Carlos A Vaz Fragoso1, Todd M Manini2, John A Kairalla3, Thomas W Buford4, Fang-Chi Hsu5, Thomas M Gill6, Stephen B Kritchevsky7, Mary M McDermott8, Jason L Sanders9, Steven R Cummings10, Gregory J Tranah10. 1. Yale School of Medicine, Department of Medicine, New Haven, CT, United States of America; Veterans Affairs Connecticut Healthcare System, Department of Medicine, West Haven, CT, United States of America. Electronic address: carlos.fragoso@yale.edu. 2. University of Florida, Department of Aging and Geriatric Research, Gainesville, FL, United States of America. 3. University of Florida, Department of Biostatistics, Gainesville, FL, United States of America. 4. University of Alabama at Birmingham, Department of Medicine, Birmingham, AL, United States of America. 5. Wake Forest School of Medicine, Department of Biostatistical Sciences, Winston-Salem, NC, United States of America. 6. Yale School of Medicine, Department of Medicine, New Haven, CT, United States of America. 7. Wake Forest School of Medicine, Sticht Center for Healthy Aging and Alzheimer's Prevention, Winston-Salem, NC, United States of America. 8. Northwestern University, Feinberg School of Medicine, Chicago, IL, United States of America. 9. Massachusetts General Hospital, Department of Medicine, Boston, MA, United States of America. 10. California Pacific Medical Center Research Institute, San Francisco, CA, United States of America.
Abstract
BACKGROUND: We provide the first examination of mitochondrial DNA (mtDNA) variants and pulmonary function in older persons. METHODS: Cross-sectional associations between mtDNA variants and pulmonary function were evaluated as a combined p-values meta-analysis, using data from two independent cohorts of older persons. The latter included white and black participants, aged ≥70 years, from the Lifestyle Interventions and Independence for Elders study (LIFE) (N = 1247) and the Health, Aging and Body Composition study (Health ABC) (N = 731), respectively. Pulmonary function included the forced expiratory volume in one-second as a Z-score (FEV1z) and the maximal inspiratory pressure (MIP) in cm of water. RESULTS: In black participants, significant associations were found between mtDNA variants and MIP: m.7146A > G, COI (p = 3E-5); m.7389 T > C, COI (p = 2E-4); m.15301G > A, CYB (p = 9E-5); m.16265A > G, HV1 (p = 9E-5); meta-analytical p-values <0.0002. Importantly, these mtDNA variants were unique to black participants and were not present in white participants. Moreover, in black participants, aggregate genetic effects on MIP were observed across mutations in oxidative phosphorylation complex IV (p = 0.004), complex V (p = 0.0007), and hypervariable (p = 0.003) regions. The individual and aggregate variant results were significant after adjustment for multiple comparisons. Otherwise, no significant associations were detected for MIP in whites or for FEV1z in whites or blacks. CONCLUSIONS: We have shown that mtDNA variants of African origin are cross-sectionally associated with MIP, a measure of respiratory muscle strength. Thus, our results establish the rationale for longitudinal studies to evaluate whether mtDNA variants of African origin identify those at risk of subsequently developing a respiratory muscle impairment (lower MIP values).
BACKGROUND: We provide the first examination of mitochondrial DNA (mtDNA) variants and pulmonary function in older persons. METHODS: Cross-sectional associations between mtDNA variants and pulmonary function were evaluated as a combined p-values meta-analysis, using data from two independent cohorts of older persons. The latter included white and black participants, aged ≥70 years, from the Lifestyle Interventions and Independence for Elders study (LIFE) (N = 1247) and the Health, Aging and Body Composition study (Health ABC) (N = 731), respectively. Pulmonary function included the forced expiratory volume in one-second as a Z-score (FEV1z) and the maximal inspiratory pressure (MIP) in cm of water. RESULTS: In black participants, significant associations were found between mtDNA variants and MIP: m.7146A > G, COI (p = 3E-5); m.7389 T > C, COI (p = 2E-4); m.15301G > A, CYB (p = 9E-5); m.16265A > G, HV1 (p = 9E-5); meta-analytical p-values <0.0002. Importantly, these mtDNA variants were unique to black participants and were not present in white participants. Moreover, in black participants, aggregate genetic effects on MIP were observed across mutations in oxidative phosphorylation complex IV (p = 0.004), complex V (p = 0.0007), and hypervariable (p = 0.003) regions. The individual and aggregate variant results were significant after adjustment for multiple comparisons. Otherwise, no significant associations were detected for MIP in whites or for FEV1z in whites or blacks. CONCLUSIONS: We have shown that mtDNA variants of African origin are cross-sectionally associated with MIP, a measure of respiratory muscle strength. Thus, our results establish the rationale for longitudinal studies to evaluate whether mtDNA variants of African origin identify those at risk of subsequently developing a respiratory muscle impairment (lower MIP values).
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