Association Between Whole Blood–Derived Mitochondrial DNA Copy Number, Low‐Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk-Reference-Cited by-同舟云学术

Association Between Whole Blood–Derived Mitochondrial DNA Copy Number, Low‐Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk

Published:2023-10-17 Issue:20 Volume:12 Page:
ISSN:2047-9980
Container-title:Journal of the American Heart Association
language:en
Short-container-title:JAHA

Author:

Liu Xue¹^ORCID,Sun Xianbang¹,Zhang Yuankai¹,Jiang Wenqing¹,Lai Meng¹,Wiggins Kerri L.²^ORCID,Raffield Laura M.³^ORCID,Bielak Lawrence F.⁴^ORCID,Zhao Wei⁴⁵^ORCID,Pitsillides Achilleas¹^ORCID,Haessler Jeffrey⁶,Zheng Yinan⁷^ORCID,Blackwell Thomas W.⁸,Yao Jie⁹^ORCID,Guo Xiuqing⁹^ORCID,Qian Yong¹⁰,Thyagarajan Bharat¹¹^ORCID,Pankratz Nathan¹²^ORCID,Rich Stephen S.¹³^ORCID,Taylor Kent D.⁹^ORCID,Peyser Patricia A.⁴^ORCID,Heckbert Susan R.¹⁴^ORCID,Seshadri Sudha¹⁵¹⁶¹⁷,Boerwinkle Eric¹⁸¹⁹^ORCID,Grove Megan L.¹⁸,Larson Nicholas B.²⁰^ORCID,Smith Jennifer A.⁴⁵^ORCID,Vasan Ramachandran S.¹⁶²¹^ORCID,Fitzpatrick Annette L.²²,Fornage Myriam²³^ORCID,Ding Jun¹⁰,Carson April P.²⁴^ORCID,Abecasis Goncalo⁸,Dupuis Josée¹²⁵^ORCID,Reiner Alexander⁶^ORCID,Kooperberg Charles⁶,Hou Lifang⁷^ORCID,Psaty Bruce M.²²⁶^ORCID,Wilson James G.²⁷,Levy Daniel¹⁶²⁸^ORCID,Rotter Jerome I.⁹^ORCID,Bis Joshua C.²^ORCID,Satizabal Claudia L.¹⁵¹⁶¹⁷^ORCID,Arking Dan E.²⁹^ORCID,Liu Chunyu¹¹⁶^ORCID,

Affiliation:

1. Department of Biostatistics, School of Public Health Boston University Boston MA USA

2. Cardiovascular Health Research Unit, Department of Medicine University of Washington Seattle WA USA

3. Department of Genetics University of North Carolina at Chapel Hill Chapel Hill NC USA

4. Department of Epidemiology, School of Public Health University of Michigan Ann Arbor MI USA

5. Survey Research Center, Institute for Social Research University of Michigan Ann Arbor MI USA

6. Fred Hutchinson Cancer Center, Division of Public Health Science Seattle WA USA

7. Feinberg School of Medicine Northwestern University Chicago IL USA

8. TOPMed Informatics Research Center University of Michigan Ann Arbor MI USA

9. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor‐UCLA Medical Center Torrance CA USA

10. Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health Baltimore MD USA

11. Department of Laboratory Medicine and Pathology University of Minnesota Minneapolis MN USA

12. Department of Computational Pathology University of Minnesota Minneapolis MN USA

13. Center for Public Health Genomics University of Virginia Charlottesville VA USA

14. Cardiovascular Health Research Unit and Department of Epidemiology University of Washington Seattle WA USA

15. Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases University of Texas Health Science Center at San Antonio San Antonio TX USA

16. Framingham Heart Study, National Heart, Lung, and Blood Institute Framingham MA USA

17. Department of Neurology Boston University School of Medicine Boston MA USA

18. Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences The University of Texas Health Science Center at Houston Houston TX USA

19. Human Genome Sequencing Center, Baylor College of Medicine Houston TX USA

20. Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science Rochester MN USA

21. Sections of Preventive Medicine and Epidemiology, and Cardiovascular Medicine Boston University School of Medicine Boston MA USA

22. Departments of Family Medicine, Epidemiology, and Global Health University of Washington Seattle WA USA

23. Center for Human Genetics University of Texas Health Science Center at Houston Houston TX USA

24. Department of Medicine University of Mississippi Medical Center Jackson MS USA

25. Department of Epidemiology, Biostatistics and Occupational Health, School of Population and Global Health McGill University Faculty of Medicine and Health Sciences Montréal Quebec Canada

26. Departments of Epidemiology, and Health Systems and Population Health University of Washington Seattle WA USA

27. Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center Boston MA USA

28. Population Sciences Branch National Heart, Lung, and Blood Institute, National Institutes of Health MD Bethesda USA

29. McKusick‐Nathans Institute Department of Genetic Medicine Johns Hopkins University School of Medicine MD Baltimore USA

Abstract

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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