Mitochondrial DNA abundance and circulating metabolomic profiling: Multivariable-adjusted and Mendelian randomization analyses in UK Biobank
Mitochondrion, vol. 80, pp. 101991
Abstract
BACKGROUND: Low leukocyte mitochondrial DNA (mtDNA) abundance has been associated with a higher risk of atherosclerotic cardiovascular disease, but through unclear mechanisms. We aimed to investigate whether low mtDNA abundance is associated with worse metabolomic profiling, as being potential intermediate phenotypes, using cross-sectional and genetic studies. METHODS: Among 61,186 unrelated European participants from UK Biobank, we performed multivariable-adjusted linear regression analyses to examine the associations between mtDNA abundance and 168 NMR-based circulating metabolomic measures and nine metabolomic principal components (PCs) that collectively covered 91.5% of the total variation of individual metabolomic measures. Subsequently, we conducted Mendelian randomization (MR) to approximate the causal effects of mtDNA abundance on the individual metabolomic measures and their metabolomic PCs. RESULTS: After correction for multiple testing, low mtDNA abundance was associated with 130 metabolomic measures, predominantly lower concentrations of some amino acids and higher concentrations of lipids, lipoproteins and fatty acids; moreover, mtDNA abundance was associated with seven out of the nine metabolomic PCs. Using MR, genetically-predicted low mtDNA abundance was associated with lower lactate (standardized beta and 95% confidence interval: -0.17; -0.26, -0.08), and higher acetate (0.15; 0.07,0.23), and unsaturation degree (0.14; 0.08,0.20). Similarly, genetically-predicted low mtDNA abundance was associated with lower metabolomic PC2 (related to lower concentrations of lipids and fatty acids), and higher metabolomic PC9 (related to lower concentrations of glycolysis-related metabolites). CONCLUSION: Low mtDNA abundance is associated with metabolomic perturbations, particularly reflecting a pro-atherogenic metabolomic profile, which potentially could link low mtDNA abundance to higher atherosclerosis risk.
Authors 7
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Jiao Min Luo Aachen
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
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Saskia le Cessie Aachen
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
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Ko Willems van Dijk Aachen
Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Affiliation as printed
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute for Clinical Research and Systems Medicine, Health and Medical University, Potsdam, Germany
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Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
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Raymond Noordam corresponding Aachen Department of Internal Medicine Section of Gerontology and Geriatrics
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: r.noordam@lumc.nl
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