FTO, Type 2 Diabetes, and Weight Gain Throughout Adult Life: A Meta-Analysis of 41,504 Subjects From the Scandinavian HUNT, MDC, and MPP Studies

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 (∆BMI = 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.