FTO, Type 2 Diabetes, and Weight Gain Throughout Adult Life

OBJECTIVE FTO is the most important polygene identified for obesity. We aimed to investigate whether a variant in FTO affects type 2 diabetes risk entirely through its effect on BMI and how FTO influences BMI across adult life span. RESEARCH DESIGN AND METHODS Through regression models, we assessed the relationship between the FTO single nucleotide polymorphisms rs9939609, type 2 diabetes, and BMI across life span in subjects from the Norwegian population-based HUNT study using cross-sectional and longitudinal perspectives. For replication and meta-analysis, we used data from the Malmö Diet and Cancer (MDC) and Malmö Preventive Project (MPP) cohorts, comprising a total sample of 41,504 Scandinavians. RESULTS The meta-analysis revealed a highly significant association for rs9939609 with both type 2 diabetes (OR 1.13; P = 4.5 × 10(-8)) and the risk to develop incident type 2 diabetes (OR 1.16; P = 3.2 × 10(-8)). The associations remained also after correction for BMI and other anthropometric measures. Furthermore, we confirmed the strong effect on BMI (0.28 kg/m(2) per risk allele; P = 2.0 × 10(-26)), with no heterogeneity between different age-groups. We found no differences in change of BMI over time according to rs9939609 risk alleles, neither overall (ΔBMI = 0.0 [-0.05, 0.05]) nor in any individual age stratum, indicating no further weight gain attributable to FTO genotype in adults. CONCLUSIONS We have identified that a variant in FTO alters type 2 diabetes risk partly independent of its observed effect on BMI. The additional weight gain as a result of the FTO risk variant seems to occur before adulthood, and the BMI difference remains stable thereafter.