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.
| Original language | English (US) |
|---|---|
| Article number | e029090 |
| Journal | Journal of the American Heart Association |
| Volume | 12 |
| Issue number | 20 |
| DOIs | |
| State | Published - Oct 17 2023 |
Funding
Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393-02S1; contract HHSN268201800001I). Additional phenotype harmonization was performed by the current study (NIA/ NIH; R01AG059727). Funding resources for all participating institutes are described below. The ARIC (Atherosclerosis Risk in Communities) study has been funded in whole or in part with federal funds from the NHLBI, National Institutes of Health, and Department of Health and Human Services, under contracts 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. The authors thank the staff and participants of the ARIC study for their important contributions. WGS for “NHLBI TOPMed: Atherosclerosis Risk in Communities” (phs001211.v3.p2.c1) was performed at the Baylor College of Medicine Human Genome Sequencing Center (3U54HG003273-12S2/HHSN268201500015C). Core support, including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support, including phenotype harmonization, data management, sample-identity quality control, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The ARIC study gratefully acknowledges the study participants who provided biological samples and data for TOPMed. The CARDIA (Coronary Artery Risk Development in Young Adults) study is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I). WGS in CARDIA (phs001612) was performed at the Baylor Human Genome Sequencing Center (HHSN268201600033I). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). The CARDIA study gratefully acknowledges the study participants who provided biological samples and data for TOPMed. We also thank the staff of the CARDIA study. The CHS (Cardiovascular Health Study) is supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006 and grants U01HL080295, U01HL130114, and R01HL105756 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI. org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Sequencing was supported and conducted in collaboration with Baylor University (HHSN268201600033I, 3U54HG003273-12S2, and HHSN268201500015C) and Broad Genomics (HHSN268201600034I) contracts from NHLBI. The WGS for FHS (Framingham Heart Study) (phs000974) was performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1 and 3U54HG003067-12S2). The FHS is funded by contracts NO1-HC-25195, HHSN268201500001I, and 75N92019D00031 from the NHLBI and grant supplement R01 HL092577-06S1 for this research. The FHS also acknowledges the dedication of the FHS participants without whom this research would not be possible. Dr Vasan is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. Xue Liu, Sudha Seshadri, Claudia L. Satizabal, and Chunyu Liu are also supported by R01AG059727. Sudha Seshadri, Claudia L. Satizabal are also supported by NIA/NIH (AG052409, AG054076, and AG059421). The GENOA (Genetic Epidemiology Network of Arteriopathy) study is supported by the NHLBI (HL054457, HL054464, HL054481, HL141292, HL119443, and HL087660) of the National Institutes of Health. Sequencing for the GENOA (phs001345. v1.p1) was performed by the University of Washington Northwest Genomics Center (3R01HL055673-18S1 from the NHLBI and at the Broad Institute of MIT and Harvard [HHSN268201500014C]). The authors thank the staff and participants of GENOA. The JHS (Jackson Heart Study) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities (NIMHD). The authors thank the staff and participants of the JHS. Molecular data for the TOPMed program were supported by the NHLBI. Genome sequencing for “NHLBI TOPMed: The Jackson Heart Study” (phs000964.v1.p1) was performed at the Northwest Genomics Center (HHSN268201100037C). Core support, including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support, including phenotype harmonization, data management, sample-identity quality control, and general program coordination, was provided by the TOPMed Data Coordinating Center (R01HL-120393 and U01HL-120393; contract HHSN268201800001I). Laura Raffield was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant KL2TR002490. The JHS gratefully acknowledges the studies and participants who provided biological samples and data for TOPMed. The MESA (Multi-Ethnic Study of Atherosclerosis) is conducted and supported by the NHLBI in collaboration with MESA investigators. MESA projects are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, and R01HL105756. WGS for the TOPMed program was supported by the NHLBI. WGS for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity quality control, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1) and TOPMed MESA Multi-Omics (HHSN2682015000031/HSN26800004). The authors thank the other investigators, the staff, and the participants of the MESA for their valuable contributions. A full list of participating MESA investigators and institutes can be found at http://www.mesa-nhlbi.org. The WHI (Women’s Health Initiative) study program is funded by the NHLBI, National Institutes of Health, US Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. The WHI study thanks all WHI study participants for their dedication and contributions. The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI, the National Institutes of Health, or the US Department of Health and Human Services.
Keywords
- Mendelian randomization
- cardiometabolic risk factors
- cardiovascular disease
- low-density lipoprotein cholesterol
- mitochondrial DNA copy number
- vascular atherosclerosis
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
