The association between mitochondrial DNA copy number, low-density lipoprotein cholesterol, and cardiovascular disease risk
The association between mitochondrial DNA copy number, low-density lipoprotein cholesterol, and cardiovascular disease risk
Abstract Mitochondria are the primary organelle to generate cellular energy. Our group and others have reported that lower mitochondrial DNA copy number (mtDNA CN) is associated with higher risk of cardiovascular disease outcomes (CVD) and higher LDL levels. However, the causal relationship between mtDNA CN and CVD remains to be studied. Here we performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and CVD outcomes in up to 27,316 participants from different racial/ethnic groups with whole genome sequencing. We validated most of the previously reported associations but effect sizes were smaller in this study. For example, one SD unit decrease in mtDNA CN was significantly associated with 1.08-fold (95% CI, 1.04, 1.12; P=1.7E-04) hazard for developing incident coronary heart disease (CHD) adjusting for age, sex and race/ethnicity. We conducted Mendelian randomization (MR) to explore causal relationships between mtDNA CN, LDL, and CHD. Bi-directional univariable MR analyses provided strong evidence indicating higher LDL level is causally associated with lower mtDNA CN, and CHD was weakly associated with lower mtDNA CN. We found no evidence supporting a causal association for lower mtDNA CN with higher CHD risk or higher LDL. In multivariable MR, no associations were observed between mtDNA CN and CHD controlling for LDL level (P =0.92), whereas strong evidence for a direct causal effect was found for higher LDL on lower mtDNA CN, adjusting for CHD status (P =8.3E-10). Findings from this study indicate high LDL underlies the complex relationships between vascular atherosclerosis and lower mtDNA CN.
Ding Jun、Abecasis Goncalo、Kooperberg Charles、Hou Lifang、Levy Daniel、TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium、Liu Xue、Sun Xianbang、Wiggins Kerri L.、Raffield Laura M.、Bielak Lawrence F.、Zhao Wei、Zheng Yinan、Yao Jie、Thyagarajan Bharat、Rich Stephen S.、Peyser Patricia A.、Larson Nicholas B.、Smith Jennifer A.、Fitzpatrick Annette L.、Psaty Bruce M.、Taylor Kent D.、Guo Xiuqing、Haessler Jeffrey、Dupuis Jos¨|e、Heckbert Susan R.、Jiang Wenqing、Qian Yong、Seshadri Sudha、Pankratz Nathan、Blackwell Thomas W.、Boerwinkle Eric、Rotter Jerome I.、Pitsillides Achilleas、Grove Megan L.、Zhang Yuankai、Satizabal Claudia L.、Arking Dan E.、Liu Chunyu、Fornage Myriam、Bis Joshua C.、Wilson James G.、Meng Lai、Vasan Ramachandran S.、Reiner Alexander、Carson April P.
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIHTOPMed Informatics Research Center, University of MichiganFred Hutchinson Cancer Research Center, Division of Public Health ScienceFeinberg School of Medicine, Northwestern UniversityFramingham Heart Study, NHLBI||Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of HealthDepartment of Biostatistics, School of Public Health, Boston UniversityDepartment of Biostatistics, School of Public Health, Boston UniversityCardiovascular Health Research Unit, Department of Medicine, University of WashingtonDepartment of Genetics, University of North Carolina at Chapel HillDepartment of Epidemiology, School of Public Health, University of MichiganDepartment of Epidemiology, School of Public Health, University of MichiganFeinberg School of Medicine, Northwestern UniversityThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterDepartment of Laboratory Medicine and Pathology, University of MinnesotaDepartment of Public Health Services, Center for Public Health Genomics, University of VirginiaDepartment of Epidemiology, School of Public Health, University of MichiganDivision of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and ScienceDepartment of Epidemiology, School of Public Health, University of MichiganDepartments of Family Medicine, Epidemiology, and Global Health, University of WashingtonCardiovascular Health Research Unit, Department of Medicine, University of Washington||Departments of Epidemiology, and Health Systems and Population Health, University of WashingtonThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterFred Hutchinson Cancer Research Center, Division of Public Health ScienceDepartment of Biostatistics, School of Public Health, Boston University||Department of Epidemiology, Biostatistics and Occupational Health, School of Population and Global Health, McGill University Faculty of Medicine and Health SciencesCardiovascular Health Research Unit and Department of Epidemiology, University of WashingtonDepartment of Biostatistics, School of Public Health, Boston UniversityLongitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIHGlenn Biggs Institute for Alzheimer?ˉs and Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio||Framingham Heart Study, NHLBI||Department of Neurology, Boston University School of MedicineDepartment of Computational Pathology, University of MinnesotaTOPMed Informatics Research Center, University of MichiganHuman Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston||Human Genome Sequencing Center, Baylor College of MedicineThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterDepartment of Biostatistics, School of Public Health, Boston UniversityHuman Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at HoustonDepartment of Biostatistics, School of Public Health, Boston UniversityGlenn Biggs Institute for Alzheimer?ˉs and Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio||Framingham Heart Study, NHLBI||Department of Neurology, Boston University School of MedicineMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of MedicineDepartment of Biostatistics, School of Public Health, Boston University||Framingham Heart Study, NHLBI.Center for Human Genetics, University of Texas Health Science Center at HoustonCardiovascular Health Research Unit, Department of Medicine, University of WashingtonDepartment of Physiology and Biophysics, University of Mississippi Medical CenterDepartment of Biostatistics, School of Public Health, Boston UniversityFramingham Heart Study, NHLBI||Sections of Preventive Medicine and Epidemiology, and Cardiovascular Medicine, Boston University School of MedicineFred Hutchinson Cancer Research Center, Division of Public Health ScienceDepartment of Medicine, University of Mississippi Medical Center
基础医学生物科学研究方法、生物科学研究技术医学研究方法
Ding Jun,Abecasis Goncalo,Kooperberg Charles,Hou Lifang,Levy Daniel,TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,Liu Xue,Sun Xianbang,Wiggins Kerri L.,Raffield Laura M.,Bielak Lawrence F.,Zhao Wei,Zheng Yinan,Yao Jie,Thyagarajan Bharat,Rich Stephen S.,Peyser Patricia A.,Larson Nicholas B.,Smith Jennifer A.,Fitzpatrick Annette L.,Psaty Bruce M.,Taylor Kent D.,Guo Xiuqing,Haessler Jeffrey,Dupuis Jos¨|e,Heckbert Susan R.,Jiang Wenqing,Qian Yong,Seshadri Sudha,Pankratz Nathan,Blackwell Thomas W.,Boerwinkle Eric,Rotter Jerome I.,Pitsillides Achilleas,Grove Megan L.,Zhang Yuankai,Satizabal Claudia L.,Arking Dan E.,Liu Chunyu,Fornage Myriam,Bis Joshua C.,Wilson James G.,Meng Lai,Vasan Ramachandran S.,Reiner Alexander,Carson April P..The association between mitochondrial DNA copy number, low-density lipoprotein cholesterol, and cardiovascular disease risk[EB/OL].(2025-03-28)[2025-08-02].https://www.medrxiv.org/content/10.1101/2022.10.23.22281418.点此复制
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