Association of mitochondrial DNA copy number with cardiometabolic diseases

Li, Xue; Longchamps, Ryan J.; Wiggins, Kerri L.; Raffield, Laura M.; Bielak, Lawrence F.; Zhao, Wei; Pitsillides, Achilleas N.; Blackwell, Thomas W.; Yao, Jie; Guo, Xiuqing; Kurniansyah, Nuzulul; Thyagarajan, Bharat; Pankratz, Nathan; Rich, Stephen S.; Taylor, Kent D.; Peyser, Patricia A.; Heckbert, Susan R.; Seshadri, Sudha; Cupples, L. Adrienne; Boerwinkle, Eric; Grove, Megan L.; Larson, Nicholas B.; Smith, Jennifer A.; Vasan, Ramachandran S.; Sofer, Tamar; Fitzpatrick, Annette L.; Fornage, Myriam; Ding, Jun; Correa, Adolfo; Abecasis, Gonçalo R.; Psaty, Bruce M.; Wilson, James G.; Levy, Daniel; Rotter, Jerome I.; Bis, Joshua C.; Satizábal, Claudia L.; Arking, Dan E.; Liu, Chunyu

doi:10.1016/j.xgen.2021.100006

Cited by 37 publications

(42 citation statements)

References 62 publications

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“…In addition to exercise and diet, we were interested in associations between mtDNA-CN and secondary outcomes such as muscle mass, insulin sensitivity, and resting metabolic rate ( Of these secondary outcomes, insulin sensitivity and metabolic syndrome were both associated with mtDNA-CN prior to multiple-testing correction. Associations between mtDNA-CN and metabolic syndrome have been previously reported, supporting this finding [19]. As individuals with prevalent diabetes are known to have lower mtDNA-CN [20] and type 2 diabetes is a disease primarily characterized by decreased insulin sensitivity [21], we re-examined this association after adjusting insulin sensitivity for diabetes status.…”

Section: Evaluating Associations Between Secondary Outcomessupporting

confidence: 74%

“…Despite the small sample size, age and sex were both significantly associated in the expected directions [18] (Figure 1). As it has been shown that the relationship between mtDNA-CN and age is nonlinear [19], We modeled the effect of age on mtDNA-CN using a natural spline, yielding a knot at 52.6 years. However, using a log likelihood test, the spline age term did not perform significantly better than a linear term (P = 0.42), potentially due to the small sample size.…”

Section: Resultsmentioning

confidence: 99%

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Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise Studies

Yang

Mirabal

Newcomb

et al. 2021

Preprint

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Mitochondrial DNA copy number (mtDNA-CN) measured in blood has been associated with many aging-related diseases, with higher mtDNA-CN typically associated with lower disease risk. Exercise training is an excellent preventative tool against aging-related disorders and has been shown to increase mitochondrial function in muscle. Using the Sugar, Hypertension, and Physical Exercise cohorts (N = 105), we evaluated the effect of 6-months of exercise intervention on mtDNA-CN measured in blood. Although there was no significant relationship between exercise intervention and mtDNA-CN change (P = 0.29), there was a nominally significant association between mtDNA-CN and metabolic syndrome (P = 0.04), which has been seen in previous literature. We also identified a nominally significant association between higher mtDNA-CN and higher insulin sensitivity (P = 0.02).

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Section: Evaluating Associations Between Secondary Outcomessupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise Studies

Yang

Mirabal

Newcomb

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Decreased MT DNA-CN has been previously associated with an increased risk of developing cardiovascular disease (CVD) outcomes [ 84 ]. More recently, similar analyses in the UK Biobank demonstrated a possible causal role of lower MT DNA-CN on higher CAD risk [ 86 ]. In an even larger cohort (of 408,361 individuals from TOPMed and UK Biobank), a decline in MT DNA-CN was observed in elderly individuals (>65 years) and lower MT DNA-CN levels also demonstrated an age-independent association with hypertension, hyperlipidemia, T2D, and obesity, i.e., the well-known CAD risk factors [ 87 ].…”

