Gene-Environment Interactions Significantly Alter the Obesity Risk of SH2B1 rs7498665 Carriers

Background: Src homology 2 B adaptor protein 1 (SH2B1) gene and variants have been found to be associated with common obesity. We aimed to investigate the association between the common missense variant SH2B1 rs7498665 and common obesity risk as well as interactions with lifestyle variables in an Israeli population. Methods: An adult cohort (n= 3,070; ≥18 years) with the SH2B1 rs7498665 variant and lifestyle, behavior (online questionnaire), and blood glucose data was analyzed. Associations between this variant, obesity risk (body mass index [BMI] ≥25 and ≥30 kg/m²), and interactions with behavioral and lifestyle factors (stress levels, eating habits score [EHS], physical activity [PA], and wine consumption) were investigated. Association and gene-environment interactions were analyzed using binary logistic regressions with interaction. Results: SH2B1rs7498665 carriers were significantly (P<0.05) more likely to be overweight (BMI ≥25 kg/m²) or obese (BMI ≥30 kg/m²) in recessive (odds ratio [OR], 1.90 and 1.36, respectively), additive (OR, 1.24 and 1.14, respectively), and codominant (OR, 2.00 and 1.41, respectively) genetic models. SH2B1 rs7498665 interacted with lifestyle and behavioral factors as well as glucose levels. PA and moderate wine consumption (1 to 3 drinks/ week) reduced obesity risk (OR, 0.35 and 0.71, respectively). Conversely, carriers of two risk alleles who reported high stress levels, had ≥median EHS, and who had a fasting glucose level ≥90 mg/dL had a significantly increased obesity risk (OR, 3.63 and 5.82, respectively). Conclusion: Carrying SH2B1rs7498665 significantly elevates the risk of obesity. Actionable lifestyle and behavioral factors significantly modulate the rs7498665 genetic predisposition to obesity; PA and moderate wine consumption attenuate the risk, while high stress, EHS, and fasting glucose level increase the obesity risk.