scholarly journals Mitochondria-DNA copy-number and incident venous thromboembolism among middle-aged women: a population-based cohort study

2021 ◽  
Author(s):  
Peter Nymberg ◽  
Ashfaque A. Memon ◽  
Jan Sundquist ◽  
Kristina Sundquist ◽  
Bengt Zöller
Keyword(s):  
Cardiovascular Disease ◽  
Venous Thromboembolism ◽  
Copy Number ◽  
Cox Regression ◽  
Digital Pcr ◽  
Population Based ◽  
Middle Aged ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Mitochondria Dna

AbstractVenous thromboembolism (VTE) is the third most common cardiovascular disease. Low amount of mitochondrial DNA copy number (mtDNA-CN) has been associated with arterial cardiovascular disease (CVD) and reflects mitochondrial dysfunctions. However, whether mtDNA-CN is associated with VTE has not been determined. To examine the association between mtDNA-CN and incident VTE among middle-aged women. 6917 women aged 50–64 years, followed for 20 years in the Women’s Health In the Lund Area (WHILA) study. DNA samples for mtDNA quantification were available from 2521 women. Quantification of mtDNA-CN was performed using a well-optimized droplet digital PCR method. After exclusions of women with anticoagulant treatment, women living in nursing homes, and women who were diagnosed with cancer, stroke, VTE, or coronary heart disease at baseline, a cohort of 2117 women remained for analysis. Cox regression was used to analyze the relationship between mtDNA-CN and time to VTE (hazard ratio = HR). In total, 87 women were diagnosed with VTE during follow-up, corresponding to an incidence rate of 2.8 per 1000 person-years. Neither crude nor adjusted HR for mtDNA-CN were significantly associated with incident VTE. A sensitivity analysis with inclusion of excluded women did not change the results. MtDNA-CN was not significantly associated with VTE. The present study suggests that mtDNA-CN, reflecting mitochondrial dysfunction, should not be considered a biomarker that plays a major role for developing VTE. However, due to limited study size we may not exclude minor associations.

Abstract 271: Mitochondrial DNA Copy Number in Peripheral Blood Cells is Associated With All -Cause Mortality in Older Cardiovascular Patients

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Oxana Galenko ◽  
James Juan ◽  
Benjamin D Horne ◽  
Stacey Knight ◽  
John F Carlquist
Keyword(s):  
Mitochondrial Dna ◽  
Mortality Risk ◽  
Copy Number ◽  
Cox Regression ◽  
Surrogate Marker ◽  
Cellular Damage ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Cardiovascular Patients ◽  
All Cause Mortality

Background: Mitochondrial DNA copy number (Mt CN) is a surrogate marker of mitochondrial function. Variations in Mt CN have been associated with several age-related diseases. Lower Mt CN may indicate impaired cellular energy production whereas higher Mt CN may compensate for energy disbalance but also may lead to cellular damage through oxidative stress. This study evaluated the association of Mt CN and all-cause mortality in older cardiovascular patients (Pt). Methods: The study was approved by the Intermountain Healthcare Institutional Review Board. Consenting subjects (n=2,253) were participants in the INSPIRE registry undergoing cardiac catheterization at the Intermountain Heart Institute. Total DNA was extracted from EDTA stabilized blood with either Puregene (Qiagen) or Reliaprep (Promega) reagents. Relative Mt CN measurements were performed with multiplexed real-time polymerase chain reaction coamplifying a stable site of Mt D- Loop and a region of a single copy nuclear β-2-microglobulin gene(β2M) and calculated as a ratio of Mt to β2M DNA. Cox regression was used to evaluate the association of Mt CN with all-cause mortality, with adjustment considering 32 covariables. Further adjustment entered the Intermountain Risk Score (IMRS), a validated mortality risk predictor. Results: Mean Pt age was age 62.3±13.8 yrs.; 65.2% were male; 1,122 (50%) died during 25.4 years of follow-up. Mt CN was lower for males (539±449 vs 654 ± 1053 for females; p=0.004). Mt CN was 616±917 in decedents and 542±438 in survivors (p=0.014). In univariable Cox regression, Quartile 1 versus Quartile 4 of Mt CN was associated with the highest mortality risk (hazard ratio [HR]=1.45, CI=1.22, 1.71, p<0.001). This association remained significant after multivariable adjustment (HR=1.30, CI=1.10, 1.54, p=0.003). There was minimal correlation between IMRS and Mt CN continuous values (r= -0.09 for males, r= -0.13 for females). In Cox regression, adjustment for IMRS and covariables showed Mt CN remained associated with mortality (HR=1.30, CI=1.08, 1.57, p=0.006). Conclusions: Low Mt CN is independently associated with higher risk of all-cause mortality. Further studies validating this finding and examining potential underlying physiologic protective mechanisms may prove to be of therapeutic and prognostic value.

