Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease

Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficie...

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Autores: Peloso, Gina M., Marrugat de la Iglesia, Jaume, Kathiresan, Sekar
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/42971
Acceso en línea:http://hdl.handle.net/10230/42971
http://dx.doi.org/10.1161/CIRCGEN.118.002376
Access Level:acceso abierto
Palabra clave:Cholesterol
Genetics
Human
Hypobetalipoproteinemia
Triglycerides
id ES_3e9f522f69f3fa50a4196e09ea5a1b5f
oai_identifier_str oai:repositori.upf.edu:10230/42971
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease
title Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease
spellingShingle Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease
Peloso, Gina M.
Cholesterol
Genetics
Human
Hypobetalipoproteinemia
Triglycerides
title_short Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease
title_full Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease
title_fullStr Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease
title_full_unstemmed Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease
title_sort Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease
dc.creator.none.fl_str_mv Peloso, Gina M.
Marrugat de la Iglesia, Jaume
Kathiresan, Sekar
author Peloso, Gina M.
author_facet Peloso, Gina M.
Marrugat de la Iglesia, Jaume
Kathiresan, Sekar
author_role author
author2 Marrugat de la Iglesia, Jaume
Kathiresan, Sekar
author2_role author
author
dc.subject.none.fl_str_mv Cholesterol
Genetics
Human
Hypobetalipoproteinemia
Triglycerides
topic Cholesterol
Genetics
Human
Hypobetalipoproteinemia
Triglycerides
description Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10-5) and 53% lower triglyceride level ( P=2×10-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10-7), a 30% decrease in triglycerides ( P=5×10-4), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/42971
http://dx.doi.org/10.1161/CIRCGEN.118.002376
url http://hdl.handle.net/10230/42971
http://dx.doi.org/10.1161/CIRCGEN.118.002376
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/EC/FP7/268834
info:eu-repo/grantAgreement/EC/FP7/279233
info:eu-repo/grantAgreement/EC/FP7/261123
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv Lippincott Williams & Wilkins
publisher.none.fl_str_mv Lippincott Williams & Wilkins
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
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spelling Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart diseasePeloso, Gina M.Marrugat de la Iglesia, JaumeKathiresan, SekarCholesterolGeneticsHumanHypobetalipoproteinemiaTriglyceridesBackground Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10-5) and 53% lower triglyceride level ( P=2×10-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10-7), a 30% decrease in triglycerides ( P=5×10-4), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD.Dr Peloso is supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health under Award Number K01HL125751. Dr Nomura was supported by the Yoshida Scholarship Foundation. Dr Khera is supported by an institutional grant from the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard (BroadIgnite), a K08 from the National Human Genome Research Institute (K08HG010155), and a Junior Faculty Award from the National Lipid Association. Dr Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and grant R01 HL127564 from the NHLBI. Funding for the EOMI study (Exome Sequencing Project Early-Onset Myocardial Infarction) was provided by grants RC2 HL103010 (HeartGO, Heart Grand Opportunity), RC2 HL102923 (LungGO, Lung Grand Opportunity), and RC2 HL102924 (WHISP) from the NHLBI. Exome sequencing was performed through grants RC2 HL102925 (BroadGO, Broad Grand Opportunity) and RC2 HL102926 (SeattleGO, Seattle Grand Opportunity) from the NHLBI. Exome sequencing in ATVB (Italian Atherosclerosis, Thrombosis, and Vascular Biology), the PROCARDIS study (Precocious Coronary Artery Disease), the OHS (Ottawa Heart Study), PROMIS (Pakistan Risk of Myocardial Infarction Study), South German MI study (South German Myocardial Infarction), and the JHS (Jackson Heart Study) was supported by grant 5U54HG003067 from the National Institutes of Health. Fieldwork, genotyping, and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, European Union (EU) Framework 6–funded Bloodomics Integrated Project, Pfizer, Novartis, and Merck. Additional support for PROMIS was provided by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), and European Commission Framework Programme 7 (HEALTH-F2-2012–279233). The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. Dr Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. REGICOR study (Registre Gironí del COR [Gerona Heart Registry]) was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigación Cardiovascular RD12/0042, PI09/90506), European Funds for Development (ERDF-FEDER), and by the Catalan Research and Technology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester (Leicester Myocardial Infarction) cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; UK Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). The South MI Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02). This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces and SFB 1123. The ATVB study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Università 2010–2012 Area 1–Strategic Programmes–Regione Emilia-Romagna. The authors would like to thank the MyCode Community Health Initiative participants for their permission to utilize their health and genomics information in the DiscovEHR (DiscovEHR partnership of the Regeneron Genetics Center and Geisinger Health System) collaboration. The DiscovEHR study was funded, in part, by the Regeneron Genetics Center.Lippincott Williams & Wilkins201920192019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/42971http://dx.doi.org/10.1161/CIRCGEN.118.002376reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésinfo:eu-repo/grantAgreement/EC/FP7/268834info:eu-repo/grantAgreement/EC/FP7/279233info:eu-repo/grantAgreement/EC/FP7/261123© 2019 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License https://creativecommons.org/licenses/by/4.0/, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/429712026-06-12T07:21:37Z
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