Mitochondrial DNA Copy Number as a Marker and Mediator of Stroke Prognosis: Observational and Mendelian Randomization Analyses

Background:Low buffy coat mitochondrial DNA copy number (mtDNA-CN) is associated with incident risk of stroke and post-stroke mortality; however, its prognostic utility has not been extensively explored.Objective:To investigate whether low buffy coat mtDNA-CN is a marker and causal determinant of post-stroke outcomes using epidemiological and genetic studies.Methods:First, we performed association testing between baseline buffy coat mtDNA-CN measurements and 1-month post-stroke outcomes in 3498 acute, first stroke cases from 25 countries from the international, multicenter case-control study, “Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World” (INTERSTROKE). Then, we performed two-sample Mendelian Randomization analyses to evaluate potential causative effects of low mtDNA-CN on 3-month modified Rankin Scale (mRS). Genetic variants associated with mtDNA-CN levels were derived from the UKBiobank study (N=383476), and corresponding effects on 3-month mRS were ascertained from the Genetics of Ischemic Stroke funCtional Outcome study (GISCOME; N=6021).Results:A 1-standard deviation (SD) lower mtDNA-CN at baseline was associated with stroke severity (baseline mRS; OR=1.27; 95% CI, 1.19-1.36; P=4.7x10-12). Independent of baseline stroke severity, lower mtDNA-CN was associated with increased odds of greater 1-month disability (ordinal mRS; OR=1.16; 95% CI, 1.08-1.24; P=4.4x10-5), poor functional outcome status (mRS 3-6 vs. 0-2; OR=1.21; 95% CI, 1.08-1.34; P=6.9x10-4), and mortality (OR=1.35; 95% CI, 1.14-1.59; P=3.9x10-4). Subgroup analyses demonstrated consistent effects across stroke type, sex, age, country income level, and education level. In addition, mtDNA-CN significantly improved reclassification of poor functional outcome status (Net Reclassification Index (NRI)=0.16; 95% CI, 0.08-0.23; P=3.6x10-5) and mortality (NRI=0.31; 95% CI, 0.19-0.43; P=1.7x10-7) beyond known prognosticators. Using independent datasets, Mendelian Randomization revealed that a 1 SD decrease in genetically determined mtDNA-CN was associated with increased odds of greater 3-month disability quantified by ordinal mRS (OR=2.35; 95% CI, 1.13-4.90; P=0.02) and poor functional outcome status (OR=2.68; 95% CI, 1.05-6.86; P=0.04).Conclusions:Buffy coat mtDNA-CN is a novel and robust marker of post-stroke prognosis that may also be a causal determinant of post-stroke outcomes.Classification of Evidence:This study provides class II evidence that low buffy coat mtDNA-CN (>1-standard deviation) was associated with worse baseline severity and 1-month outcomes in patients with ischemic or hemorrhagic stroke.

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Mitochondrial DNA copy number and diabetes: the Atherosclerosis Risk in Communities (ARIC) study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001204 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001204

Author(s):

Bailey DeBarmore ◽

Ryan J Longchamps ◽

Yiyi Zhang ◽

Rita R Kalyani ◽

Eliseo Guallar ◽

...

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Dysfunction ◽

Copy Number ◽

Buffy Coat ◽

Incident Diabetes ◽

Atherosclerosis Risk In Communities ◽

Mitochondrial Dna Copy Number ◽

Atherosclerosis Risk ◽

Aric Study

IntroductionMitochondrial DNA copy number (mtDNA-CN) is a measure of mitochondrial dysfunction and is associated with diabetes in experimental models. To explore the temporality of mitochondrial dysfunction and diabetes, we estimated the prevalent and incident association of mtDNA-CN and diabetes.Research design and methodsWe assessed the associations of mtDNA-CN measured from buffy coat with prevalent and incident diabetes, stratified by race, in 8954 white and 2444 black participants in the Atherosclerosis Risk in Communities (ARIC) study, an observational cohort study. Follow-up for incident analyses was complete through visit 6, 2016.ResultsMean age at mtDNA-CN measurement was 57 years and 59% were female. Prevalence of diabetes at time of mtDNA-CN measurement was higher in blacks (563/2444, 23%) than whites (855/8954, 10%). The fully adjusted odds of prevalent diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.05 (95% CI 0.74 to 1.49) among black and 1.49 (95% CI 1.20 to 1.85) among white participants. Over a median follow-up time of 19 years (Q1, Q3: 11, 24 years), we observed 617 incident diabetes cases among 1744 black and 2121 cases among 7713 white participants free of diabetes at baseline. The fully adjusted hazard of incident diabetes for the 10th vs 90th percentile of mtDNA-CN was 1.07 (95% CI 0.84 to 1.38) among black and 0.97 (95% CI 0.86 to 1.10) among white participants.ConclusionsLower mtDNA-CN in buffy coat was associated with prevalent diabetes in white but not black ARIC participants. Lower mtDNA-CN was not associated with incident diabetes over 20 years of follow-up in whites or blacks.

