Bioinformatics Lab, Rīga Stradiņš University, LV-1007 Riga, Latvia.
Scientific Laboratory of Molecular Genetics, Rīga Stradiņš University, LV-1007 Riga, Latvia.
Genes (Basel). 2022 Mar 15;13(3):516. doi: 10.3390/genes13030516.
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.
大规模全基因组关联研究已经确定了数百个与冠状动脉疾病（CAD）显著相关的单核苷酸变异（SNV）。然而，这些变异总共仅能解释<20%的遗传率。假说：在这里，我们假设线粒体（MT）-SNVs 可能是这种“遗传缺失”的一个潜在来源。方法：我们分析了约 50 万英国生物库个体中的 265 个 MT-SNV，探索了两种不同的 CAD 定义：更严格的（心肌梗死和/或血运重建；HARD = 20,405）和更广泛的（心绞痛和慢性缺血性心脏病；SOFT = 34,782）。结果：在 HARD 病例中，最显著的（p<0.05）关联是 m.295C>T（控制区）和 m.12612A>G（ND5），在病例中更为常见（OR=1.05），可能与运动时心肺功能下降有关，以及 m.12372G>A（ND5）和 m.11467A>G（ND4），在对照组中更为常见（OR=0.97），先前与较低的 ROS 产生率有关。在 SOFT 病例中，有四个 MT-SNV 在多重测试校正后仍然显著（FDR<5%），这四个 SNV 都可能增加 CAD 风险。其中，m.11251A>G（ND4）和 m.15452C>A（CYB）先前与身高显著相关。与此一致的是，我们观察到 CAD 病例的身体活动量略低，平均身高比对照组低约 2.00 厘米；这两个特征都与增加的 CAD 风险有关。基于基因的测试确定 CO2 与 HARD/SOFT CAD 相关，而 ND3 和 CYB 与 SOFT 病例相关（p<0.05），它们的功能障碍与 MT 氧化应激、肥胖/T2D（CO2）、BMI（ND3）和心绞痛/运动不耐受（CYB）有关。最后，我们观察到宏单倍群 I 在 HARD 病例中明显（p<0.05）比对照组更为常见（3.35%比 3.08%），可能与对运动的反应有关。结论：我们仅发现 MT 基因组变异与 HARD/SOFT CAD 之间存在虚假关联，我们得出结论，可能需要更大的 MT-SNV 数据甚至更大的研究队列才能最终确定 MT DNA 在 CAD 中的作用。
