Using an MDR approach, our study suggests a three-way gene-gene interaction between inflammatory gene IL4Ra, obesity-related gene INSIG2, and antioxidative gene GSTP1. The three-way gene-gene interaction between IL4Ra, INSIG2, and GSTP1 was not only identified in gene-gene analyses but also confirmed in gene-environment analyses in MDR approach. This evidence concerns the gene GSTP1 and obesity due to melanocortin 4 receptor deficiency.