Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease
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Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. / Zanoni, Paolo; Khetarpal, Sumeet A; Larach, Daniel B; Hancock-Cerutti, William F; Millar, John S; Cuchel, Marina; DerOhannessian, Stephanie; Kontush, Anatol; Surendran, Praveen; Saleheen, Danish; Trompet, Stella; Jukema, J Wouter; De Craen, Anton; Deloukas, Panos; Sattar, Naveed; Ford, Ian; Packard, Chris; Majumder, Abdullah al Shafi; Alam, Dewan S; Di Angelantonio, Emanuele; Abecasis, Goncalo; Chowdhury, Rajiv; Erdmann, Jeanette; Nordestgaard, Børge G; Nielsen, Sune F; Tybjærg-Hansen, Anne; Schmidt, Ruth Frikke; Kuulasmaa, Kari; Liu, Dajiang J; Perola, Markus; Blankenberg, Stefan; Salomaa, Veikko; Männistö, Satu; Amouyel, Philippe; Arveiler, Dominique; Ferrieres, Jean; Müller-Nurasyid, Martina; Ferrario, Marco; Kee, Frank; Willer, Cristen J; Samani, Nilesh; Schunkert, Heribert; Butterworth, Adam S; Howson, Joanna M M; Peloso, Gina M; Stitziel, Nathan O; Danesh, John; Kathiresan, Sekar; Rader, Daniel J; CHD Exome+ Consortium.
In: SCIENCE, Vol. 351, No. 6278, 11.03.2016, p. 1166-1171.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 - Jukema, J Wouter
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 - Schmidt, Ruth Frikke
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 - Müller-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
AU - CHD Exome+ Consortium
N1 - Copyright © 2016, American Association for the Advancement of Science.
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 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).
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 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).
KW - Aged
KW - Amino Acid Substitution
KW - Animals
KW - Cholesterol, HDL/blood
KW - Coronary Disease/blood
KW - DNA Mutational Analysis
KW - Female
KW - Genetic Variation
KW - Heterozygote
KW - Homozygote
KW - Humans
KW - Leucine/genetics
KW - Male
KW - Mice
KW - Middle Aged
KW - Proline/genetics
KW - Protein Processing, Post-Translational
KW - Risk
KW - Scavenger Receptors, Class B/genetics
U2 - 10.1126/science.aad3517
DO - 10.1126/science.aad3517
M3 - SCORING: Journal article
C2 - 26965621
VL - 351
SP - 1166
EP - 1171
JO - SCIENCE
JF - SCIENCE
SN - 0036-8075
IS - 6278
ER -