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: SH2B1 rs7498665 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 SH2B1 rs7498665 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.

Circulating SH2B1 is associated with an increased risk of gastric cancer.

Gastric cancer (GC) is one of the most common types of cancer in humans and the second leading cause of cancer-associated mortality worldwide. Identifying novel risk factors will facilitate the development of therapeutic strategies to prevent and treat GC. Increased expression of the Src homology 2 B adaptor protein 1 (SH2B1) may stimulate the malignant progression of lung cancer, esophageal cancer and neuroblastoma. However, its function in GC has not yet been investigated. To identify whether increased serum SH2B1 is a risk factor for GC, the present study performed a nested case-control study of patients within the Chinese cohort study. Levels of serum SH2B1 were measured in 563 patients diagnosed with GC during the follow-up period and in 1,126 matched healthy controls. The results demonstrated that high levels of serum SH2B1 were associated with an increased GC risk (odds ratio, 3.23; 95% confidence interval, 2.45-5.65). When analyses were stratified further by sex, age and smoking, an association between increased levels of SH2B1 and GC was identified in males but not in females. Furthermore, the association between SH2B1 levels and GC was more evident in younger than in older participants, and statistically significant in current smokers but not in nonsmokers. These results were not altered following the exclusion of outliers. Furthermore, it was demonstrated that overexpression of SH2B1 contributes to the malignant transformation of normal gastric epithelial cells. Thus, the present study demonstrated that elevated serum SH2B1 levels may increase the risk of GC.