Title | Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Zanoni 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 Authors | Rader DJ |
Corporate Authors | CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, Global Lipids Genetics Consortium |
Journal | Science |
Volume | 351 |
Issue | 6278 |
Pagination | 1166-71 |
Date Published | 2016 Mar 11 |
ISSN | 1095-9203 |
Keywords | Aged, 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). |
DOI | 10.1126/science.aad3517 |
Alternate Journal | Science |
PubMed ID | 26965621 |
PubMed Central ID | PMC4889017 |
Grant List | G0800270 / 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 |