Abstract
AbstractBackgroundLarge-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.HypothesisHere, we hypothesize that mitochondrial (MT) SNVs might present one potential source of this “missing heritability”.MethodsWe 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).ResultsIn 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.ConclusionsWe 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献