Abstract 4143732: Mitochondrial DNA heteroplasmy and incident cardiovascular disease

Background: Variants of mitochondrial DNA (mtDNA) may exist in heteroplasmy and have been associated with increased risk of mortality and cancer. While variation in mtDNA has been associated with cardiomyopathy in mitochondrial disease, the association between mtDNA heteroplasmy and cardiovascular disease (CVD) in the general population has not been well studied. Methods: We quantified mtDNA heteroplasmy from whole genome sequencing data in 476,434 participants in the UK Biobank. We defined a variant allele frequency of 5–95% as heteroplasmic. We functionally characterized mtDNA single nucleotide variants using a constraint-based score, mitochondrial local constraint score sum (MSS). We evaluated the associations of MSS and incident CVD, defined as fatal or non-fatal myocardial infarction (MI) or ischemic stroke (IS), using Cox proportional hazards models adjusted for demographic, lifestyle, and clinical factors in 463,705 participants free of CVD. We further tested the interactions with clonal hematopoiesis of indeterminant potential (CHIP) and leukocyte telomere length (LTL) in the association between heteroplasmy and CVD. We performed additional analysis stratified by MSS for each complex/region in the mtDNA, and subgroup analysis by sex and C-reactive protein (CRP; ≥3mg/L). Lastly, we performed analysis separately for MI and IS. Results: During a median (1 st and 3 rd quartiles) follow-up of 13.6 (13.1–14.5) years, there were 24,723 incident CVD events (16,959 MI and 9671 IS cases). 28.3% of the study population had 1 or more heteroplasmies. We found that higher MSS was associated with CVD (adjusted hazard ratio [aHR] for a 1-unit increase in MSS 1.08; 95% confidence interval 1.00–1.17). In particular, a higher MSS was associated with MI (aHR 1.13; 1.02–1.24) but not with IS (aHR 1.03; 0.90–1.17). The association between MSS and MI was stronger for fatal MI (aHR 1.52; 1.10–2.10) than for non-fatal MI (aHR 1.10; 0.99–1.21). When stratified by complex/region, higher MSS in Complex I increased the risk of MI by 27% (aHR 1.27; 1.06–1.53) but not in other complexes/regions. Although LTL was inversely associated with CVD outcomes, there were no associations with CHIP. Furthermore, there was no interactions by LTL, CHIP, sex, and CRP in the association between MSS and CVD outcomes. Conclusion: These results indicate that mitochondria may have a functional role in the development of CVD, particularly MI, and MSS may serve as a biomarker for CVD risk.