AUTHOR=Tessier François , Fontaine-Bisson Bénédicte , Lefebvre Jean-François , El-Sohemy Ahmed , Roy-Gagnon Marie-Hélène 

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

JOURNAL=Frontiers in Genetics

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00151

DOI=10.3389/fgene.2019.00151

ISSN=1664-8021

ABSTRACT=<p><bold>Introduction:</bold> Animal studies suggested that <italic>NFKB1</italic>, <italic>IKBKB</italic>, and <italic>SOCS3</italic> 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.</p><p><bold>Methods:</bold> 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 (<italic>n</italic> = 1639) using dichotomized body mass index (BMI) and waist circumference as obesity-related phenotypes. Exposure variables included genotype on 54 single nucleotide polymorphisms (<italic>NFKB1</italic>: 18, <italic>IKBKB</italic>: 9, <italic>SOCS3</italic>: 27), macronutrient (carbohydrates, protein, fat) and alcohol intakes and ethno-cultural background.</p><p><bold>Results:</bold> After correction for multiple testing, no interaction was found using logistic regression. MDR identified interactions between SOCS3 rs6501199 and rs4969172, and <italic>IKBKB</italic> rs3747811 affecting BMI in the Caucasian population; SOCS3 rs6501199 and <italic>NFKB1</italic> 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.</p><p><bold>Conclusion:</bold> 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.</p>