Cardiovascular Journal of Africa: Vol 26 No 2 Supplement (March/April 2015)

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S46 AFRICA
CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
replicability of association between a candidate SNP and trait
outcome provides support for a causal relationship. However, the
high levels of genomic diversity among Africans pose a potential
challenge of false-positive associations due to population
stratification, while heterogeneity of haplotype structure may
reduce statistical power to detect true-positive signals by GWAS.
To combat these challenges, the SIREN project has been
designed in compliance with the recommendations of Dichgans
et al.88 with due attention to adequate sample size, rigorous
and accurate phenomic characterisation of cases, control
for confounders, and planned validation of findings in an
independent African American stroke population participating
in the REGARDS study29,116,117 (Table 4). In addition, the
SIREN project will utilise GWAS approaches using customised
chips including unique African variants,10 whole-genome and
whole-exome sequencing (WGS/WES) and other emergent
high-throughput approaches for future analyses. Furthermore,
‘pathway-based analysis’ of genomic data52 will chart new paths
in our understanding of the molecular trajectories of stroke and
unravel new options of stroke diagnostics and therapeutics in the
emerging milieu of personalised medicine
Conclusion
Understanding the interactionbetweengenetic andenvironmental
conditions that predispose to stroke and impede favourable
post-stroke outcomes is crucial for the formulation of targeted
treatment strategies aimed at the successful prevention of and
recovery from stroke. Unravelling the genomic underpinnings of
stroke in populations of African ancestry will greatly improve
our broad understanding of the molecular pathways of stroke
and likely add substantially to ongoing efforts to mitigate the
devastating global consequences of stroke.
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 are
potential challenges to translating genomic advances into real-
world clinical applications in Africa. These suggest that caution
should be exercised with regard to the expectations from stroke
genomics research in Africa, while rigorous detection, evaluation,
treatment and control of high blood pressure cannot be over-
emphasised as a pragmatic strategy to curtail stroke in Africa.
The Stroke Investigative Research and Education Network (SIREN) project is
a part of the Human Health and Heredity in Africa (H3Africa) Consortium
and is supported by NIH Grant NIH U54HG007479-01. We thank Dr
Adebowale Adeyemo for reading through the manuscript and making useful
suggestions.
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Table 4. Unique features of SIREN meeting the standard criteria for
stroke genomics studies
Criteria for Stroke
Genomics Studies81 How met in SIREN – SIBS Genomics
Venice ‘ A’ rating
for sample size
large sample size > 3000 case – control pairs
Phenomic
characterization
Rigorous phenotypic assessment in patients and in controls
Detailed investigations (min of CT) and accurate
classification using OCSP, TOAST, ASCO, CCS. Data
verification and Quality control System
Control for
confounders
Measurement and documentation of conventional vascular
risk factors to be controlled for in the analysis
External validation External Validation in REGARDS cohort (12,500)
Others Low genotyping error rate (Hardy-Weinberg Equilibrium
will be stated in cases and controls) Genomic controls, and
other methods to account for population stratification, low
P value (corrected for multiple testing)