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

2.50
Hdl Handle:
http://hdl.handle.net/2336/620640
Title:
Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease
Authors:
Helgadottir, Anna; Sulem, Patrick; Thorgeirsson, Gudmundur; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Jensson, Brynjar Ö; Arnadottir, Gudny A; Olafsson, Isleifur; Eyjolfsson, Gudmundur I; Sigurdardottir, Olof; Thorsteinsdottir, Unnur; Gudbjartsson, Daniel F; Holm, Hilma; Stefansson, Kari
Citation:
Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease 2018, 39 (23):2172 European Heart Journal
Issue Date:
14-Jun-2018
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.
Description:
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files
Additional Links:
https://academic.oup.com/eurheartj/article/39/23/2172/4955244
Rights:
Archived with thanks to European Heart Journal

Full metadata record

DC FieldValue Language
dc.contributor.authorHelgadottir, Annaen
dc.contributor.authorSulem, Patricken
dc.contributor.authorThorgeirsson, Gudmunduren
dc.contributor.authorGretarsdottir, Solveigen
dc.contributor.authorThorleifsson, Gudmaren
dc.contributor.authorJensson, Brynjar Öen
dc.contributor.authorArnadottir, Gudny Aen
dc.contributor.authorOlafsson, Isleifuren
dc.contributor.authorEyjolfsson, Gudmundur Ien
dc.contributor.authorSigurdardottir, Olofen
dc.contributor.authorThorsteinsdottir, Unnuren
dc.contributor.authorGudbjartsson, Daniel Fen
dc.contributor.authorHolm, Hilmaen
dc.contributor.authorStefansson, Karien
dc.date.accessioned2018-07-05T13:42:30Z-
dc.date.available2018-07-05T13:42:30Z-
dc.date.issued2018-06-14-
dc.date.submitted2018-
dc.identifier.citationRare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease 2018, 39 (23):2172 European Heart Journalen
dc.identifier.issn0195-668X-
dc.identifier.issn1522-9645-
dc.identifier.doi10.1093/eurheartj/ehy169-
dc.identifier.urihttp://hdl.handle.net/2336/620640-
dc.descriptionTo access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Filesen
dc.description.abstractAIMS: 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.en
dc.description.sponsorshipdeCODE genetics/Amgenen
dc.language.isoenen
dc.publisherOxford University Pressen
dc.relation.urlhttps://academic.oup.com/eurheartj/article/39/23/2172/4955244en
dc.rightsArchived with thanks to European Heart Journalen
dc.subjectKransæðasjúkdómaren
dc.subjectKólesterólen
dc.subjectCAR12en
dc.subjectMAB12en
dc.subject.meshCoronary Artery Diseaseen
dc.subject.meshCholesterolen
dc.titleRare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery diseaseen
dc.typeArticleen
dc.contributor.department1 ] deCODE Genet Amgen Inc, Sturlugata 8, IS-101 Reykjavik, Iceland Show more [ 2 ] Univ Iceland, Fac Med, Dept Med, Saemundargata 2, IS-101 Reykjavik, Iceland Show more [ 3 ] Natl Univ Hosp Iceland, Landspitali, Dept Internal Med, Div Cardiol, IS-101 Reykjavik, Iceland Show more [ 4 ] Natl Univ Hosp Reykjavik, Landspitali, Dept Clin Biochem, IS-101 Reykjavik, Iceland [ 5 ] RAM, Lab Mjodd, IS-109 Reykjavik, Iceland [ 6 ] Akureyri Hosp, Dept Clin Biochem, IS-600 Akureyri, Iceland Show more [ 7 ] Univ Iceland, Sch Engn & Nat Sci, IS-101 Reykjavik, Icelanden
dc.identifier.journalEuropean Heart Journalen
dc.rights.accessOpen Access - Opinn aðganguren
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutionDepartment of Clinical Biochemistry, Landspitali, National University Hospital, Hringbraut, 101 Reykjavik, Iceland-
dc.contributor.institutionThe Laboratory in Mjodd, RAM, 109 Reykjavik, Iceland-
dc.contributor.institutionDepartment of Clinical Biochemistry, Akureyri Hospital, 600 Akureyri, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.contributor.institutiondeCODE Genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland-
dc.departmentcodeCAR12, MAB12-
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