Multifactor dimensionality reduction and classification and regression tree approaches were combined with logistic regression to discover high-order gene-gene interactions in studiedgenes involved in RHD susceptibility.In univariate logistic regression analysis, we found significant association of variant-containing genotypes (CT&TT) of TGF-β1 869T/C [rs1982073]; [p=0.0.004 & 0.001, OR (95% CI)=1.65 (1.2-2.3) & 2.25 (1.4-3.6) respectively], variant genotype (CC) of IL-1β -511C/T [rs2853550]; [p=0.001, OR (95% CI)=2.33 (1.4-3.8)] and IL-1 VNTR [rs2234663]; [p=0.03, OR (95% CI)=5.25 (1.2-23.4)] SNPs with RHD risk.