Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease
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 e...
Published in: | European Heart Journal |
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Format: | Article in Journal/Newspaper |
Language: | English |
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Oxford University Press (OUP)
2018
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Online Access: | https://hdl.handle.net/20.500.11815/1476 https://doi.org/10.1093/eurheartj/ehy169 |
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ftopinvisindi:oai:opinvisindi.is:20.500.11815/1476 2023-05-15T16:52:40+02:00 Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease 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 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) 2018-03-27 2172-2178 https://hdl.handle.net/20.500.11815/1476 https://doi.org/10.1093/eurheartj/ehy169 en eng Oxford University Press (OUP) European Heart Journal;39(23) http://academic.oup.com/eurheartj/article-pdf/39/23/2172/25041378/ehy169.pdf 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 0195-668X 1522-9645 (eISSN) https://hdl.handle.net/20.500.11815/1476 European Heart Journal doi:10.1093/eurheartj/ehy169 info:eu-repo/semantics/openAccess Coronary artery disease HDL cholesterol Mutation SR-BI Coronary arteriosclerosis Kransæðasjúkdómar Gen Stökkbreytingar Kólesteról Erfðafræði info:eu-repo/semantics/article 2018 ftopinvisindi https://doi.org/20.500.11815/1476 https://doi.org/10.1093/eurheartj/ehy169 2022-11-18T06:51:50Z 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 ... Article in Journal/Newspaper Iceland Opin vísindi (Iceland) European Heart Journal 39 23 2172 2178 |
institution |
Open Polar |
collection |
Opin vísindi (Iceland) |
op_collection_id |
ftopinvisindi |
language |
English |
topic |
Coronary artery disease HDL cholesterol Mutation SR-BI Coronary arteriosclerosis Kransæðasjúkdómar Gen Stökkbreytingar Kólesteról Erfðafræði |
spellingShingle |
Coronary artery disease HDL cholesterol Mutation SR-BI Coronary arteriosclerosis Kransæðasjúkdómar Gen Stökkbreytingar Kólesteról Erfðafræði 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 Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease |
topic_facet |
Coronary artery disease HDL cholesterol Mutation SR-BI Coronary arteriosclerosis Kransæðasjúkdómar Gen Stökkbreytingar Kólesteról Erfðafræði |
description |
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 ... |
author2 |
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 |
author |
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 |
author_facet |
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 |
author_sort |
Helgadottir, Anna |
title |
Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease |
title_short |
Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease |
title_full |
Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease |
title_fullStr |
Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease |
title_full_unstemmed |
Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease |
title_sort |
rare scarb1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease |
publisher |
Oxford University Press (OUP) |
publishDate |
2018 |
url |
https://hdl.handle.net/20.500.11815/1476 https://doi.org/10.1093/eurheartj/ehy169 |
genre |
Iceland |
genre_facet |
Iceland |
op_relation |
European Heart Journal;39(23) http://academic.oup.com/eurheartj/article-pdf/39/23/2172/25041378/ehy169.pdf 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 0195-668X 1522-9645 (eISSN) https://hdl.handle.net/20.500.11815/1476 European Heart Journal doi:10.1093/eurheartj/ehy169 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/20.500.11815/1476 https://doi.org/10.1093/eurheartj/ehy169 |
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European Heart Journal |
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39 |
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23 |
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2172 |
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2178 |
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