26 / 64
S24
AFRICA
CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
about a single ‘rheumatic’HLAallele, and there are likelymultiple
HLA alleles that, in combination, increase an individual’s
susceptibility to ARF and RHD.
2
HLA-D8/17 and HLA-DR7 types are the most represented in
the literature, but many other HLA alleles have been identified
in single studies of patients with ARF and RHD (Table 1),
a variability that could be caused by genetic differences in
the populations studied or differences in local streptococcal
strains. A study in Uganda comparing the frequency of HLA
class II DR alleles between RHD cases and healthy controls
found HLA-DR1 to be more common in normal controls while
HLA-DR11 was more common among RHD cases.
1
Candidate
HLA gene studies that have been performed to date had small
sample sizes and found inconsistent and conflicting results.
36,40
High-resolution HLA analysis and genome-wide association
studies have therefore been recommended.
Single-nucleotide polymorphisms in a number of genes were
found in patients with RHD compared to controls, namely
protein tyrosine phosphatase non-receptor 22 (PTPN22),
41
signal
transducers and activators of transcription (STAT),
42
angiotensin
converting enzyme (ACE I/D),
43
TNF-
α
,
44,45
transforming growth
factor (TGF-
β
1),
46,47
and TLR5
48
(Table 2). Studies in North
Indians with RHD suggest that the (PTPN22) haplotype,
which encodes an important negative regulator of T-cell
activation, modulates the risk of developing RHD.
41
In a Turkish
population, however, it was demonstrated that the PTPN22
R620W polymorphism was not associated with RHD,
49
showing
that genetic differences exist among populations from different
regions of the world, therefore making it relevant to implement
similar studies in Africa.
Overall, the current knowledge of genetic susceptibility for
RHD comes from small studies (Table 2). Moreover, because
subclinical disease is frequent in Africa and RHD is diagnosed
in the late stages, it is related to high morbidity rates, premature
mortality and excessive social and economic costs. The finding
of genetic biomarkers could direct the scarce resources available
on the continent to those persons at higher risk, thus reducing
the workload of health professionals, avoiding the high burden
related to this condition, and improving outcomes.
The Global Registry of RHD
30
represents a platform for
such genetic studies on RHD in Africa. These studies will
improve our understanding of genomic and epigenetic drivers
of heterogeneity in the response of different individuals to GAS
infections, and explore the determinants and drivers of the
variability in natural history, clinical phenotype, prognosis, and
the role of genetic differences in determining allergy and drug
resistance to penicillin in sub-Saharan Africa. The discovery of
genetic susceptibility loci through whole-genome scanning may
be clinically useful by introducing genetic risk-prediction tools
for ARF and RHD.
Conclusion
Research to determine the role of genetic factors in determining
susceptibility to ARF and RHD in African populations is
needed. These genetic studies in the African context may
contribute to a greater understanding of the genomic and
epigenetic drivers of heterogeneity in individual responses to
GAS infections and progression to RHD. Discovery of genetic
susceptibility loci through whole-genome scanning may provide
a clinically useful genetic risk-prediction tool that will potentially
allow echocardiographic screening and secondary prophylaxis to
be directed to those at higher risk, thus reducing the burden of
the disease on the health system, the work health force and the
communities of this resource-strained continent.
References
1.
Okello E, Beaton A, Mondo CK, Kruszka P, Kiwanuka N, Odoi-
Adome R,
et al
. Rheumatic heart disease in Uganda: the association
between MHC class II HLA DR alleles and disease: a case control study.
BMC Cardiovasc Disord
2014;
14
: 28. doi: 10.1186/1471-2261-14-28
2.
Seckeler MD, Hoke TR. The worldwide epidemiology of acute rheu-
matic fever and rheumatic heart disease.
Clin Epidemiol
2011;
3
: 67–84.
doi:
10.2147/CLEP.S12977.
3.
Rothenbühler M, O’Sullivan CJ, Stortecky S, Stefanini GG, Spitzer E,
Estill J,
et al
. Active surveillance for rheumatic heart disease in endemic
regions: a systematic review and meta-analysis of prevalence among
children and adolescents.
Lancet Glob Health
2014;
2
(12): e717–726. doi:
10.1016/S2214-109X(14)70310-9.
4.
Shulman ST, Stollermwan R, Beall B, Dale JB, Tanz RR. Temporal
changes in streptococcal M protein types and the near-disappearance
of acute rheumatic fever in the United States.
Clin Infect Dis
2006;
42
:
441–447.
5.
Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM; World Heart
Federation. Position statement of the World Heart Federation on the
prevention and control of rheumatic heart disease.
Nat Rev Cardiol
2013;
10
(5): 284–292. doi:
10.1038/nrcardio.2013.34.
6.
Maganti K, Rigolin VH, Sarano ME, Bonow RO. Valvular heart
disease: diagnosis and management.
Mayo Clinic Proc
2010;
85
(5):
483–500. doi:
10.4065/mcp.2009.0706.
7.
WHO Regional Committee for Africa. Cardiovascular diseases in
Table 2. Genes found in ARF/RHD studies.
The country and number of participants are indicated.
Author, year Country Sample size
Genes
Gupta
et al
.
2014
41-43
India 400 RHD patients
300 controls
PTPN22 polymorphisms
JAK/STAT polymorphisms
300 RHD patients
200 controls
ACE I/D polymorphisms
Aksoy
et al
.
2011
49
Turkey 120 RHD
160 controls
PTPN22 R620W gene poly-
morphism
Mahomed
et al.
2010
44
Saudi
Arabia
80 RHD patients
50 controls
TNF-
α
polymorphisms
Kamal
et al
.
2010
47
Egypt 73 RHD patients
55 controls
TGF-
β
1 polymorphisms
Key messages
•
ARF, the precursor of RHD, is usually underdiagnosed
•
RHD is highly prevalent in Africa, where it affects much
younger people
•
ARF and RHD are caused by a combination of immune,
environmental and genetic factors
•
The magnitude of the genetic effect remains unclear but
high heritability has been shown
•
Africa has the most virulent and rapidly progressive
forms of ARF and RHD
•
Genetic studies may help to explore determinants of vari-
ability in the natural history and phenotype.