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Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease.

Accepted version
Peer-reviewed

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Article

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Authors

Peloso, Gina M 
Nomura, Akihiro 
Khera, Amit V 
Chaffin, Mark 
Won, Hong-Hee 

Abstract

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.

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Keywords

cholesterol, genetics, human, hypobetalipoproteinemia, triglycerides, Adult, Aged, Apolipoproteins B, Case-Control Studies, Cholesterol, LDL, Coronary Disease, Female, Genetic Variation, Humans, Japan, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide, Risk Factors, Triglycerides

Journal Title

Circ Genom Precis Med

Conference Name

Journal ISSN

2574-8300
2574-8300

Volume Title

12

Publisher

Ovid Technologies (Wolters Kluwer Health)

Rights

All rights reserved
Sponsorship
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
GMP is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K01HL125751. AN was supported by the Yoshida Scholarship Foundation. AK is supported by an institutional grant from the Broad Institute of MIT and Harvard (BroadIgnite), a K08 from the National Human Genome Research Institute (K08HG010155), and a Junior Faculty Award from the National Lipid Association. SK is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and grant R01 HL127564 from the National Heart, Lung, and Blood Institute. Funding for the Exome Sequencing Project Early-Onset Myocardial Infarction study was provided by grants RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP) from the National Heart, Lung, and Blood Institute. Exome sequencing was performed through grants RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO) from the National Heart, Lung, and Blood Institute. Exome sequencing in ATVB, the Precocious Coronary Artery Disease study (PROCARDIS), the Ottawa Heart Study, PROMIS, South German Myocardial Infarction study, and the Jackson Heart Study was supported by grant 5U54HG003067 from the National Institutes of Health (Drs Lander and Gabriel). Field work, genotyping, and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, U.K. Medical Research Council, Wellcome Trust, EU Framework 6–funded Bloodomics Integrated Project, Pfizer, Novartis, and Merck. Additional support for PROMIS was provided by the U.K. Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), U.K. 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 National Heart, Lung, and Blood Institute (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 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 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 Munich 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 Italian Atherosclerosis, Thrombosis, and Vascular Biology (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 collaboration. The DiscovEHR study was funded, in part, by the Regeneron Genetics Center. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the NHLBI; the National Institutes of Health; or the U.S. Department of Health and Human Services