scholarly journals Association of mitochondrial DNA copy number with prevalent and incident type 2 diabetes in women: A population-based follow-up study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ashfaque A. Memon ◽  
Jan Sundquist ◽  
Anna Hedelius ◽  
Karolina Palmér ◽  
Xiao Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Smoking Status ◽  
Population Based ◽  
Dna Copy Number ◽  
Follow Up Study ◽  
Mitochondrial Dna Copy Number

AbstractMitochondrial dysfunction is an important factor of the aging process and may play a key role in various diseases. Mitochondrial DNA copy number (mtDNA-CN) is an indirect measure of mitochondrial dysfunction and is associated with type 2 diabetes mellitus (T2DM); however, whether mtDNA-CN can predict the risk of developing T2DM is not well-known. We quantified absolute mtDNA-CN in both prevalent and incident T2DM by well-optimized droplet digital PCR (ddPCR) method in a population-based follow-up study of middle aged (50–59 years) Swedish women (n = 2387). The median follow-up period was 17 years. Compared to those who were free of T2DM, mtDNA-CN was significantly lower in both prevalent T2DM and in women who developed T2DM during the follow-up period. Mitochondrial DNA-copy number was also associated with glucose intolerance, systolic blood pressure, smoking status and education. In multivariable Cox regression analysis, lower baseline mtDNA-CN was prospectively associated with a higher risk of T2DM, independent of age, BMI, education, smoking status and physical activity. Moreover, interaction term analysis showed that smoking increased the effect of low mtDNA-CN at baseline on the risk of incident T2DM. Mitochondrial DNA-copy number may be a risk factor of T2DM in women. The clinical usefulness of mtDNA-CN to predict the future risk of T2DM warrants further investigation.

scholarly journals Mitochondrial DNA copy number and incident atrial fibrillation

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Di Zhao ◽  
Traci M. Bartz ◽  
Nona Sotoodehnia ◽  
Wendy S. Post ◽  
Susan R. Heckbert ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Copy Number ◽  
Quantitative Polymerase Chain Reaction ◽  
Snp Array ◽  
Cardiovascular Health Study ◽  
Inverse Association ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Increased Risk ◽  
Mitochondria Dna

Abstract Background Mechanistic studies suggest that mitochondria DNA (mtDNA) dysfunction may be associated with increased risk of atrial fibrillation (AF). The association between mtDNA copy number (mtDNA-CN) and incident AF in the general population, however, remains unknown. Methods We conducted prospective analyses of 19,709 participants from the Atherosclerosis Risk in Communities Study (ARIC), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study (CHS). mtDNA-CN from the peripheral blood was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array 6.0 in ARIC and MESA and from multiplexed real-time quantitative polymerase chain reaction (qPCR) in CHS. Incident AF cases were identified through electrocardiograms, review of hospital discharge codes, Medicare claims, and death certificates. Results The median follow-up time was 21.4 years in ARIC, 12.9 years in MESA, and 11.0 years in CHS, during which 4021 participants developed incident atrial fibrillation (1761 in ARIC, 790 in MESA, and 1470 in CHS). In fully adjusted models, participants with the lowest quintile of mitochondria DNA copy number had an overall 13% increased risk (95% CI 1 to 27%) of incident atrial fibrillation compared to those with the highest quintile. Dose-response spline analysis also showed an inverse association between mitochondria DNA copy number and hazard for atrial fibrillation for all three cohorts. These associations were consistent across subgroups. Conclusions Mitochondria DNA copy number was inversely associated with the risk of AF independent of traditional cardiovascular risk factors. These findings implicate mitochondria DNA copy number as a novel risk factor for atrial fibrillation. Further research is warranted to understand the underlying mechanisms and to evaluate the role of mitochondria DNA copy number in the management of atrial fibrillation risk.

scholarly journals Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Jason A. Sumpter ◽  
Charles E. Newcomb ◽  
John A. Lane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Nuclear Dna ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
Genome Wide Significance ◽  
Experimental Modification

Abstract Background Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. Methods To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. Results Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10− 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10− 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the “neuroactive ligand receptor interaction” KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10− 12), as well as the TFAM knockout methylation (P = 4.41 × 10− 4) and expression (P = 4.30 × 10− 4) studies. Conclusions These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

scholarly journals Mitochondrial DNA copy number and trimethylamine levels in the blood: New insights on cardiovascular disease biomarkers

2021 ◽  
Vol 35 (7) ◽  
Author(s):  
Laura Bordoni ◽  
Irene Petracci ◽  
Iwona Pelikant‐Malecka ◽  
Adriana Radulska ◽  
Marco Piangerelli ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Dna Copy Number ◽  
Disease Biomarkers ◽  
Mitochondrial Dna Copy Number
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