Heteroplasmic mitochondrial DNA variants in cardiovascular diseases

Area of Science:

• Genetics
• Cardiology
• Mitochondrial Biology

Background:

• Mitochondria play a role in cardiovascular disease (CVD) pathogenesis.
• Homoplasmic mitochondrial DNA (mtDNA) variants are linked to cardiometabolic traits and CVD risk.
• The role of heteroplasmic mtDNA mutations in CVD is unclear.

Purpose of the Study:

• To investigate the role of heteroplasmic mitochondrial DNA single nucleotide variants (mtSNVs) in cardiovascular diseases.
• To determine if heteroplasmic mtSNVs are associated with hypertension, ischemic heart disease, or ischemic stroke.

Main Methods:

• High-depth mtDNA sequencing of blood DNA from 1,399 individuals with hypertension, 1,946 with ischemic heart disease, 2,146 with ischemic stroke, and 723 controls.
• Analysis of heteroplasmic variant burden, heteroplasmic fraction (HF), and variant type (synonymous/non-synonymous).
• Statistical correction for age and other potential confounders.

Main Results:

• The burden of heteroplasmic mtSNVs increases with age, particularly low-level heteroplasmies (HF 5-10%), suggesting acquired somatic events.
• Intermediate heteroplasmies (HF 10-95%) were more prevalent in individuals with hypertension after adjusting for confounders.
• Non-synonymous variants affecting respiratory chain proteins were notably associated with hypertension.

Conclusions:

• Heteroplasmic mtSNVs accumulate with age and are associated with hypertension.
• These findings suggest a potential role for heteroplasmic mtSNVs in the pathophysiology of hypertension.
• Further research is warranted to elucidate the precise mechanisms by which heteroplasmic mtSNVs contribute to cardiovascular disease.