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Eur Heart J. 2018 Jun 14;39(23):2172-2178. doi: 10.1093/eurheartj/ehy169.

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

Author information

1
deCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland.
2
Faculty of Medicine, Department of Medicine, University of Iceland, Saemundargata 2, 101 Reykjavik, Iceland.
3
Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Hringbraut, 101 Reykjavik, Iceland.
4
Department of Clinical Biochemistry, Landspitali, National University Hospital, Hringbraut, 101 Reykjavik, Iceland.
5
The Laboratory in Mjodd, RAM, 109 Reykjavik, Iceland.
6
Department of Clinical Biochemistry, Akureyri Hospital, 600 Akureyri, Iceland.
7
School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland.

Abstract

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.

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