Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease

• Published in: European Heart Journal
• Main Authors: Helgadottir, Anna, sulem, patrick, Thorgeirsson, Gudmundur, Grétarsdóttir, Sólveig, Thorleifsson, Gudmar, Jensson, Brynjar Örn, Arnadottir, Gudny, Olafsson, Isleifur, Eyjólfsson, Guðmundur I., Sigurdardottir, Olof, Thorsteinsdottir, Unnur, Gudbjartsson, Daniel, Holm, Hilma, Stefansson, Kari
• Other Authors: Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI)
• Format: Article in Journal/Newspaper
• Language: English
• Published: Oxford University Press (OUP) 2018
• Subjects: Coronary artery disease; HDL cholesterol; Mutation; SR-BI; Coronary arteriosclerosis; Kransæðasjúkdómar; Gen; Stökkbreytingar; Kólesteról; Erfðafræði; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/1476; https://doi.org/10.1093/eurheartj/ehy169

Publisher's version (útgefin grein). Aims Scavenger receptor Class B Type 1 (SR-BI) is a major receptor for high-density lipoprotein (HDL) that promotes hepatic uptake of cholesterol from HDL. A rare mutation p.P376L, in the gene encoding SR-BI, SCARB1, was recently reported to associate with elevated HDL cholesterol (HDL-C) and increased risk of coronary artery disease (CAD), suggesting that increased HDL-C caused by SR-BI impairment might be an independent marker of cardiovascular risk. We tested the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-C also associate with increased risk of CAD in the relatively homogeneous population of Iceland. Methods and results Using a large resource of whole-genome sequenced Icelanders, we identified thirteen SCARB1 coding mutations that we examined for association with HDL-C (n = 136 672). Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M (combined allelic frequency = 0.2%) associate with elevated levels of HDL-C (p.G319V: β = 11.1 mg/dL, P = 8.0 × 10 -7; p.V111M: β = 8.3 mg/dL, P = 1.1 × 10 -6; p.V32M: β = 10.2 mg/dL, P = 8.1 × 10 -4). These mutations do not associate with CAD (36 886 cases/306 268 controls) (odds ratio = 0.90, 95% confidence interval 0.67-1.22, P = 0.49), despite effects on HDL-C comparable to that reported for p.P376L, both in terms of direction and magnitude. Furthermore, HDL-C raising alleles of three common SCARB1 non-coding variants, including one previously unreported (rs61941676-C: β = 1.25 mg/dL, P = 1.7 × 10 -18), and of one low frequency coding variant (p.V135I) that independently associate with higher HDL-C, do not confer increased risk of CAD. Conclusion Elevated HDL-C due to genetically compromised SR-BI function is not a marker of CAD risk. The authors thank all the individuals who participated in this study and whose contribution made this work possible. We also thank our valued colleagues who contributed to the data collection and phenotypic characterization of clinical samples ...