Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations

Overview

Journal J Allergy Clin Immunol

Specialty Allergy & Immunology

Date 2024 Sep 5

PMID 39237012

Authors

Weiling Xu

Yun Soo Hong

Bo Hu

Suzy A A Comhair

Allison J Janocha

Joe G Zein

Ruoying Chen

Deborah A Meyers

David T Mauger

Victor E Ortega

Eugene R Bleecker

Mario Castro

Loren C Denlinger

John V Fahy

Elliot Israel

Bruce D Levy

Nizar N Jarjour

Wendy C Moore

Sally E Wenzel

Benjamin Gaston

Chunyu Liu

Dan E Arking

Serpil C Erzurum

Affiliations

Soon will be listed here.

Abstract

Background: Asthma pathophysiology is associated with mitochondrial dysfunction. Mitochondrial DNA copy number (mtDNA-CN) has been used as a proxy of mitochondrial function, with lower levels indicating mitochondrial dysfunction in population studies of cardiovascular diseases and cancers.

Objectives: We investigated whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations.

Methods: mtDNA-CN is evaluated in blood from 2 cohorts: UK Biobank (UKB) (asthma, n = 39,147; no asthma, n = 302,302) and Severe Asthma Research Program (SARP) (asthma, n = 1283; nonsevere asthma, n = 703).

Results: Individuals with asthma have lower mtDNA-CN compared to individuals without asthma in UKB (beta, -0.006 [95% confidence interval, -0.008 to -0.003], P = 6.23 × 10). Lower mtDNA-CN is associated with asthma prevalence, but not severity in UKB or SARP. mtDNA-CN declines with age but is lower in individuals with asthma than in individuals without asthma at all ages. In a 1-year longitudinal study in SARP, mtDNA-CN was associated with risk of exacerbation; those with highest mtDNA-CN had the lowest risk of exacerbation (odds ratio 0.333 [95% confidence interval, 0.173 to 0.542], P = .001). Biomarkers of inflammation and oxidative stress are higher in individuals with asthma than without asthma, but the lower mtDNA-CN in asthma is independent of general inflammation or oxidative stress. Mendelian randomization studies suggest a potential causal relationship between asthma-associated genetic variants and mtDNA-CN.

Conclusion: mtDNA-CN is lower in asthma than in no asthma and is associated with exacerbations. Low mtDNA-CN in asthma is not mediated through inflammation but is associated with a genetic predisposition to asthma.

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References

Szefler S, Wenzel S, Brown R, Erzurum S, Fahy J, Hamilton R . Asthma outcomes: biomarkers. J Allergy Clin Immunol. 2012; 129(3 Suppl):S9-23. PMC: 3390196. DOI: 10.1016/j.jaci.2011.12.979. View

Xu W, Ghosh S, Comhair S, Asosingh K, Janocha A, Mavrakis D . Increased mitochondrial arginine metabolism supports bioenergetics in asthma. J Clin Invest. 2016; 126(7):2465-81. PMC: 4922712. DOI: 10.1172/JCI82925. View

Wallace D . A mitochondrial bioenergetic etiology of disease. J Clin Invest. 2013; 123(4):1405-12. PMC: 3614529. DOI: 10.1172/JCI61398. View

Ghosh S, Willard B, Comhair S, Dibello P, Xu W, Shiva S . Disulfide bond as a switch for copper-zinc superoxide dismutase activity in asthma. Antioxid Redox Signal. 2012; 18(4):412-23. PMC: 3526896. DOI: 10.1089/ars.2012.4566. View

Dweik R, Boggs P, Erzurum S, Irvin C, Leigh M, Lundberg J . An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011; 184(5):602-15. PMC: 4408724. DOI: 10.1164/rccm.9120-11ST. View

Chung K, Wenzel S, Brozek J, Bush A, Castro M, Sterk P . International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2013; 43(2):343-73. DOI: 10.1183/09031936.00202013. View

Ashar F, Moes A, Moore A, Grove M, Chaves P, Coresh J . Association of mitochondrial DNA levels with frailty and all-cause mortality. J Mol Med (Berl). 2014; 93(2):177-186. PMC: 4319988. DOI: 10.1007/s00109-014-1233-3. View

Comhair S, Xu W, Ghosh S, Thunnissen F, Almasan A, Calhoun W . Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity. Am J Pathol. 2005; 166(3):663-74. PMC: 1602353. DOI: 10.1016/S0002-9440(10)62288-2. View

Zhou W, Kanai M, Wu K, Rasheed H, Tsuo K, Hirbo J . Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease. Cell Genom. 2023; 2(10):100192. PMC: 9903716. DOI: 10.1016/j.xgen.2022.100192. View

10.

Mengel-From J, Thinggaard M, Dalgard C, Kyvik K, Christensen K, Christiansen L . Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly. Hum Genet. 2014; 133(9):1149-59. PMC: 4127366. DOI: 10.1007/s00439-014-1458-9. View

11.

Battle S, Puiu D, Verlouw J, Broer L, Boerwinkle E, Taylor K . A bioinformatics pipeline for estimating mitochondrial DNA copy number and heteroplasmy levels from whole genome sequencing data. NAR Genom Bioinform. 2022; 4(2):lqac034. PMC: 9112767. DOI: 10.1093/nargab/lqac034. View

12.

Cocco M, White E, Xiao S, Hu D, Mak A, Sleiman P . 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. PLoS One. 2020; 15(11):e0242364. PMC: 7688161. DOI: 10.1371/journal.pone.0242364. View

13.

Bender A, Krishnan K, Morris C, Taylor G, Reeve A, Perry R . High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006; 38(5):515-7. DOI: 10.1038/ng1769. View

14.

Longchamps R, Yang S, Castellani C, Shi W, Lane J, Grove M . Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation. Hum Genet. 2021; 141(1):127-146. PMC: 8758627. DOI: 10.1007/s00439-021-02394-w. View

15.

Moore W, Bleecker E, Curran-Everett D, Erzurum S, Ameredes B, Bacharier L . Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. J Allergy Clin Immunol. 2007; 119(2):405-13. PMC: 2837934. DOI: 10.1016/j.jaci.2006.11.639. View

16.

Enright H, MILLER W, Hays R, Floyd R, Hebbel R . Preferential targeting of oxidative base damage to internucleosomal DNA. Carcinogenesis. 1996; 17(5):1175-7. DOI: 10.1093/carcin/17.5.1175. View

17.

Comhair S, Erzurum S . Antioxidant responses to oxidant-mediated lung diseases. Am J Physiol Lung Cell Mol Physiol. 2002; 283(2):L246-55. DOI: 10.1152/ajplung.00491.2001. View

18.

Liu X, Longchamps R, Wiggins K, Raffield L, Bielak L, Zhao W . Association of mitochondrial DNA copy number with cardiometabolic diseases. Cell Genom. 2022; 1(1). PMC: 8758111. DOI: 10.1016/j.xgen.2021.100006. View

19.

Zein J, Wu C, Attaway A, Zhang P, Nazha A . Novel Machine Learning Can Predict Acute Asthma Exacerbation. Chest. 2021; 159(5):1747-1757. PMC: 8129731. DOI: 10.1016/j.chest.2020.12.051. View

20.

Wang Z, Xu W, Comhair S, Fu X, Shao Z, Bearden R . Urinary total conjugated 3-bromotyrosine, asthma severity, and exacerbation risk. Am J Physiol Lung Cell Mol Physiol. 2022; 323(5):L548-L557. PMC: 9602918. DOI: 10.1152/ajplung.00141.2022. View