncalo

AU - Chowdhury, Rajiv

AU - Erdmann, Jeanette

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Tybjærg-Hansen, Anne

AU - Ruth Frikke Schmidt, Frikke Schmidt

AU - Kuulasmaa, Kari

AU - Liu, Dajiang J.

AU - Perola, Markus

AU - Blankenberg, Stefan

AU - Salomaa, Veikko

AU - Männistö, Satu

AU - Amouyel, Philippe

AU - Arveiler, Dominique

AU - Ferrieres, Jean

AU - Möller-Nurasyid, Martina

AU - Ferrario, Marco

AU - Kee, Frank

AU - Willer, Cristen J.

AU - Samani, Nilesh

AU - Schunkert, Heribert

AU - Butterworth, Adam S.

AU - Howson, Joanna M.M.

AU - Peloso, Gina M.

AU - Stitziel, Nathan O.

AU - Danesh, John

AU - Kathiresan, Sekar

AU - Rader, Daniel J.

PY - 2016/3/11

Y1 - 2016/3/11

N2 - 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 lossof-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).

AB - 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 lossof-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).

UR - http://www.scopus.com/inward/record.url?scp=84960897316&partnerID=8YFLogxK

U2 - 10.1126/science.aad3517

DO - 10.1126/science.aad3517

M3 - Journal articles

C2 - 26965621

AN - SCOPUS:84960897316

SN - 0036-8075

VL - 351

SP - 1166

EP - 1171

JO - Science

JF - Science

IS - 6278

ER -

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

Abstract

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