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The association between mitochondrial DNA copy number and longitudinal lung function decline among people with or at risk of HIV
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High mtDNA Copy Number Doubles COPD Odds in Smokers With or at Risk for HIV
10th International Workshop on HIV and Aging, October 10-11, 2019, New York
Mark Mascolini
A study of 501 HIV-positive or negative people--three quarters of them smokers and 20% active drug injectors--linked higher mitochondrial DNA (mtDNA) copy number to doubled odds of baseline chronic obstructive pulmonary disease (COPD) [1]. Higher mtDNA copy number also propelled faster lung function decline in HIV-negative (but not positive) study participants older than 50.
Lung function tends to decline faster in people with than without HIV infection, and COPD prevalence and incidence are higher in HIV groups. Mechanisms underlying these changes remain unclear, noted Johns Hopkins researchers who conducted this study. They decided to focus on mtDNA because research links mitochondrial function to oxidative stress and several age-related conditions and to mortality in the general population. mtDNA copy number, readily measured in peripheral blood, provides a marker of mitochondrial depletion. Recent work by these researchers found a close association between mtDNA copy number and HIV disease severity and mortality [2].
The new study involved the SHIELD cohort, a consortium of two ongoing Baltimore cohorts to explore the etiology of lung disease. Twice a year, cohort members make study visits to complete surveys, give blood samples, and have lung function measured by spirometry. This analysis focused on samples collected on visits from 2009 to 2017. The researchers defined COPD as a less than 70% ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC). They measured mtDNA copy number by qPCR.
The study population included 501 people, 172 of them (34%) with HIV infection. Two thirds of participants were men and more than 90% black. Almost two thirds of the study group were older than 50, and three quarters smoked at the time of the study. Similar proportions with and without HIV (18.6% and 22.8%, P = 0.30) currently injected drugs.
The baseline evaluation determined that 125 people (25%) had COPD. After adjustment for confounders, an mtDNA copy number in the highest quartile doubled the odds of COPD at baseline (odds ratio [OR] 1.97, P < 0.01). Three other variables predicted baseline COPD in this analysis: Currently smoking more than 40 pack-years of cigarettes boosted COPD odds 75% (OR 1.75, P = 0.04). Current drug injection lifted the odds 63% (OR 1.63, P = 0.05), and being a woman halved the odds of baseline COPD (OR 0.49, P = 0.03).
The FEV1/FVC ratio began to drop after age 50 in cohort members with or without HIV, and it dropped faster in people with HIV. But in participants without HIV, FEV1/FCV declined significantly faster in people with a higher mtDNA copy number versus a lower copy number (0.21% drop per year versus 0.16% drop per year, P = 0.02). Higher mtDNA copy number did not affect decreasing FEV1/FVC in HIV-positive study participants.
The Johns Hopkins investigators believe these findings support the idea that high mtDNA copy number predicts worse lung outcomes in older people without HIV. But they wondered whether this association reflects an mtDNA compensatory response to hypoxemia (low oxygen levels in blood), especially in people with COPD. Analysis of mtDNA copy number by COPD severity in the 9000-person atherosclerosis-focused ARIC* cohort (few of whom have HIV) showed that people with very severe COPD had significantly higher mtDNA copy numbers than people with three lower levels of COPD severity or no COPD.
Turning back to HIV-positive and negative members in the Baltimore SHIELD cohort, the researchers confirmed that mtDNA copy number was higher in HIV-positive people with COPD than in HIV-positive people without COPD. That same COPD-driven difference applied to cohort member without HIV, but the copy number difference with versus without COPD was much greater in these HIV-negative people.
The researchers concluded that mtDNA copy number predicts higher odds of COPD in older smokers. That association, they surmised, probably reflects a mitochondrial compensatory response to oxidative stress and hypoxemia in COPD. In people with HIV, mitochondrial function may be so impaired that mitochondria cannot provide as much of a compensatory response under stress.
*Atherosclerosis Risk in Communities.
References
1. Sun J, Piggott D, Astemborski J, Brown R, Arking D, Kirk G. The association between mitochondrial DNA copy number and longitudinal lung function decline among people with or at risk of HIV. 10th International Workshop on HIV and Aging, October 10-11, 2019, New York. Abstract 7.
2. Sun J1, Longchamps RJ, Piggott DA et al. Association between HIV infection and mitochondrial DNA copy number in peripheral blood: a population-based, prospective cohort study. J Infect Dis. 2019;219:1285-1293.
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