Association of Rare Protein-Truncating DNA Variants in <i>APOB</i> or <i>PCSK9</i> With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease-Reference-Cited by-同舟云学术

Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease

Published:2023-03-01 Issue:3 Volume:8 Page:258
ISSN:2380-6583
Container-title:JAMA Cardiology
language:en
Short-container-title:JAMA Cardiol

Author:

Dron Jacqueline S.¹²,Patel Aniruddh P.¹²³⁴,Zhang Yiyi⁵,Jurgens Sean J.²⁶,Maamari Dimitri J.¹²³,Wang Minxian⁷⁸,Boerwinkle Eric⁹,Morrison Alanna C.⁹,de Vries Paul S.⁹,Fornage Myriam⁹¹⁰,Hou Lifang¹¹,Lloyd-Jones Donald M.¹¹,Psaty Bruce M.¹²¹³¹⁴,Tracy Russell P.¹⁵¹⁶,Bis Joshua C.¹²,Vasan Ramachandran S.¹⁷¹⁸¹⁹,Levy Daniel¹⁹²⁰,Heard-Costa Nancy¹⁹²¹,Rich Stephen S.²²,Guo Xiuqing²³,Taylor Kent D.²³,Gibbs Richard A.²⁴,Rotter Jerome I.²³,Willer Cristen J.²⁵,Oelsner Elizabeth C.⁵,Moran Andrew E.⁵,Peloso Gina M.²⁶,Natarajan Pradeep²³⁴,Khera Amit V.¹²³²⁷

Affiliation:

1. Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston

2. Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts

3. Department of Medicine, Harvard Medical School, Boston, Massachusetts

4. Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston

5. Division of General Medicine, Columbia University, New York, New York

6. Department of Experimental Cardiology, Amsterdam UMC, Amsterdam, the Netherlands

7. CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China

8. University of Chinese Academy of Sciences, Beijing, China

9. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston

10. Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston

11. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois

12. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle

13. Department of Epidemiology, University of Washington, Seattle

14. Department of Health Systems and Population Health, University of Washington, Seattle

15. Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Colchester, Vermont

16. Department of Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, Vermont

17. Sections of Preventive Medicine and Epidemiology, Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts

18. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts

19. Framingham Heart Study, Framingham, Massachusetts

20. Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland

21. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts

22. Center for Public Health Genomics, University of Virginia, Charlottesville

23. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California

24. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas

25. Internal Medicine, University of Michigan, Ann Arbor

26. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts

27. Verve Therapeutics, Boston, Massachusetts

Abstract

ImportanceProtein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.ObjectiveTo evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.Design, Setting, and ParticipantsThis studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.ExposuresPTVs in APOB and PCSK9.Main Outcomes and MeasuresEstimated untreated LDL cholesterol levels and CHD.ResultsAmong 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004).Conclusions and RelevanceAmong 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.

Publisher

American Medical Association (AMA)

Subject

Cardiology and Cardiovascular Medicine

Link

https://jamanetwork.com/journals/jamacardiology/articlepdf/2801002/jamacardiology_dron_2023_oi_220085_1678219707.23567.pdf

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