Journal Article

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

Mak, Angel, Abecasis, Gonçalo, Germer, Soren, Martinez, Fernando, Hochstadt, Samantha, White, Evan, Gui, Hongsheng, Yang, Mao, Lanfear, David E., Whitehouse, Kyle, Hakonarson, Hakon, Williams, L. Keoki, Barczak, Andrea J., Bobbitt, Kevin R., Kumar, Rajesh, Gauderman, W. James, Burchard, Esteban G., Sleiman, Patrick, Ding, Jun, Nickerson, Deborah A., Kang, Hyun Min, Hu, Donglei, Xiao, Shujie, Cocco, Maxwell P., Levin, Albert M., Gilliland, Frank, Erle, David J., Blackwell, Thomas W., Rynkowski, Dean

2020

Overview

Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis. 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. 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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / African Americans - genetics / Apoptosis / Asthma / Asthma - ethnology / Asthma - genetics / Base Sequence / Biology and Life Sciences / Calcium / Calcium homeostasis / Children & youth / Chronic obstructive pulmonary disease / Cohort Studies / Collaboration / Copy number / Deoxyribonucleic acid / Disease / DNA / DNA Copy Number Variations / DNA, Mitochondrial - blood / DNA, Mitochondrial - genetics / Electron Transport Chain Complex Proteins - genetics / Female / Flow Cytometry / Gene expression / Gene sequencing / Genes / Genomes / Genomics / Health care / Health sciences / Homeostasis / Humans / Internal medicine / Leukocytes / Leukocytes - ultrastructure / Logistic Models / Male / Medicine / Medicine and Health Sciences / Middle Aged / Minority & ethnic groups / Mitochondria / Mitochondrial DNA / Nucleotide sequence / Oxidative phosphorylation / Oxidative stress / Oxygen / Pediatrics / People and places / Peripheral blood / Pharmacogenomics / Phenotypes / Phosphorylation / Precision medicine / Preventive medicine / Proportional Hazards Models / Public health / Reactive oxygen species / Research and Analysis Methods / Respiration / Ribonucleic acid / RNA / RNA - genetics / SAGE satellite / Sapphire / Sensitivity and Specificity / Translational Medical Research / Whole Genome Sequencing / Young Adult