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

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


Title: Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease
Author: Helgadottir, Anna   orcid.org/0000-0002-1806-2467
Sulem, Patrick   orcid.org/0000-0001-7123-6123
Thorgeirsson, Gudmundur   orcid.org/0000-0002-7146-1395
Grétarsdóttir, Sólveig
Thorleifsson, Gudmar   orcid.org/0000-0003-4623-9087
Jensson, Brynjar Örn
Arnadottir, Gudny   orcid.org/0000-0001-6571-423X
Olafsson, Isleifur   orcid.org/0000-0002-3921-5805
Eyjólfsson, Guðmundur I.
Sigurdardottir, Olof
... 4 more authors Show all authors
Date: 2018-03-27
Language: English
Scope: 2172-2178
University/Institute: Háskóli Íslands (HÍ)
University of Iceland (UI)
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
School of Engineering and Natural Sciences (UI)
Verkfræði- og náttúruvísindasvið (HÍ)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: European Heart Journal;39(23)
ISSN: 0195-668X
1522-9645 (eISSN)
DOI: 10.1093/eurheartj/ehy169
Subject: Coronary artery disease; HDL cholesterol; Mutation; SR-BI; Coronary arteriosclerosis; Kransæðasjúkdómar; Gen; Stökkbreytingar; Kólesteról; Erfðafræði
URI: https://hdl.handle.net/20.500.11815/1476

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Citation:

Anna Helgadottir, Patrick Sulem, Gudmundur Thorgeirsson, Solveig Gretarsdottir, Gudmar Thorleifsson, Brynjar Ö Jensson, Gudny A Arnadottir, Isleifur Olafsson, Gudmundur I Eyjolfsson, Olof Sigurdardottir, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Hilma Holm, Kari Stefansson, Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease, European Heart Journal, Volume 39, Issue 23, 14 June 2018, Pages 2172–2178, https://doi.org/10.1093/eurheartj/ehy169

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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