1. Asthma and its relationship to mitochondrial copy number: Results from the Asthma Translational Genomics Collaborative (ATGC) of the Trans-Omics for Precision Medicine (TOPMed) program.
- Author
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Cocco MP, White E, Xiao S, Hu D, Mak A, Sleiman P, Yang M, Bobbitt KR, Gui H, Levin AM, Hochstadt S, Whitehouse K, Rynkowski D, Barczak AJ, Abecasis G, Blackwell TW, Kang HM, Nickerson DA, Germer S, Ding J, Lanfear DE, Gilliland F, Gauderman WJ, Kumar R, Erle DJ, Martinez F, Hakonarson H, Burchard EG, and Williams LK
- Subjects
- Adult, Asthma ethnology, Base Sequence, Cohort Studies, DNA, Mitochondrial blood, Electron Transport Chain Complex Proteins genetics, Female, Flow Cytometry, Humans, Leukocytes ultrastructure, Logistic Models, Male, Middle Aged, Proportional Hazards Models, RNA genetics, Sensitivity and Specificity, Translational Research, Biomedical, Whole Genome Sequencing, Young Adult, Black or African American genetics, Asthma genetics, DNA Copy Number Variations, DNA, Mitochondrial genetics
- Abstract
Background: Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis., Objective: Given the heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma., Methods: Whole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing., Results: Average mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes., Conclusions: We observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group., Competing Interests: Dr. Abecasis reported receiving personal fees and salary support from Regeneron Pharmaceuticals. This support was outside of the submitted work and did not alter our adherence to PLOS ONE policies regarding the sharing of data and/or research materials. The remaining authors reported no competing interests.
- Published
- 2020
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