Abstract 10452: Exploring the Role of Mitochondrial Genetic Variants in Coronary Artery Disease

Abstract

Introduction: Large-scale genome-wide association studies have identified >200 single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD), collectively explaining <20% of the heritability. Hypothesis: Mitochondrial (MT) genetic variants presents an underexplored one potential source of the “missing heritability”. Methods: We analyzed 265 MT-SNVs in ∼500,000 UK Biobank individuals, exploring two different CAD definitions: including (SOFT=34,782) vs. excluding (HARD=20,405) angina, using the array, sex, birth year and first five principal components as covariates. Results: In SOFT cases, four MT-SNVs survived multiple testing correction (at FDR<5%), all conferring increased CAD risk: m.10400C>T (rs28358278, OR=1.28, MAF=0.02, T114T in MT-ND3), m.15301G>A (rs527236045, OR=1.03, MAF=0.04, L185L in MT-CYB), m.11251A>G (rs869096886, OR=1.03, MAF=0.2, L164L in MT-ND4) and m.15452C>A (rs193302994, OR=1.03, MAF=0.2, L236I in MT-CYB), the latter two previously associated with height in the UK Biobank. In HARD cases, no MT-SNVs survived multiple testing correction, the most significant nominal (P <0.05) findings being for four SNVs, whereof m.295C>T (rs41528348, OR=1.05, MAF=0.1, in the D-LOOP) and m.12612A>G (rs28359172, OR=1.05, MAF=0.04, V92V in MT-ND5) could potentially increase CAD risk, whereas m.12372G>A (rs2853499, OR=0.97, MAF=0.22, L12L in MT-ND5), m.11467A>G (rs2853493, OR=0.97, MAF=0.22, L236L in MT-ND4) and m.15301G>A (rs193302991, OR=0.97, MAF=0.04, L185L in MT-CYB) may confer protective effects. Previously, several of these variants have been associated with a number of blood cell traits in the UK Biobank, including the mean corpuscular hemoglobin levels (m.295C>T, m.12612A>G, m.12372G>A) and volume (m.295C>T and m.12612A>G). In addition, m.12372G>A was significantly association with five other blood cell traits, including the mean platelet volume and white/red blood cell count, as well as with several renal biomarkers, and m.12612A>G was associated with height. Conclusions: Our results indicated only spurious associations of the MT-SNV with the occurrence of CAD. More data in larger study cohorts may be needed to conclusively determine the role of MT-DNA in CAD.