Section: Discussionmentioning

confidence: 98%

Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease

Vilne

Sawant

Rudaka

2022

Genes

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Large-scale genome-wide association studies have identified hundreds of single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD). However, collectively, these explain <20% of the heritability. Hypothesis: Here, we hypothesize that mitochondrial (MT)-SNVs might present one potential source of this “missing heritability”. Methods: We analyzed 265 MT-SNVs in ~500,000 UK Biobank individuals, exploring two different CAD definitions: a more stringent (myocardial infarction and/or revascularization; HARD = 20,405), and a more inclusive (angina and chronic ischemic heart disease; SOFT = 34,782). Results: In HARD cases, the most significant (p < 0.05) associations were for m.295C>T (control region) and m.12612A>G (ND5), found more frequently in cases (OR = 1.05), potentially related to reduced cardiorespiratory fitness in response to exercise, as well as for m.12372G>A (ND5) and m.11467A>G (ND4), present more frequently in controls (OR = 0.97), previously associated with lower ROS production rate. In SOFT cases, four MT-SNVs survived multiple testing corrections (at FDR < 5%), all potentially conferring increased CAD risk. Of those, m.11251A>G (ND4) and m.15452C>A (CYB) have previously shown significant associations with body height. In line with this, we observed that CAD cases were slightly less physically active, and their average body height was ~2.00 cm lower compared to controls; both traits are known to be related to increased CAD risk. Gene-based tests identified CO2 associated with HARD/SOFT CAD, whereas ND3 and CYB associated with SOFT cases (p < 0.05), dysfunction of which has been related to MT oxidative stress, obesity/T2D (CO2), BMI (ND3), and angina/exercise intolerance (CYB). Finally, we observed that macro-haplogroup I was significantly (p < 0.05) more frequent in HARD cases vs. controls (3.35% vs. 3.08%), potentially associated with response to exercise. Conclusions: We found only spurious associations between MT genome variation and HARD/SOFT CAD and conclude that more MT-SNV data in even larger study cohorts may be needed to conclusively determine the role of MT DNA in CAD.

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“…More recently, similar analyses in the UK Biobank demonstrated a possible causal role of lower MT DNA-CN on higher CAD risk [67]. In an even larger cohort (of 408,361 individuals from TOPMed and UK Biobank), a decline in MT DNA-CN was observed in elderly individuals (>65 years) and lower MT DNA-CN levels also demonstrated an age-independent associations with hypertension, hyperlipidemia, T2D and obesity, i.e., the well-known CAD risk factors [64]. However, none of these studies compared the MT DNA-CN levels between HARD vs. SOFT CAD phenotypes, which could be a subject of future studies.…”

Section: Discussionmentioning

confidence: 99%

Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease

Vilne

Sawant

Rudaka

2022

Preprint

View full text Add to dashboard Cite

Background: Large-scale genome-wide association studies have identified hundreds of single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD). However, collectively, these explain <20% of the heritability. Hypothesis: Here, we hypothesize that mitochondrial (MT) SNVs might present one potential source of this "missing heritability". Methods: We analyzed 265 MT-SNVs in ~500,000 UK Biobank individuals, exploring two different CAD definitions: a more stringent (myocardial infarction and/or revascularisation; HARD=20,405), and a more inclusive (also angina and chronic ischemic heart disease; SOFT=34,782). Results: In HARD cases, the most significant (P<0.05) associations were for m.295C>T (control region) and m.12612A>G (ND5), found more frequently in cases (OR=1.05), potentially related to reduced cardiorespiratory fitness in response to exercise, as well as for m.12372G>A (ND5) and m.11467A>G (ND4), present more frequently in controls (OR=0.97), previously associated with lower ROS production rate. In SOFT cases, four MT-SNVs survived multiple testing correction (at FDR<5%), all potentially conferring increased CAD risk. Of those, m.11251A>G (ND4) and m.15452C>A (CYB) have previously shown significant associations with body height. In line with this, we observed that CAD cases were slightly less physically active and their average body height was ~2.00 cm lower compared to controls, both traits known to be related to an increased CAD risk. Gene-based tests identified CO2 associated with HARD/SOFT CAD, whereas ND3 and CYB associated with SOFT cases (P<0.05), dysfunction of which has been related to MT oxidative stress, obesity/T2D (CO2), BMI (ND3) and angina/exercise intolerance (CYB). Finally, we observed that macro-haplogroup I was significantly (P<0.05) more frequent in HARD cases vs. controls (3.35% vs. 3.08%), potentially associated with response to exercise. Conclusions: We found only spurious associations between MT genome variation and HARD/SOFT CAD and conclude that more MT- SNV data in even larger study cohorts may be needed to conclusively determine the role of MT-DNA in CAD.

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Association of mitochondrial DNA copy number with cardiometabolic diseases

Cited by 37 publications

References 62 publications

Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise Studies

Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise Studies

Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease

Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease

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