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Animal studies suggested that  NFKB1 ,  IKBKB , and  SOCS3  genes could be involved in the association between overnutrition and obesity. This study aims to investigate interactions involving these genes and macronutrient intakes affecting obesity-related phenotypes.   Methods:  We used a traditional statistical method, logistic regression, and compared it to alternative statistical method, multifactor dimensionality reduction (MDR) and penalized logistic regression (PLR), to better detect genes/environment interactions in the Toronto Nutrigenomics and Health Study ( n  = 1639) using dichotomized body mass index (BMI) and waist circumference as obesity-related phenotypes. Exposure variables included genotype on 54 single nucleotide polymorphisms ( NFKB1 : 18,  IKBKB : 9,  SOCS3 : 27), macronutrient (carbohydrates, protein, fat) and alcohol intakes and ethno-cultural background.   Results:  After correction for multiple testing, no interaction was found using logistic regression. MDR identified interactions between SOCS3 rs6501199 and rs4969172, and  IKBKB  rs3747811 affecting BMI in the Caucasian population; SOCS3 rs6501199 and  NFKB1  rs1609798 affecting WC in the Caucasian population; and SOCS3 rs4436839 and IKBKB rs3747811 affecting WC in the South Asian population. PLR found a main effect of SOCS3 rs12944581 on BMI among the South Asian population.   Conclusion:  While MDR and PLR had discordant results, some models support results from previous studies. These results emphasize the need to use alternative statistical methods to investigate high-order interactions and suggest that variants in the nutrient-responsive hypothalamic IKKB/NF-kB signaling pathway may be involved in obesity pathogenesis.

Investigating Gene–Gene and Gene–Environment Interactions in the Association Between Overnutrition and Obesity-Related Phenotypes