Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease
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...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-03-01
|
| Series: | Genes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4425/13/3/516 |
| _version_ | 1797471386026901504 |
|---|---|
| author | Baiba Vilne Aniket Sawant Irina Rudaka |
| author_facet | Baiba Vilne Aniket Sawant Irina Rudaka |
| author_sort | Baiba Vilne |
| collection | DOAJ |
| description | 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 (<i>p</i> < 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 (<i>p</i> < 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 (<i>p</i> < 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. |
| first_indexed | 2024-03-09T19:47:44Z |
| format | Article |
| id | doaj.art-dbfe961f1cb146fe8c0cc64054fe4986 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T19:47:44Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-dbfe961f1cb146fe8c0cc64054fe49862023-11-24T01:19:31ZengMDPI AGGenes2073-44252022-03-0113351610.3390/genes13030516Examining the Association between Mitochondrial Genome Variation and Coronary Artery DiseaseBaiba Vilne0Aniket Sawant1Irina Rudaka2Bioinformatics Lab, Rīga Stradiņš University, LV-1007 Riga, LatviaBioinformatics Lab, Rīga Stradiņš University, LV-1007 Riga, LatviaScientific Laboratory of Molecular Genetics, Rīga Stradiņš University, LV-1007 Riga, LatviaLarge-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 (<i>p</i> < 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 (<i>p</i> < 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 (<i>p</i> < 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.https://www.mdpi.com/2073-4425/13/3/516coronary artery diseasemitochondriamitochondrial DNA variantshaplogroupsassociationcommon and rare variants |
| spellingShingle | Baiba Vilne Aniket Sawant Irina Rudaka Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease Genes coronary artery disease mitochondria mitochondrial DNA variants haplogroups association common and rare variants |
| title | Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease |
| title_full | Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease |
| title_fullStr | Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease |
| title_full_unstemmed | Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease |
| title_short | Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease |
| title_sort | examining the association between mitochondrial genome variation and coronary artery disease |
| topic | coronary artery disease mitochondria mitochondrial DNA variants haplogroups association common and rare variants |
| url | https://www.mdpi.com/2073-4425/13/3/516 |
| work_keys_str_mv | AT baibavilne examiningtheassociationbetweenmitochondrialgenomevariationandcoronaryarterydisease AT aniketsawant examiningtheassociationbetweenmitochondrialgenomevariationandcoronaryarterydisease AT irinarudaka examiningtheassociationbetweenmitochondrialgenomevariationandcoronaryarterydisease |