Few genetic polymorphisms in the innate proteins that participate in the immune responses have been implicated in RF and RHD vulnerability . Unfortunately, studies on the significance of ficolins in RF and RHD are insufficient, despite their obvious contribution in the activation of the innate immune response through complements and in autoimmunity . Few previous studies on FCN1 and FCN2 genes have determined that some polymorphisms of both genes could give a protective role against RF, by empowering bacterial elimination in addition to activation of the expression of these genes leading to an increase in the production of their proteins [20-22].
Up till now, the role of FCN3 gene polymorphisms in RF and RHD pathogenesis remains unknown. As far as we could possibly know, this is the first study to investigate FCN3 gene polymorphisms (rs4494157 and rs10794501) together with their related genotypes and levels of serum ficolin-3 in patients suffering from RF and RHD.
In the current study, the significant higher serum level of ficolin-3 in RF patients with and without RHD than the control subjects reflects its role in complements initiation and subsequent pathogenesis of RF and RHD. There have been no reports concerning the relationship between ﬁcolin-3 and RF but several ﬁndings are indicating that high levels of ﬁcolin-3 may contribute to the induction of inflammation as in diabetic retinopathy , leprosy , ovarian cancer , acute leukemia  and associated with post-operative graft loss in kidney transplantation .
Interestingly, lectin pathway activators, including mannose-binding lectin (MBL), both ficolin-1 and ficolin-2 were appeared to bind to Streptococcus pyogenes leading to MBL associated serine proteases activation . Although, no direct binding of ficolin-3 on Streptococcus pyogenes was found, it is known that the Streptococcus pyogenes cell wall contains long polymers of ficolins target; GlcNAc  and hence could be a potential ligand for ficolin-3. Therefore, our findings open a new window to study the potential interaction between ficolin-3 and Streptococcus pyogenes.
Ficolins are group of proteins with different pattern in tissue expression as well as their immunological roles. The reason beyond the decline in ficolin-1 and ficolin-2 levels in RF patients like what was found in other studies [20-22] may be a result of their consumption on the surface of GAS, in addition to the possibility of transcriptional mutations in their genes that may affect their levels.
As the most abundant ficolins in plasma , ficolin-3 level was more elevated even after being utilized in immune reactions against GAS, besides the possible effect of our studied SNPs on its expression. In addition to, the compensatory mechanisms of up-regulation of this protein that resulted from its interaction with GlcNAc as well as complement activation.
Given the (rs4494157), we observed that higher ficolin-3 levels were also associated with certain genotypes of FCN3 that contain the A allele in intron 7. Interestingly, intron 7 contains CpG islands and enriched for typical modifications of histone that are known to characterize active enhancers [36, 37].
The most important result in this study was related to the FCN3 A allele (rs4494157). Our finding suggests that this allele may be a risk factor for the progression of RF to its chronic consequences. Thus, FCN3 A allele carrying patients may be at high risk for recurrent infection, and a higher likelihood to develop RHD. Consequently, early identification, careful monitoring should be given for those patients. Furthermore, clinicians must confirm adherence of those patients to secondary prophylaxis intervention . In fact, secondary prophylaxis adherence of RF patients is typically poor, especially in young people which was perceived as the principal explanation for RF repeats and RHD advancement [38, 39].
What is more, the presence of the C allele in controls in a higher significant pattern than RF patients could show that the presence of the C allele may pose a defensive action against the occurrence of RF and RHD. Moreover, these data propose that the cardiac manifestations development of RF is related to high ficolin-3 levels and its linked genotypes, also, this relationship is a direct result of a certain mechanism related to FCN3 gene polymorphism but not secondary to the acute phase of GAS infection. This mechanism may involve the recognition of structures on damaged/altered cardiac cells by ficolin-3 that mediates complement activation and increases tissue injury, which may become permanent in the cardiac valves.