Heteroplasmic mitochondrial DNA variants in cardiovascular diseases

Mitochondria are implicated in the pathogenesis of cardiovascular diseases (CVDs) but the reasons for this are not well understood. Maternally-inherited population variants of mitochondrial DNA (mtDNA) which affect all mtDNA molecules (homoplasmic) are associated with cardiometabolic traits and the risk of developing cardiovascular disease. However, it is not known whether mtDNA mutations only affecting a proportion of mtDNA molecules (heteroplasmic) also play a role. To address this question, we performed a high-depth (similar to 1000fold) mtDNA sequencing of blood DNA in 1,399 individuals with hypertension (HTN), 1,946 with ischemic heart disease (IHD), 2,146 with ischemic stroke (IS), and 723 healthy controls. We show that the per individual burden of heteroplasmic single nucleotide variants (mtSNVs) increases with age. The age-effect was stronger for low-level heteroplasmies (heteroplasmic fraction, HF, 5-10%), likely reflecting acquired somatic events based on trinucleotide mutational signatures. After correcting for age and other confounders, intermediate heteroplasmies (HF 10-95%) were more common in hypertension, particularly involving non-synonymous variants altering the amino acid sequence of essential respiratory chain proteins. These findings raise the possibility that heteroplasmic mtSNVs in the pathophysiology of hypertension. Author summary Inherited homoplasmic variants affecting all mitochondrial DNA (mtDNA) molecules are associated with cardiovascular diseases, but the role of variants causing a mixed population of mtDNA (heteroplasmy) is not well understood. Here we sought to characterize the role of mtDNA heteroplasmic variants in hypertension, ischemic heart disease, and ischemic stroke, by deep-sequencing of the whole mtDNA molecule in 5,491 individuals including healthy controls. We measured the burden of low and intermediate level heteroplasmic single-nucleotide variants (mtSNVs) annotated in different genomic regions. In addition to an age-related accumulation of heteroplasmic mtDNA variants, we show that hypertensive individuals have a greater burden of mtSNVs variants particularly at intermediate heteroplasmy levels (HF 10-95%). These mtSNVs mostly involve non-synonymous variants in mtDNA genes coding for critical respiratory chain proteins. These findings raise the possibility that mtDNA heteroplasmy contributes to the pathogenesis of hypertension through an effect on mitochondrial respiratory chain function.

Automated summary

Heteroplasmic mitochondrial DNA mutations may play a role in the pathogenesis of cardiovascular diseases, particularly hypertension.