RHD and rheumatic fever: However the fact that there was very little association between individual two-component IGRs and ARF/RHD underscores the complexity of GAS disease, and indicates that while transcription regulatory networks of GAS and the virulence genes they control contribute to ARF/RHD pathogenesis, the presence and/or absence of individual genes or genetic markers are not sufficient to predict the disease causing potential of individual GAS isolates.