Key result
Mitochondrial genome variation showed only spurious associations with coronary artery disease, with variant m.10400C>T showing the strongest association with inclusive CAD (OR 1.28).
Why the study?
Nuclear genome-wide association studies explain <20% of CAD heritability, leading to the hypothesis that mitochondrial single-nucleotide variants may account for part of the missing heritability.
Does mitochondrial genome variation associate with the risk of coronary artery disease in a large population-based cohort?
Observational (n=391,345)
Does mitochondrial genome variation associate with the risk of coronary artery disease in a large population-based cohort?
Odds Ratio: 1.28 (95% CI 1.21–1.35)
p-value: p=0.0007
Mitochondrial genome variation shows only spurious associations with coronary artery disease in the UK Biobank, suggesting that larger cohorts are needed to determine its role in the missing heritability of CAD.
Mitochondrial genotyping adds no value to CAD risk prediction; leaves open rare variant effects in targeted subgroups.
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 revascularization; 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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Vilne et al. (2022) conducted an observational in Coronary Artery Disease (n=391,345). Mitochondrial single-nucleotide variants (MT-SNVs) vs. Absence of specific MT-SNVs / Controls without CAD was evaluated on SOFT CAD (inclusive definition including myocardial infarction, revascularization, angina, and chronic ischemic heart disease) (OR 1.28, 95% CI 1.21-1.35, p=0.0007). Mitochondrial genome variation showed only spurious associations with coronary artery disease, with variant m.10400C>T showing the strongest association with inclusive CAD (OR 1.28).
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