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

Abstract

Rationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation.

Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations.

Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations.

Measures and main results: In UK Biobank, asthmatics (n = 29,768) have lower mtDNA-CN compared to non-asthmatics (n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46×10^-5). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (F_ENO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007).

Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.

Keywords: Asthma; Exacerbations; Mitochondrial DNA.

Figure 1.

Asthmatics have lower mitochondrial DNA copy number (mtDNA-CN) compared to non-asthmatics in the UK Biobank (UKB). Forest plot depicting beta value and associated 95% confidence interval (CI) of mtDNA-CN in all asthmatics, mild or moderate-severe asthmatics as compared to non-asthmatics.

Figure 2.

mtDNA-CN inversely related with age in the UKB. (A- B) The predicted mtDNA-CN residuals using the unadjusted model (including only non-linear age (restricted cubic splines with 3 knots), asthma status, and an interaction between non-linear age and asthma status) decreases with age in non-asthmatics and all asthmatics (A), and in mild asthmatics, and moderate-severe asthmatics (B). (C- D) The predicted mtDNA-CN residuals marginally adjusted for sex, center, log-transformed neutrophil and eosinophil counts, and platelet counts were significantly related with age in non-asthmatics and all asthmatics (C), and in mild asthmatics, and moderate-severe asthmatics (D).

Figure 3.

mtDNA-CN related with age in SARP. (A) mtDNA-CN residuals are inversely related to age in severe asthmatics and all asthmatics but not in non-severe asthmatics, (B) while adjusted mtDNA-CN is not related to age in severe or non-severe asthmatics.

Figure 4.

Odds ratios for risk of three or more exacerbations in the subsequent year for biomarkers of asthma. Cutoff values were determined (Table E5) for mtDNA-CN, serum superoxide dismutase activity, and fractional exhaled nitric oxide. A higher mtDNA-CN predicted a lower risk of three or more exacerbations, while a higher fractional exhaled nitric oxide predicted a greater risk of three or more exacerbations.