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AFRICA
S43
CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
modifier mutations
GOLGB1
(
Y1212C
) and
ENPP1
(
K173Q
)
associated with protection from stroke in a cohort of children
with sickle cell anaemia.
74
However, the interactions between SCD, its associatedmodifier
genes, and environmental factors to produce an intermediate
phenotype (TCD velocity
>
200 cm/s) and stroke have not
been examined in people of indigenous sub-Saharan Africa.
Knowledge of these interactions and the metabolic pathways
involved may unmask targets for preventative and therapeutic
interventions in the sub-population of people living with SCD.
Cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) is associated
with mutations in the
NOTCH3
gene and presents with migraine
headache, followed by depression and ischaemic stroke in the
deep gray structures and subcortical white matter, cognitive
decline, and dementia.
75,76
A model of small-vessel disease, the
first case of CADASIL in populations of African ancestry,
was recently reported in a 73-year-old African American with
a 15-base-pair heterozygous duplication of the exon 7 of
the
NOTCH 3
gene.
77
Other related monogenic small-vessel
cerebrovascular disorders include cerebral autosomal recessive
arteriopathy with subcortical infarcts and leukoencephalopathy
(CARASIL), retinal vasculopathy with cerebral leukodystrophy
(RVCL), and Fabry disease.
78
Genetic linkage studies
Genetic linkage studies have contributed to our understanding
of the heritability of stroke and especially chromosomal regions
and sub-regions involved, even though most studies have focused
more on the ischaemic phenotype. Table 1 shows findings
from a few linkage studies in stroke,
79-82
including genome-wide
linkage studies. Much of these findings are further confirmed
by more specific candidate gene analysis and the more rigorous
approaches of association studies. A relative strength of linkage
studies is the feasibility of working with a few hundred subjects
using the case–control approach.
Stroke candidate genes
Identification of the phosphodiesterase 4D (
PDE4D
) and
5-lipoxygenase activating protein (
ALOX5AP
) genes through
linkage analysis by the Icelandic Decode group was a significant
landmark in the history of stroke genomics.
1,2,4
The rs918592
SNP variant of
PDE4D
was found to be significantly associated
with stroke in current smokers in an African American cohort,
7
while mutations in the
NOS3
have also been significantly
associated with large-artery stroke in African Americans.
6
Other
variants significantly associated with ischaemic stroke in African
Americans include the
IL6R
polymorphisms and the kappa-
casein gene
CSN3
found on chromosome 4, the latter through
exome sequencing.
3,5
The genetics of intracerebral haemorrhage (ICH) has
also been explored through a range of candidate gene and
GWAS approaches. Genes involved in the renin–angiotensin–
aldosterone system, coagulation pathway, lipid metabolism,
homocysteine metabolism and inflammation are among the
most explored.
83
The
APOE
ε
2 and
APOE
ε
4 genes have been
associated with lobal ICH in Caucasian, Asian and African
American populations with a high prevalence of cerebral
amyloid angiopathy (CAA).
84,85
The association of
APOE
ε
4 genes with deep ICH is rather
inconsistent.
85
It is widely accepted that CAA is a frequent cause
of ICH and the presence of an APOE
ε
4 allele substantially
increases the risk of CAA.
86
Whether the risk of CAA or ICH
is different in Africans is uncertain but it has long been known
that the frequency of the APOE
ε
4 alleles, irrespective of tribal
origin, is highly represented in the general African population.
87
Deep ICH is also more aetiologically related to hypertensive
chronic small-vessel disease and is likely to be more relevant
in African populations where hypertension is the dominant
stroke risk factor. Other genes with significant polymorphisms
related to ICH include the methylenetetrahydrofolatereductase
(
MTHFR
), interleukin-6, tumour necrosis factor-
α
, angiotensin
converting enzyme (ACE), factor VII, factor XIII, platelet
activating factor and
β
-tubulin, although most are described in
populations of non-African ancestry.
83
Stroke GWAS and WES studies
The candidate genes approach has proved disappointing in
identifying genes contributing to the risk of multifactorial or
polygenic stroke. This is a situation shared with other complex
diseases.
88
Recently, the GWAS approach has revolutionised the
field of stroke genetics. GWAS enables markers spanning the
whole genome to be genotyped in a single experiment. Using
a case–control methodology and rigorous statistical methods
to account for the multiple comparisons made, associations
between completely unexpected chromosomal loci and disease
can be identified.
88,89
Table 1. Genetic linkage studies in stroke
First author (year) Study type
Phenotype
Sample
Salient findings
Craig
et al.
(1998)
74
Linkage analysis Cerebral
cavernous
malformation
20 non-Hispanic
Caucasian families
CCM – 1(7q) (found in Hispanic Americans), CCM2 (7p13-15) and
CCM3 at 3q25.2-27 all found in non-Hispanic Caucasian families.
Nilsson-Ardnor
et
al.
(2007)
76
Genome-wide
linkage analysis
All strokes;
ischaemic
stroke
56 Swedish families
with familial stroke
LOD scores > 1.2 at 9 1ocations: 1p34, 5q13, 7q35, 9q22, 9q34, 13q32,
14q32, 18p11, and moderate linkage on chromosomes 5q, 9q, 13q, and
18p.
Additional 53 families
with familial strokes
Analysis of 53 additional families, further confirmed linkage on chromo-
somes 5q, 13q, and 18p.
Janunger
et al.
(2009)
75
Genome-wide
linkage analysis
All strokes
7 nuclear Swedish
families with a common
ancestor and connected
over 8 generations
A maximum allele-sharing LOD score of 4.81 on chromosome 9q31-q33
was detected.
Haplotype analysis identified a region for intracerebral haemorrhage.
Wang
et al.
(2014)
77
Linkage and asso-
ciation analysis
Ischaemic
stroke
227 Chinese families
with ischaemic stroke
SNP rs1800798 in the IL-8 gene is signficantly linked to ischaemic stroke
(
p
=
0.002) and small arterial occlusion (small-vessel disease) (
p
=
0.022).