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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 2, March/April 2018
122
AFRICA
Review Article
The aetiology of cardiovascular disease: a role for
mitochondrial DNA?
Marianne Venter, Francois H van der Westhuizen, Joanna L Elson
Abstract
Cardiovascular 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 iden-
tify 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 muta-
tional 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 associa-
tion 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 varia-
tion in CVD and other common complex disease.
Keywords:
mitochondrial DNA, cardiovascular disease,MutPred,
mutational load, African
Submitted 7/11/16, accepted 31/7/17
Published online 24/8/17
Cardiovasc J Afr
2017;
29
: 122–132
www.cvja.co.zaDOI: 10.5830/CVJA-2017-037
Mitochondrial DNA
Cardiovascular disease (CVD) remains the main non-
communicable cause of morbidity and mortality in humans.
1
While environmental factors and lifestyle choices play a major
role in CVD, it is also recognised that genetic factors contribute
significantly to the aetiology thereof. In this regard, several
studies, most recently genome-wide association studies (GWAS),
have contributed to identifying genetic loci involved in CVDs, and
their association with behavioural and biological risk factors.
2-7
Despite the numerous nuclear DNA (nDNA) variants
identified, only a small portion of the heredity of CVDs can
thus far be accounted for by variants discovered with GWAS
studies.
8
For instance, the 46 loci identified for coronary artery
disease (CAD) only account for about six to 13% of CAD
hereditability.
9-11
The mitochondrion is the only other source of DNA apart
from the nucleus. Mitochondrial DNA (mtDNA) encodes for 22
tRNAs, two rRNAs and 13 polypeptides thought important in
the catalytic cores of complexes I, III, IV and V of the oxidative
Human Metabolomics, North-West University,
Potchefstroom, South Africa
Marianne Venter, PhD,
20196946@nwu.ac.zaFrancois H van der Westhuizen, PhD
Joanna L Elson, PhD
Institute of Genetic Medicine, Newcastle University, United
Kingdom
Joanna L Elson, PhD
Fig. 1.
mtDNA encodes for 22 tRNA and two rRNA molecules,
as well as 13 polypeptide sub-units of the OXPHOS
enzyme complexes, as indicated by colour. Enzyme
complexes I–IV are involved in a series of redox
reactions, which transfer electrons from carriers nico-
tinamide adenine dinucleotide (NADH) and flavin
adenine dinucleotide (FADH
2
) to oxygen molecules.
During these catalytically favourable reactions, H
+
ions are pumped from the mitochondrial matrix into
the mitochondrial intermembrane space to create a
proton-motor force across the inner mitochondrial
membrane. This force is used by complex V to catalyse
the phosphorylation of adenosine diphosphate (ADP)
to adenosine triphosphate (ATP). Complex I: NADH
dehydrogenase; complex II: succinate dehydrogenase;
complex III: cytochrome c reductase; complex IV:
cytochrome c oxidase; complex V: ATP synthase.