The aetiology of cardiovascular disease: a role for mitochondrial DNA?

Abstract

SummaryCardiovascular disease (CVD) is a world-wide cause of mortality in humans and its incidence is on the rise in Africa. In this review, we discuss the putative role of mitochondrial dysfunction in the aetiology of CVD and consequently identify mitochondrial DNA (mtDNA) variation as a viable genetic risk factor to be considered. We then describe the contribution and pitfalls of several current approaches used when investigating mtDNA in relation to complex disease. We also propose an alternative approach, the adjusted mutational load hypothesis, which would have greater statistical power with cohorts of moderate size, and is less likely to be affected by population stratification. We therefore address some of the shortcomings of the current haplogroup association approach. Finally, we discuss the unique challenges faced by studies done on African populations, and recommend the most viable methods to use when investigating mtDNA variation in CVD and other common complex disease.

Mitochondrial DNA copy number is associated with all‐cause mortality and cardiovascular events in patients with peripheral arterial disease

“…These findings suggest a link between mtDNA damage and atherosclerosis but the precise mechanism underlying this relationship and the exact role of mitochondrial ROS are still poorly understood. Inflammation and an increased oxidative stress due to an excessive production of ROS are key drivers in the development of atherosclerosis . ROS is able to oxidize lipids, promotes the uptake of inflammatory cells into the vessel wall and enhances the proliferation of vascular smooth muscle cells .…”

“…As mitochondria play an essential role in a number of mechanisms, their dysfunction leads to a multilevel failure and, in turn, causes a decline in muscle performance in patients suffering from vascular disease . Furthermore, dysfunctional mitochondria might be a key factor in the development of atherosclerosis via excessive production of reactive oxygen species (ROS) driving subclinical inflammation and increased oxidative stress . The mitochondrial DNA copy number (mtDNA‐CN) is a potential biomarker for mitochondrial dysfunction and has been associated with various diseases .…”

New mtDNA Association Model, MutPred Variant Load, Suggests Individuals With Multiple Mildly Deleterious mtDNA Variants Are More Likely to Suffer From Atherosclerosis

“…A role for mitochondrial dysfunction in many common complex, metabolic, and degenerative diseases has been suggested and investigated in many studies (Wallace, 2005, 2013). Supporting this, mitochondria are central to pathways crucial for cellular homeostasis (Wallace, 2013; Venter et al, 2018).…”

Mitochondrial DNA Mutations and Rheumatic Heart Diseases

“…ARF and rheumatic heart disease (RHD) have a high prevalence in developing countries in contrast with developed countries where these diseases have largely regressed [2]. ARF results in high morbidity and mortality rates worldwide and its incidence is the highest in Sub-Saharan Africa [3]. ARF incidence in developing countries exceeds 50 per 100,000 children [4].…”

“…This study aimed to investigate mutations in MT-CYB in ARF and RHD in Senegalese patients. The following were the objectives of our study: (1) To investigate MT-CYB polymorphisms in ARF; (2) to evaluate the genetic diversity of MT-CYB in ARF; (3) to determine the genetic structure of MT-CYB based on populations; (4) to identify the type of MT-CYB mutations in ARF.…”