Supplementary Data Table 1
Findings from studies investigating genes suspected to be associated with genetic susceptibility to
rheumatic fever and rheumatic heart disease (original table)
Country
India [1]
Population
400 RHD patients,
300 healthy
controls
Genes investigated
Signal transducers
and activators of
transcription (STAT)


India [2]
300 RHD patients,
200 healthy
controls
angiotensin Iconverting enzyme
(ACE)
polymorphism


Uganda [3]
96 RHD patients,
103 healthy
controls
MHC Class II Human 
Leucocyte Antigen
(HLA) variants

Turkey [4]
38 children with
ARF,
40 controls
Mannose binding
lectin-2 (MBL2) and
macrophage
migration inhibitory
factor (MMIF)
polymorphisms


Findings
STAT3 G allele and STAT5b T
allele associated with increased
risk of RHD
Haplotype
Grs4796793Trs6503691
significantly associated with
increased risk of RHD
Carriage of deletion (D) allele
associated with increased risk of
RHD
RHD patients with D allele could
be treated with ACE inhibitors
HLA-DR1 allele associated with
decreased risk of RHD
HLA-DR11 allele significantly
associated with RHD
Homozygous variant allele of
codon 54 of MBL2 is a risk factor
for ARF
carriage of the MMIF -173C
allele associated with ARF
References
1.
2.
3.
4.
Gupta U, Mir SS, Srivastava A, et al. Signal transducers and activators of transcription (STATs)
gene polymorphisms related with susceptibility to rheumatic heart disease in north Indian
population. Immunol Lett. 2014;161(1):100-5.
Gupta U, Mishra A, Rathore SS, et al. Association of angiotensin I-converting enzyme gene
insertion/deletion polymorphism with rheumatic heart disease in Indian population and
meta-analysis. Mol Cell Biochem. 2013;382(1-2):75-82.
Okello E, Beaton A, Mondo CK, 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.
Col-Araz N, Pehlivan S, Baspinar O, et al. Association of macrophage migration inhibitory
factor and mannose-binding lectin-2 gene polymorphisms in acute rheumatic fever. Cardiol
Young. 2013;23(4):486-90.
1
Supplementary Data Table 2
Joachim clinical decision rules (adapted from [1])
Criteria
Points
1
2
3
+ number of bacterial
signs
Age
≤35 months
36-59 months
≥ 60 months
Bacterial signs?
Tender cervical node
Headache
Petechia on the palate
Abdominal pain
Sudden onset (<12 hours)
Viral signs
Conjunctivitis
Coryza
Diarrhoea





- number of viral signs
Total score
Bacteriologic diagnosis unavailable
≤2
≥3
Limited bacteriologic diagnosis
available
≤2
3
≥4



Total score
RADT
Treatment
Symptomatic
Antibiotic
No
Yes
No
Symptomatic
Antibiotic with positive RADT
Antibiotic
Reference:
1.
Joachim L, Jr DC, Smeesters PR. Pragmatic scoring system for pharyngitis in low-resource
settings. Pediatr Int. 2010;126(3):e608-14.
Supplementary Data Table 3
Recently identified biomarker candidates for the diagnosis of RHD (original table)
2
Biomarker candidate
Alpha-1-antichymotrypsin[1]
Antibodies against the GAS Group A
Carbohydrate [2]
CD306 and sCD305 [3]
Expected change in RHD patients
Reduced
Elevated in subclinical RHD cases
Collagen metabolism markers and collagen
degrading enzymes[4]
Desmin[5]
Elevated
Heat Shock Protein 60[5]
Elevated
Intercellular adhesion molecule 1 (ICAM-1)
vascular cell adhesion molecule 1 (VCAM-1)
endothelial selectin (E selectin) [6]
Rheumatic carditis with residual lesions >
rheumatic carditis no lesions > healthy
controls
Ischaemia modified albumin [7]
PDZ and LIM domain protein 1[5]
Elevated in ARF (pre-treatment), normal
in RHD
Elevated
Plasma complement C4-A[1]
Protease subunit alpha type-1[5]
Elevated
Elevated
Elevated*
Elevated
Ratio of T helper 17 cells: regulatory T cells [8]
Serotransferrin[1]
Tenascin-C [9]
Elevated
Reduced
Reduced in rheumatic carditis (pretreatment)
Reduced in severe RHD
Elevated in mild and moderate RHD
*also elevated in patients with non-rheumatic immune and inflammatory diseases
References
1.
2.
3.
4.
5.
6.
7.
Gao G, Xuan C, Yang Q, et al. Identification of altered plasma proteins by proteomic study in
valvular heart diseases and the potential clinical significance. PLoS ONE. 2013;8(8):1-9.
Beaton A, Kabat B, Rippe J, et al. Usefulness of anti-streptococcal antibody profiling for
confirmation of latent rheumatic heart disease in asymptomatic Ugandan schoolchildren
diagnosed by echocardiography. Poster session presented at: World Congress of Cardiology;
2014 May 4-7; Melbourne.
Xie X, Wang C, Xie Y, et al. Development and evaluation of a sandwich ELISA method for the
detection of human CD306. J Immunol Methods. 2013;396(1-2):65-73.
Banerjee T, Mukherjee S, Ghosh S, et al. Clinical significance of markers of collagen
metabolism in rheumatic mitral valve disease. PLoS ONE. 2014;9(3):1-12.
Zheng DW, Xu LM, Sun LB, et al. Comparison of the ventricle muscle proteome between
patients with rheumatic heart disease and controls with mitral valve prolapse: HSP 60 may
be a specific protein in RHD. Biomed Research International. 2014:9.
Hafez M, Yahia S, Eldars W, et al. Prediction of residual valvular lesions in rheumatic heart
disease: role of adhesion molecules. Pediatr Cardiol. 2013;34(3):583-90.
Karatas Z, Baysal T, Sap F, et al. Increased ischaemia-modified albumin is associated with
inflammation in acute rheumatic fever. Cardiol Young. 2014;24(3):430-6.
3
8.
9.
Bas HD, Baser K, Yavuz E, et al. A shift in the balance of regulatory T and T helper 17 cells in
rheumatic heart disease. J Investig Med. 2014;62(1):78-83.
Karatas Z, Baysal T, Alp H, et al. Serum tenascin-C: A novel biomarker for diagnosis and
predicting prognosis of rheumatic carditis? J Trop Pediatr. 2013;59(6):476-82.
4