| Summary: | The fat mass and obesity-associated (<i>FTO</i>) gene is a significant genetic contributor to polygenic obesity. We investigated whether physical activity (PA) modulates the effect of <i>FTO</i> rs3751812 on body mass index (BMI) among Taiwanese adults. Analytic samples included 10,853 Taiwan biobank participants. Association of the single-nucleotide polymorphism (SNP) with BMI was assessed using linear regression models. Physical activity was defined as any kind of exercise lasting 30 min each session, at least three times a week. Participants with heterozygous (TG) and homozygous (TT) genotypes had higher BMI compared to those with wild-type (GG) genotypes. The β value was 0.381(<i>p</i> < 0.0001) for TG individuals and 0.684 (<i>p</i> = 0.0204) for TT individuals. There was a significant dose-response effect among carriers of different risk alleles (<i>p</i> trend <0.0001). Active individuals had lower BMI than their inactive counterparts (β = −0.389, <i>p</i> < 0.0001). Among the active individuals, significant associations were found only with the TG genotype (β = 0.360, <i>p</i> = 0.0032). Inactive individuals with TG and TT genotypes had increased levels of BMI compared to those with GG genotypes: Their β values were 0.381 (<i>p</i> = 0.0021) and 0.950 (<i>p</i> = 0.0188), respectively. There was an interaction between the three genotypes, physical inactivity, and BMI (<i>p</i> trend  = 0.0002). Our data indicated that increased BMI owing to genetic susceptibility by <i>FTO</i> rs3751812 may be reduced by physical activity.
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