In this study, we investigated gene–gene and gene–environment interactions in the association between variants of three genes (NFKB1, IKBKB, SOCS3), macronutrient and alcohol intakes, and obesity-related phenotypes (BMI, alternative BMI cut-offs for East and South Asians, and waist circumference). This evidence concerns the gene SOCS3 and obesity due to melanocortin 4 receptor deficiency.