Mitochondrial GWAS and association of nuclear – mitochondrial epistasis with BMI in T1DM patients

Ludwig-Słomczyńska, Agnieszka H.; Seweryn, Michał; Kapusta, Przemysław; Pitera, Ewelina; Handelman, Samuel K.; Mantaj, Urszula; Cyganek, Katarzyna; Gutaj, Paweł; Dobrucka, Łucja; Wender-Ożegowska, Ewa; Małecki, Maciej; Wołkow, Paweł

doi:10.1186/s12920-020-00752-7

Cited by 14 publications

(14 citation statements)

References 65 publications

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“…Moreover, genetic variants in nuclear genes could lead to oxidative disorders or modulate the mitochondrial variants [ 81 ], and mild nuclear gene variants could potentially become clinically relevant when combined with an incompatible MT DNA [ 92 ]. Additive interactions (epistasis) between mitochondrial variants in the MT-ND2 gene and nuclear variants in genes responsible for mitochondrial replication and transcription have been demonstrated to influence the BMI and obesity phenotype [ 93 ]. Similarly, our previous investigations have demonstrated the role of nuclear-encoded mitochondria imported genes in coordinating the response to hypercholesterolemia and atherosclerotic lesion expansion, as well as foam cell formation [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease

Vilne

Sawant

Rudaka

2022

Genes

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“…Interactions involving mtDNA haplogroups are not new. Different studies revealed mito-nuclear genetic interactions that modulate the effect of specific nuclear genetic variants on the risk of Alzheimer 26 , Parkinson 27 , multiple sclerosis 28 or increased BMI in patients with type I Diabetes mellitus 29 . In addition, mitochondrial variation also influences the DNA methylome of articular chondrocytes 30 as well as global methylation levels in peripheral blood DNA 31 .…”

Section: Discussionmentioning

confidence: 99%

mtDNA haplogroup A enhances the effect of obesity on the risk of knee OA in a Mexican population

Ramos‐Louro

Vertti

Reyes

et al. 2022

Sci Rep

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To evaluate the influence of mitochondrial DNA haplogroups on the risk of knee OA in terms of their interaction with obesity, in a population from Mexico. Samples were obtained from (n = 353) knee OA patients (KL grade ≥ I) and (n = 364) healthy controls (KL grade = 0) from Mexico city and Torreon (Mexico). Both Caucasian and Amerindian mtDNA haplogroups were assigned by single base extension assay. A set of clinical and demographic variables, including obesity status, were considered to perform appropriate statistical approaches, including chi-square contingency tables, regression models and interaction analyses. To ensure the robustness of the predictive model, a statistical cross-validation strategy of B = 1000 iterations was used. All the analyses were performed using boot, GmAMisc and epiR package from R software v4.0.2 and SPSS software v24. The frequency distribution of the mtDNA haplogroups between OA patients and healthy controls for obese and non-obese groups showed the haplogroup A as significantly over-represented in knee OA patients within the obese group (OR 2.23; 95% CI 1.22–4.05; p-value = 0.008). The subsequent logistic regression analysis, including as covariate the interaction between obesity and mtDNA haplogroup A, supported the significant association of this interaction (OR 2.57; 95% CI 1.24–5.32; p-value = 0.011). The statistical cross-validation strategy confirmed the robustness of the regression model. The data presented here indicate a link between obesity in knee OA patients and mtDNA haplogroup A.

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“…Moreover, genetic variants in nuclear genes could lead to oxidative disorders or modulate the mitochondrial variants [81] and mild nuclear gene variants could potentially become clinically relevant when combined with an incompatible MT DNA [105]. Additive interactions (epistasis) between mitochondrial variants in MT-ND2 gene and nuclear variants in genes responsible for mitochondrial replication and transcription have been demonstrated to influence the BMI and obesity phenotype [66]. Similarly, our previous investigations have demonstrated the role of nuclear encoded mitochondria imported genes in coordinating the response to hypercholesterolemia and atherosclerotic lesion expansion, and foam cell formation [102].…”

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.

show abstract

Mitochondrial GWAS and association of nuclear – mitochondrial epistasis with BMI in T1DM patients

Cited by 14 publications

References 65 publications

Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease

Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease

mtDNA haplogroup A enhances the effect of obesity on the risk of knee OA in a Mexican population

Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease

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