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Abstract P38: Pooled Analysis of Long and Short Term Outcomes After Subarachnoid Hemorrhage - International Stroke Outcomes Study (INSTRUCT)

Stroke ◽

10.1161/str.52.suppl_1.p38 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Sabah Rehman ◽

Hoang T Phan ◽

Mathew J Reeves ◽

Amanda G Thrift ◽

Dominique A Cadilhac ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Functional Outcome ◽

Stroke Severity ◽

Poor Functional Outcome ◽

Stroke Incidence ◽

Stroke Outcomes ◽

Current Smoking ◽

Incidence Studies ◽

History Of ◽

Outcomes Study

Background: Outcomes after subarachnoid hemorrhage (SAH) have been rarely examined in large cohorts. Methods: This is an extension of the International Stroke Outcomes Study (INSTRUCT) pooling 13 ‘ideal’ stroke incidence studies (n=657 with SAH from 1993-2017, median age 56 years; 46% men). The primary outcomes were mortality and functional outcome (mRS score 3-5). Harmonized study factors included age, sex, behaviors (current smoking, alcohol intake), comorbidities (history of hypertension, ischemic heart disease, atrial fibrillation), stroke severity (e.g. NIHSS score) and year of stroke. In the pooled dataset, we estimated predictors of mortality using Poisson regression, to estimate incidence rate ratio (IRR) at 1 month (11 studies), 1 year (12 studies) and 5 years (7 studies). Generalized equation estimates in the log-binomial family were used to calculate risk ratios (RRs) for predictors of poor functional outcome at 1 month (5 studies) and 1 year (8 studies). Results: Mortality was 33% at 1 month, 43% at 1 year, and 47% at 5 years (Fig 1). Poor functional outcome was 25% at 1 month and 15% at 1 year (Fig 1). In multivariable analysis, age and stroke severity were associated with mortality at all time points, together with current smoking at 1 and 5 years, and history of hypertension at 5 years (Fig 2). Poor functional outcome was predicted by age (RR 1.03; 95% CI 1.01-1.04) at 1 month and by age (RR 1.04; 95% CI 1.00-1.08) and stroke severity (RR 1.94; 95% CI 1.02-2.87) at 1 year. Conclusion: Risk factors that predict SAH incidence including hypertension and smoking make outcomes worse. Better management of older patients and those with severe strokes could improve outcomes after SAH.

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From Normal to Obesity and Back: The Associations between Mitochondrial DNA Copy Number, Gender, and Body Mass Index

Cells ◽

10.3390/cells8050430 ◽

2019 ◽

Vol 8 (5) ◽

pp. 430 ◽

Cited By ~ 6

Author(s):

Daria Skuratovskaia ◽

Larisa Litvinova ◽

Maria Vulf ◽

Pavel Zatolokin ◽

Konstantin Popadin ◽

...

Keyword(s):

Body Mass Index ◽

Mitochondrial Dna ◽

Body Mass ◽

Copy Number ◽

Buffy Coat ◽

Control Group ◽

Obese Patients ◽

Mtdna Copy Number ◽

Mitochondrial Dna Copy Number ◽

One Year

Mitochondrial DNA (mtDNA) encodes core subunits of oxidative phosphorylation complexes and, as a result of intricate regulatory crosstalk between nuclear and mitochondrial genomes, the total number of mtDNA copies fits the requirements of each cell type. Deviations from the physiological number of mtDNA copies are expected to be deleterious and might cause some inherited diseases and normal ageing. We studied 46 obese patients with type 2 diabetes (T2DM) one year after a laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB). The results were compared with normal-weight patients without T2DM (control group 1) (body mass index (BMI) = 22.5 ± 3.01 kg/m2) and patients with obesity without T2DM (control group 2) (BMI = 36 ± 3.45 kg/m2). We detected an increase of mtDNA copy number in the cells of the buffy coat obtained from peripheral blood, sampled one year after bariatric surgery. We also found that average mtDNA copy number as well as its dynamics (before and after the surgery) are gender-specific. To the best of our knowledge, this is the first evidence for the restoration of mtDNA copy number in obese patients after LSG and RYGB.

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GWAS and ExWAS of blood Mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia

eLife ◽

10.7554/elife.70382 ◽

2022 ◽

Vol 11 ◽

Author(s):

Michael Chong ◽

Pedrum Mohammadi-Shemirani ◽

Nicolas Perrot ◽

Walter Nelson ◽

Robert Morton ◽

...

Keyword(s):

Mitochondrial Dna ◽

Health Research ◽

Copy Number ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Dna Copy Number ◽

Mtdna Depletion ◽

Mitochondrial Dna Copy Number ◽

Increased Risk

Background: Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation.Methods: We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called 'AutoMitoC'. We applied AutoMitoC to 395,781 UKBiobank study participants and performed genome and exome-wide association studies, identifying novel common and rare genetic determinants. Finally, we performed two-sample Mendelian Randomization to assess whether genetically low mtDNA-CN influenced select mitochondrial phenotypes.Results: Overall, genetic analyses identified 71 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, dNTP metabolism, and the mitochondrial central dogma. Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta=0.23 SDs; 95% CI, 0.18- 0.29; P=2.6x10-19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR=1.91; 95% CI, 1.52-2.40; P=2.7x10-8). Finally, Mendelian randomization analyses suggest a causal effect of low mtDNA-CN on dementia risk (OR=1.94 per 1 SD decrease in mtDNA-CN; 95% CI, 1.55-2.32; P=7.5x10-4).Conclusions: Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific mitochondrial processes related to mtDNA regulation, and that these processes are causally related to human diseases.Funding: No funds supported this specific investigation. Awards and positions supporting authors include: Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award (MC, PM); CIHR Post-Doctoral Fellowship Award (RM); Wellcome Trust Grant number: 099313/B/12/A; Crasnow Travel Scholarship; Bongani Mayosi UCT-PHRI Scholarship 2019/2020 (TM); Wellcome Trust Health Research Board Irish Clinical Academic Training (ICAT) Programme Grant Number: 203930/B/16/Z (CJ); European Research Council COSIP Grant Number: 640580 (MO); E.J. Moran Campbell Internal Career Research Award (MP); CISCO Professorship in Integrated Health Systems and Canada Research Chair in Genetic and Molecular Epidemiology (GP).

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