| Summary: | The transmembrane protein 18 (<i>TMEM18</i>) gene plays a central and peripheral role in weight regulation. <i>TMEM18</i> genetic polymorphisms have been identified as an important risk factor for obesity, depending on ethnic population and age. This research aimed to study the association of common <i>TMEM18</i> polymorphisms with obesity and their interactions with modifiable factors, namely drinking habits (sugar-sweetened beverages (SSBs), flavored water and wine) and physical activity (PA) in the Israeli population. Adults (n = 3089) were analyzed for common <i>TMEM18</i> polymorphisms and lifestyle and nutrition habits were obtained from questionnaires using adjusted (age, sex) binary logistic regression models. <i>TMEM18</i> rs939583 and rs1879523 were significantly associated with increased obesity risk (OR = 1.35, 95% CI (1.17–1.57) and OR = 1.66, 95% CI (1.29–2.15), respectively). <i>TMEM18</i> rs939583 interacted with consumption of 1–3 weekly glasses of wine and PA to attenuate obesity risk (OR = 0.82 95% CI (0.74–0.9; <i>p</i> < 0.001) and OR = 0.74 95% CI (0.68–0.8), respectively), while physical inactivity, SSBs and flavored water consumption significantly enhanced obesity risk (OR = 1.54 95% CI (1.41–1.67), OR = 1.31 95% CI (1.14–1.51) and OR = 1.35 95% CI (1.13–1.62), respectively). PA duration was significantly associated with a lower BMI for rs939583 risk carriers, with a PA cutoff of >30 min/week (<i>p</i> = 0.005) and >90 min/week (<i>p</i> = 0.01). Common <i>TMEM18</i> SNPs were significantly linked with adult obesity risk and interacted with modifiable lifestyle factors.
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