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CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
reported association in two loci: 2p14 –p13.1 and 7p21.3 –p15.3,
the second locus being attributed to the Nigerian sample and
suggesting a unique locus for blood pressure variation in people
of African ancestry.
53
In the GenHAT study evaluating the pharmacogenetic effects
of candidate gene complexes on stroke, significant genetic
difference was found between hypertension drug treatment
groups in patients who had experienced stroke, especially among
African Americans and non-Hispanic whites.
54
Given the fact
that hypertension is the most dominant risk factor for stroke
among people of African ancestry in Africa,
15,24,27,28
and the
diaspora,
30,50
it would be worthwhile exploring the possible
contribution of these hypertension-related genotypes in people
of African ancestry.
A Nigerian study assessed glucose and insulin responses to an
oral glucose load among offspring of parents with type 2 diabetes
mellitus (T2DM) and found higher levels of fasting plasma
glucose, fasting plasma insulin, and two-hour post-glucose load
plasma insulin, indicating a higher risk for developing diabetes.
55
A Cameroonian case–control pedigree study showed increased
prevalence of diabetes and impaired glucose tolerance in the
offspring of parents with T2DM.
56
The Africa America Diabetes Mellitus (AADM) study has
utilised genome-wide linkage and association studies to provide
insight into the genomics of T2DM in Niger-Kordofanian
African populations of Nigeria and Ghana. Multiple linkage
analysis provided evidence of regions of chromosome 12,
19 and 20 (the strongest being 20q13.3).
57
The loci found to
influence C-peptide plasma levels (10q23, 4p15) were found
to harbour multiple T2DM candidate genes [phosphatase and
tensin homolog (PTEN), protein phosphatase 1, regulatory
subunit 3C (PPP1R3C), insulin degrading enzyme (IDE), and
peroxisome proliferator activated receptor gamma, coactivator
1 alpha (PPARGC1)].
58
Collaborative GWAS and other studies
have identified further susceptibility (CDKAL1, CAPN10,
TCF7L2 variants and PPARG variants) and protective loci
(TCF2, AGRP -38C/T).
57
Chronic kidney disease (CKD) is an identified risk factor for
cerebral vascular disease.
59
Multiple common SNPs in the gene
that encodes non-muscle myosin heavy-chain type II isoform A
(MYH9) have been associated with an increase in the risk of
focal segmental glomerulosclerosis and end-stage renal disease,
60
while more recently the apolipoprotein L1 (
APOL1
) gene has
been identified as a risk locus for CKD in African Americans,
and replications confirmed in Nigerian Yoruba CKD patients.
61,62
In Africa,
APOL1
confers resistance to infection from
Trypanosoma brucei brucei
, one of the trypanosomes that cause
African sleeping sickness and it is believed that its evolutionary
history lies in its positive selection due to its protection against
sleeping sickness.
63
Interestingly, an inverse relationship between
high-density lipoprotein cholesterol (HDL-C) and kidney
function in African ancestry populations has also been described
in individuals with the nephropathy risk
APOL1
gene.
64
Higher
HDL-C was associated with worse kidney function in those with
the risk genotype, while no association was observed among
those without the genotype. Therefore, the increasing incidence of
cardiovascular disorders (CVDs) in Africa along with the evidence
of genetic variants that increase susceptibility to CVDs signals
the need for large-scale genomic epidemiology studies in Africa in
search of other putative protective and susceptibility loci.
12
Population-attributable risks of genetic variants differ
depending on whether they are monogenic, common variants
or rare variants of multiple genes of polygenic disorders.
2,3
More
important, however, is the functional significance of the variants
in the biological pathways where their gene products contribute
to the biology of the disease and may possibly be of therapeutic
or preventative importance.
65
This is the major thrust of our
proposed study of genetic variants relevant to stroke in people of
African ancestry. African representation in the 1 000 Genomes
study is limited,
41
while the H3Africa projects
11
offer robust
opportunities for detailed exploration of genomic data relevant
to African and global populations.
Intermediate phenotypes: WMH and CIMT
Both twin and family studies have shown that magnetic resonance
imaging of white matter hyperintensities has shown a heritability
(proportion of variation explained by genetic factors) of up to
70%.
66
CIMT measured by ultrasound and believed to represent
the early stages of atherosclerosis and related to large-artery
stroke has been estimated to have a heritability of between 30
and 70%.
67
Monogenic stroke disorders
Monogenic disorders may cause stroke as part of multi-systemic
manifestations or solely as a clinical phenotype limited to the
central nervous system. They are important for individual
patients but may not account for much population-attributable
risk.
46
Sickle cell disease (SCD) is of particular importance in
people of African ancestry. It is caused by a point mutation
at codon 6 of the beta-globin gene, leading to a glutamic acid
to valine (Glu
→
Val) substitution in the beta-globin chain of
human adult haemoglobin, and producing sickle haemoglobin
(HbS). Inherited autosomal recessively, either two copies of
HbS or one copy of HbS plus another beta-globin variant (such
as HbC) are required for disease expression. HbS carriers are
protected from malaria infection, and this selective pressure is
believed to have led to the high frequency of HbS (up to 40%)
in individuals of African ancestry, especially in areas of high
malaria endemicity.
68,69
The spread of SCD to the Americas is inextricably linked to
slavery and the large-scale forced translocation of populations
fromWest Africa.
70
Large- or small-vessel cerebral ‘vasculopathy’
characterised by proximal intracranial arterial stenoses, often
leading to a moyamoya pattern, commonly complicates SCD
and may manifest as abnormal transcranial Doppler velocity (
>
200 cm/s) or frank stroke, particularly in younger patients with
sickle cell anaemia, while complicated (hemiplegic) migraine
was previously reported in Nigerian adults with sickle cell trait
(HbAS).
71
By middle age, up to 25% of SCD patients develop
overt stroke.
72
Certain genetic polymorphisms may be associated with stroke
in SCD as modifier genes. For instance whereas
α
-thalassaemia
genes may be protective, mutations in the glucose-6-phosphate
dehydrogenase (G6PD) genes and certain SNPs, including
ANXA2
,
rs11853426
,
TEK rs489347
, and
TGFBR3 rs284875
variants, have been associated with increased stroke risk.
73
A
recent whole-exome sequencing (WES) study identified two