ABSTRACT
Aim: The filariasis infection is initiated by mosquito derived third stage larva (L3), which establishes itself in different immunocompetent niches by adopting different evasion and immunomodulatory mechanisms. Immunological and clinical outcomes can vary considerably at the individual and population levels during lymphatic filariasis infection. The protein product coded by the interleukin-10 (IL-10) gene has broad immunomodulatory function in filarial load and patency of the disease. The potential influence of altered IL-10 expression encoded by IL-10 promoter single nucleotide polymorphisms (SNPs) and IL-10RA signaling pathway, in pathogenesis and clinical outcome of filarial infection was established in the present study Study Design: Genetic association based on case-control study. Place and Duration of Study: Lymphatic filariasis cases referred to National Filariasis Control Program (NFCP), Siddipet, Medak, Andhra Pradesh, India between Feb 2006 to Dec 2009. Methodology: A total of 100 non-endemic, 50 endemic and 118 lymphatic filariasis patients were included in the present study based on clinical and diagnostic criteria. Genetic polymorphisms in the IL-10 promoter region (-1082G/A, -819C/T and -592 A/C) and IL-10 RA coding region S138G were screened following PCR-RFLP and ARMS-PCR technique respectively. Results: Patients with familial aggregation of lymphedema exhibited significant association with IL-10 -1082 ‘A’ allele (A vs G OR 2.68, CI - 1.12-6.37, P=0.02) coding for lower IL-10 levels. Similarly the G variant of IL-10RA S138G SNP revealed a significant association with lymphatic filariasis in the endemic population studied (GG vs AA OR 2.50 CI-1.22-5.13, P= 0.021). The Haplotype analysis also revealed the low signaling ATA is significantly associated with the disease in this cohort (P=0.03). The Multifactor Dimensionality Reduction Analysis (MDR) for IL-10 and IL-10RA SNPs interaction revealed the three locus model as the best model wherein the epistatic interactions of variant G allele of IL-10RA S138G, the A allele of the -1082G/A and the T allele of the -819C/T SNPs in IL-10 were found to be a possible risk genotype for filarial infection. (TA = 0.5230, CV-10/10, P=0.001). Conclusion: IL-10 promoter haplotypes and IL-10 RA S138G polymorphisms are the possible genetic determinants of susceptibility to lymphatic filariasis. Further functional studies are warranted to validate these results.