The association between mitochondrial DNA copy number, low-density lipoprotein cholesterol, and cardiovascular disease risk

Mitochondria are the primary organelle to generate cellular energy. Our group and others have reported that lower mitochondrial DNA copy number (mtDNA CN) is associated with higher risk of cardiovascular disease outcomes (CVD) and higher LDL levels. However, the causal relationship between mtDNA CN and CVD remains to be studied. Here we performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and CVD outcomes in up to 27,316 participants from different racial/ethnic groups with whole genome sequencing. We validated most of the previously reported associations but effect sizes were smaller in this study. For example, one SD unit decrease in mtDNA CN was significantly associated with 1.08-fold (95% CI, 1.04, 1.12; P=1.7E-04) hazard for developing incident coronary heart disease (CHD) adjusting for age, sex and race/ethnicity. We conducted Mendelian randomization (MR) to explore causal relationships between mtDNA CN, LDL, and CHD. Bi-directional univariable MR analyses provided strong evidence indicating higher LDL level is causally associated with lower mtDNA CN, and CHD was weakly associated with lower mtDNA CN. We found no evidence supporting a causal association for lower mtDNA CN with higher CHD risk or higher LDL. In multivariable MR, no associations were observed between mtDNA CN and CHD controlling for LDL level (P =0.92), whereas strong evidence for a direct causal effect was found for higher LDL on lower mtDNA CN, adjusting for CHD status (P =8.3E-10). Findings from this study indicate high LDL underlies the complex relationships between vascular atherosclerosis and lower mtDNA CN.