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

P Zanoni, SA Khetarpal, DB Larach, WF Hancock-Cerutti, JS Millar, M Cuchel, S DerOhannessian, A Kontush, P Surendran, D Saleheen, S Trompet, JW Jukema, A De Craen, P Deloukas, N Sattar, I Ford, C Packard, AA Majumder, DS Alam, E Di AngelantonioG Abecasis, R Chowdhury, J Erdmann, BG Nordestgaard, SF Nielsen, A Tybjaerg-Hansen, RF Schmidt, K Kuulasmaa, DJ Liu, M Perola, S Blankenberg, V Salomaa, S Mannisto, P Amouyel, D Arveiler, J Ferrieres, M Muller-Nurasyid, M Ferrario, F Kee, CJ Willer, N Samani, H Schunkert, AS Butterworth, JMM Howson, GM Peloso, NO Stitziel, J Danesh, S Kathiresan, DJ Rader

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342 Citations (Scopus)


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).
Original languageUndefined/Unknown
Pages (from-to)1166-1171
Number of pages6
Issue number6278
Publication statusPublished - 2016
Externally publishedYes

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