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

TitleRare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsZanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, DerOhannessian S, Kontush A, Surendran P, Saleheen D, Trompet S, J Jukema W, De Craen A, Deloukas P, Sattar N, Ford I, Packard C, Majumder Aal Shafi, Alam DS, Di Angelantonio E, Abecasis G, Chowdhury, iv R, Erdmann J, Nordestgaard BG, Nielsen SF, Tybjærg-Hansen A, Schmidt RFrikke, Kuulasmaa K, Liu DJ, Perola M, Blankenberg S, Salomaa V, Männisto S, Amouyel P, Arveiler D, Ferrières J, Müller-Nurasyid M, Ferrario M, Kee F, Willer CJ, Samani N, Schunkert H, Butterworth AS, Howson JMM, Peloso GM, Stitziel NO, Danesh J, Kathiresan S
Secondary AuthorsRader DJ
Corporate AuthorsCHD Exome+ Consortium, CARDIOGRAM Exome Consortium, Global Lipids Genetics Consortium
JournalScience
Volume351
Issue6278
Pagination1166-71
Date Published2016 Mar 11
ISSN1095-9203
KeywordsAged, Amino Acid Substitution, Animals, Cholesterol, HDL, Coronary Disease, DNA Mutational Analysis, Female, Genetic Variation, Heterozygote, Homozygote, Humans, Leucine, Male, Mice, Middle Aged, Proline, Protein Processing, Post-Translational, Risk, Scavenger Receptors, Class B
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).

DOI10.1126/science.aad3517
Alternate JournalScience
PubMed ID26965621
PubMed Central IDPMC4889017
Grant ListG0800270 / MRC_ / Medical Research Council / United Kingdom
R01 HL111398 / HL / NHLBI NIH HHS / United States
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
R01 DK089256 / DK / NIDDK NIH HHS / United States
R01 HL117078 / HL / NHLBI NIH HHS / United States
U01 HG006398 / HG / NHGRI NIH HHS / United States
TL1RR024133 / RR / NCRR NIH HHS / United States
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
MR/N003284/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL089309 / HL / NHLBI NIH HHS / United States
TL1R000138 / / PHS HHS / United States
R21 DA040177 / DA / NIDA NIH HHS / United States
RG/08/014/24067 / BHF_ / British Heart Foundation / United Kingdom
K08 HL114642 / HL / NHLBI NIH HHS / United States
R01 HG008983 / HG / NHGRI NIH HHS / United States
G0401527 / MRC_ / Medical Research Council / United Kingdom
TL1 RR024133 / RR / NCRR NIH HHS / United States
MR/K013351/1 / MRC_ / Medical Research Council / United Kingdom
PG/08/094/26019 / BHF_ / British Heart Foundation / United Kingdom
G0801566 / MRC_ / Medical Research Council / United Kingdom
RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom