FTO predicts weight regain in the Look AHEAD clinical trial

Background: Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss. Methods: Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and diabetes support and education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1. Results: No single-nucleotide polymorphisms (SNPs) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, fat mass and obesity associated gene ( FTO ) rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, P =0.005), but not ILI ( P =0.761), resulting in SNP × treatment arm interaction ( P =0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance ( P =0.051). Conclusions: Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.