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AFRICA
CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
GWAS has been employed to identify genetic loci for many
other cardiovascular diseases such as coronary heart disease,
diabetes and hypertension, and is just being applied to stroke.
The pitfalls of previous studies of genomic contributions
to stroke include poor phenotyping, underpowered studies,
confounders, winner’s curse, and non-validation in independent
populations.
88,90
For example, the Siblings With Ischemic Stroke
study (SWISS) did not demonstrate any significant genome-wide
association.
91
However, certain novel genetic variants have been
identified as risk factors in stroke populations, with some being
replicated in other populations.
The International Stroke Genetics Consortium and the
Wellcome Trust Case–Control Consortium published the
largest GWAS for ischaemic stroke carried out to date. This
study successfully demonstrated the importance of very large
multicentre study samples, identified a new associated genetic
variant and replicated findings of previous stroke GWAS. The
findings also demonstrated the value of clear phenotyping and
the fact that different stroke phenotypes may differ in their
genetic architectures. Table 2 summarises the findings of salient
recent GWAS studies in stroke, including a single study by Cole
et al
. in 2012, which utilised exome sequencing.
3,92-103
Genetic studies of stroke in Africa
To date, only a few stroke genetic studies (Table 3) have been
reported from North Africa and remarkably, none from sub-
Saharan Africa where the burden of stroke is disproportionately
heavy and the phenomics of stroke appears relatively different.
Saidi and colleagues working consistently with a growing
Tunisian stroke cohort have reported significant association
between ischaemic stroke and polymorphisms in several genes,
including plasminogen activator inhibitor,
APOE
ε
4, human
plasminogen activator, human platelet antigen, angiotensin
converting enzyme
Del/Del
genotype, angiotensinogen, endothe-
lial nitric oxide synthase and aldosterone synthase.
104-111
A single study from Egypt noted that the presence of the
ACE
D allele significantly predisposed to stroke in children with sickle
cell anaemia.
112
It is, however, significant to note that the people
of North Africa have a different ancestral origin (predominantly
Arabian and Berber) from sub-Saharan African populations.
9
Therefore, significant differences may be anticipated in the
genomic profile of stroke and subtypes in sub-Saharan Africans.
Problems and perspectives
Apart from the lack of community-based ideal stroke
epidemiological data sets and the challenge of accurate
phenotypic characterisation of cases in sub-Saharan Africa,
there are other inherent problems of genomic research ranging
from the negative impact of cultural and religious beliefs, issues
of autonomy of decision making and voluntary participation,
as well as poor understanding of the health impact of
genomics.
113-115
In a qualitative study assessing knowledge and
attitude towards personal genomics testing for complex diseases
among Nigerians, even though respondents felt the outcome
of genomic testing might aid healthful lifestyle modifications,
attitude was influenced by religion and culture, especially aspects
that might directly contradict beliefs and practices or lead to
actions contradicting religious beliefs.
115
All these aspects introduce critical ethical issues into the
framework of genomics research in Africa, which need to
be addressed in order to achieve success and popularise the
prospects of personalised genomic medicine. In addition, there
are also the challenges of adequate infrastructure for genomic
studies and analysis of genomic data, a paucity of appropriately
trained scientists and physicians who have the capacity to design,
implement and interpret such studies and lead translational
applications, and insufficient bio-informaticians with analysis
expertise and research managers. Unstable power supply and
political instability are other bottlenecks.
Opportunities through H3 Africa: SIREN chart-
ing new paths
Although African populations harbour the greatest human
genomic diversity, the potential of this for understanding human
evolutionary biology and disparities in health and disease are
Table 2. Recent GWAS andWES studies in stroke
First author
Study
type Phenotype
Sample size
Sample ancestry
Associated regions
Hata
et al.
(2011)
85
GWAS Ischaemic stroke
1 112 cases, 1 112 controls
Japanese
14q22 (PRKCH), 11q12 (AGTRL1)
Matarin
et al.
(2009)
89
GWAS Ischaemic stroke
249 cases, 268 controls
White
None
Gretasrdottri and Gudjarts-
son
et al.
(2008, 2009)
87,88
GWAS Ischaemic stroke
1 661 cases, 10 815 controls
Icelandic
4q25 (PITX2), 16q22.3 (ZFHX3)
Bilguvar
et al.
(2008)
89
GWAS lntracranial aneurysms
2 100 cases, 8 000 controls
Finish, Dutch,
Japanese
2q33 (PLCL1), 8q12 (SOX17), 9p21.3
(CDKN2A, CDK N2B, ANRIL)
lkram
et al.
(2009)
90
GWAS Ischaemic stroke
Cohort of 19 602, 1 164 events Caucasian
12p13.33 (NINJ2)
Yamada
et al.
(2009)
91
GWAS Ischaemic stroke
992 cases, 5 349 controls
Japanese
22q13 (CELSR1)
Zhang
et al.
(2012)
92
GWAS Ischaemic and haemor-
rhagic stroke
1 657 cases, 1 664 controls
Chinese
9p21.3 (ANRIL)
Matsushita
et al.
(2010)
93
GWAS Atherothrombotic stroke 2 775 cases, 2 839 controls
Japanese
ARHGEF 10
ISGC and WTCCC
(2012)
94
GWAS Large-vessel stroke
3 548 cases, 5 972 controls
European
7p21.1 (HDAC9); replicated previ-
ous finding for cardio-embolic stroke
near PITX2 and ZFHX3
Holliday
et al.
(2012)
95
GWAS Large-vessel stroke
1 162 cases, 1 244 controls
Australian
6p21.1
Cole
et al.
(2012)
3
WES Lacunar stroke
889 cases, 927 controls
(10 for exome sequencing)
African American
European American
4q21.1 (CSN3) **identified by exome
sequencing following previous GWAS
Zhou
et al.
(2014)
96
GWAS Lacunar strokes
systemic vasculopathy
9 subjects (exome sequencing) European American,
European
ADA
2 gene