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

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S52 AFRICA
CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
performance of Cameroonian SCD children was evaluated using
a neuropsychological test battery assessing four domains of
cognitive functioning (executive function, attention, memory
and sensory-motor skills). A high prevalence of cognitive deficits
was found, increasing with age, and with a specific impairment
of executive functions and attention.31 Up to 37.5% of the 96
SCD patients aged six to 24 years (M = 13.5, SD = 4.9) had mild-
to-severe cognitive deficits, which tended to increase with age.
Structural equation models showed a significant association
between (1) severe anaemia and lower executive functioning, (2)
low foetal haemoglobin levels and lower executive functioning
and attention, (3) history of cerebrovascular accidents and lower
performances on executive functioning, sensory-motor and
memory tasks, (4) pathological electroencephalogram and lower
attention span, and (5) abnormal transcranial Doppler and
lower memory function.31
The feasibility of using transcranial Doppler (TCD)
ultrasonography in Africa to determine risk of stroke in children
with SCD has been demonstrated in studies in Tanzania,24
Cameroon,31 Nigeria32 and Kenya.33 However, because of limited
resources and inefficient transfusion services, TCD is seldom
established as part of routine healthcare followed by transfusion
therapy to prevent overt stroke in those found to have abnormal
blood flow velocity.33
Pulmonary arterial hypertension (PAH) is common, with a
prevalence of 30% in SCD patients, and all-cause mortality rates
of 40% at 40 months after diagnosis in the USA.34 Studies in
Nigeria indicate PAH could represent a significant complication
of SCD on the African continent.35
N-terminal (NT) pro-brain natriuretic peptide (proBNP)
≥ 160 ng/l has a 78% positive predictive value for pulmonary
hypertension. NT-proBNP elevation is common and is associated
with markers of anaemia, inflammation and iron status and with
severe functional impairment among sickle cell anaemia patients
in Nigeria.36
The prevalence of elevated tricuspid regurgitant velocity
(TRV) measured by echocardiogram, which predicts risk for
pulmonary hypertension and death in adult sickle cell anaemia,
was similar among SCD patients in Tanzania and those from
the USA.37 In addition, there is accumulating clinical evidence to
suspect a high prevalence of kidney disease among African SCD
patients in France,38 Nigeria,39,40 Ghana41 and the Congo.42 The
data revealed and emphasised the need to draft a specific research
agenda to include Africa in future comprehensive studies on the
epidemiology and genetics of end-organ complications of SCD.
Addressing the genomics of cardiovascular diseases
in SCD in Africa
Despite the evidence of a high burden of cardiovascular events
in SCD patients, the magnitude of this problem in Africa has not
been defined. The clinical variability and environmental factors
influencing these events have not been clearly and systematically
studied, despite the availability of some encouraging data on
the genetics of these cardiovascular phenotypes of SCD among
African populations from the diaspora (Table 2). Previous
studies of sibling pairs have demonstrated a genetic component
to the development of cerebrovascular disease in SCD stroke.43
In addition, a child with SCD had an increased risk for stroke if
they had siblings who had experienced an overt stroke.44
A few genetic modifiers have confirmed the association with
stroke, such as α-thalassaemia trait being protective against
stroke20 (Table 1), but these do not explain the entire genetic
contribution to stroke risk. In addition, several retrospective
studies, mostly among African Americans, have identified
specific SNPs associated with stroke in patients with SCD, using
candidate gene approaches, but failed to be replicated using
independent validation cohorts.45
Recent data that used genetic mapping and exome sequencing
revealed that one mutation in GOLGB1 (Y1212C) and another
mutation in ENPP1 (K173Q) were confirmed as having
significant associations with a decreased risk for stroke among
African Americans with SCD25 (Table 1). These studies need to
be validated and extended in SCD patients in Africa.
Like stroke, renal failure occurs in 5–18% of SCD patients
and is associated with early mortality. 46 At-risk SCD patients
cannot be identified prior to the appearance of proteinuria. The
myosin, heavy-chain 9, non-muscle (MYH9) and apolipoprotein
L1 (APOL1) genes have been associated with risk for focal
segmental glomerulosclerosis and end-stage renal disease in
African Americans. 47
Seven SNPs in MYH9 and one in APOL1 were significantly
associated with proteinuria among African American SCD
patients. In addition, glomerular filtration rate was negatively
correlated with proteinuria ( p < 0.0001), and was significantly
predicted by an interaction between MYH9 and APOL148 (Table
2). Further studies with independent data sets from sub-Saharan
Africa are now needed to confirm this association, to identify
more of the genes involved, and the interaction with various
African environments, in order to address preventative measures
of SCD nephropathy.
Moreover, an increased tricuspid regurgitation jet velocity
(TRV > 2.5 m/s) and pulmonary hypertension defined by right
heart catheterisation both independently conferred increased
mortality in SCD.34 A preliminary genetic association study
comparing patients with an elevated ( n = 49) versus normal (n =
63) TRV revealed significant association with five SNPs within
GALNT13 (p < 0.005), and a quantitative trait locus upstream of
the adenosine-A2B receptor gene (ADORA2B)49 (Table 2).
Limited genetic studies associated with these critical
cardiovascular phenotypes in SCD (stroke, pulmonary
hypertension, kidney disease) have not been reported in SCD
patients who reside in Africa. This indicates an urgent need
to perform these studies, which could inform the global SCD
communities in a unique way, on the value of gene and
environmental interactions in the pathogenesis and hopefully the
care of SCD.
Table 2. Selected genes associated with cardiovascular
phenotypes among African American SCD patients
Cardiovascular
phenotypes in SCD Associated genes References
Stroke HBA (3.7 alpha-
globin gene deletion)
Hsu et al .
2003; 25(8): 622–628
GOLGB1 (Y1212C) Flanagan et al. 2013;
121(16): 3237–3245
ENPP1 (K173Q)
Kidney disease
(proteinuria)
MYH9
APOL1
Ashley-Koch et al.
2011; 155(3): 386–394
Pulmonary
hypertension
GALNT13 Desai et al.
2012; 186 (4): 359–368
ADORA2B