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Physical activity (PA) has been shown to reduce the impact of  FTO  variation and obesity genetic risk scores (GRS) on BMI. We examined this interaction using a quantitative measure of PA and two adiposity indexes in a longitudinal multi-ethnic study. We analyzed the impact of PA on the association between 14 obesity predisposing variants (analyzed independently and as a GRS) and baseline/follow-up obesity measures in the multi-ethnic prospective cohort EpiDREAM (17423 participants from six ethnic groups). PA was analyzed using basic (low-moderate-high) and quantitative measures (metabolic equivalents (METS)), while BMI and the body adiposity index (BAI) were used to measure obesity. Increased PA was associated with decreased BMI/BAI at baseline/follow-up.  FTO  rs1421085,  CDKAL1  rs2206734,  TNNl3K  rs1514176,  GIPR  rs11671664 and the GRS were associated with obesity measures at baseline and/or follow-up. Risk alleles of three SNPs displayed nominal associations with increased ( NTRK2  rs1211166,  BDNF  rs1401635) or decreased ( NPC1  rs1805081) basic PA score independently of BMI/BAI. Both basic and quantitative PA measures attenuated the association between  FTO  rs1421085 risk allele and BMI/BAI at baseline and follow-up. Our results show that physical activity can blunt the genetic effect of  FTO  rs1421085 on adiposity by 36–75% in a longitudinal multi-ethnic cohort.

Physical activity and genetic predisposition to obesity in a multiethnic longitudinal study