Abstract 19040: Different SCARB1 Locus Variants Associate With Hdl-Cholesterol and the Risk of Coronary Artery Disease
Background and objective: Scavenger receptor class B type 1 (SR-B1), encoded by the SCARB1 gene, promotes uptake of cholesterol from circulating HDL and plays a role in reverse cholesterol transport. Genome-wide association studies (GWAS) have identified common variants at the SCARB1 locus that associate with HDL-C and rare SCARB1 coding variants have been shown to increase HDL-C. Recently a rare missense variant p.P376L in SCARB1 that raises HDL-C was reported to increase CAD risk, in contrast to expected cardiovascular protection as observed in epidemiologic studies. GWAS studies have also found common SCARB1 locus variants that associate with levels of vitamin E and Lp-PLA2 activity, highlighting the complexity of the association signals at this locus. We aim to examine the relationship between HDL-C associating variants at the SCARB1 locus and the risk of CAD.
Methods and results: We examined all sequence variants in the SCARB1 locus identified through whole-genome sequencing of 8,453 Icelanders and subsequently imputed into a large population-based dataset for association with HDL-C (n= 136,672) and CAD (39,904 cases/306,338 controls). Apart from replicating association of two common HDL-C variants we identified the third common variant that independently associates with HDL-C (β= -1.25 mg/dL, P=1.7x10-18). In addition, we identified two rare missense variants, occurring in the large extracellular loop of the SR-BI protein, that associate with elevated levels of HDL-C (p.G319V: β=11.12 mg/dL, P=8.0x10-7 and p.V111M: β=8.25 mg/dL, P=1.1x10-6). None of the five independent variants that associate with HDL-C at the SCARB1 locus associate with CAD. However, another intronic SCARB1 variant, that correlated with markers previously shown to associate with Lp-PLA2 and vitamin E, associates with CAD (OR=1.08, P=1.9x10-8), but not with HDL-C.
Conclusion: While rare and common HDL-C associating variants at the SCARB1 locus do not associate with CAD, a different common variant at the same locus does. This suggests that the CAD associating locus variant mediates its effect through HDL-C independent mechanisms.
Author Disclosures: A. Helgadottir: Employment; Modest; deCODE genetics is owned by Amgen. P. Sulem: Employment; Modest; deCODE genetics is owned by Amgen. G. Thorgeirsson: None. I. Olafsson: None. G.I. Eyjolfsson: None. O. Sigurdardottir: None. U. Thorsteinsdottir: Employment; Modest; deCODE genetics is owned by Amgen. D.F. Gudbjartsson: Employment; Modest; deCODE genetics is owned by Amgen. H. Holm: Employment; Modest; deCODE genetics is owned by Amgen. K. Stefansson: Employment; Modest; deCODE genetics is owned by Amgen.
- © 2016 by American Heart Association, Inc.