Aim: FTO is the most important polygene for obesity and type 2 diabetes. Our aims were to investigate whether a variant in FTO affects glucose dysregulation through its effect on fat accumulation or distribution, and when and how FTO influences fat accumulation and distribution and glucose dysregulation from birth until midlife.
Methods: A total of 454 Japanese female university students (mean age: 20 years) and 132 middle-aged women (mean age: 50 years) who were the biological mothers of the students underwent the following: genotyping for rs1558902 in the FTO gene, assessment of fat accumulation and distribution, obesity-related metabolic traits and serum adipokine measurement. A subsample of 364 students reported their weight history since birth.
Results: The A allele in rs1558902 was substantially less common in young and middle-aged Japanese women (18 and 17%, respectively) than in the European population (45%). The strong effect of genotype AA on BMI was evident at age 12, 15, 20 and 50 years whereas there was no effect on birth weight. In young and middle-aged women, the variant was strongly associated with higher body weight and fat mass. The effects on abdominal girth, fasting glucose, homeostasis model assessment insulin resistance and HbA1c were evident in mothers but not in students. In addition, genotype AA was associated with increased white blood cell counts and hsCRP in mothers only. Associations with fasting glucose, insulin resistance, and white blood cell counts remained after correction for BMI, abdominal girth and fat mass. In multiple logistic regression analysis, AA homozygote in FTO was associated with higher odds of overweight (BMI ≥25kg/m2) in young (OR 1.73 (95%CI 1.06-30.0)) and middle-aged women (OR 1.73 (95%CI 1.06-30.0)). It was also associated with higher odds of abdominal fat accumulation (abdominal girth ≥90cm, OR 1.73 (95%CI 1.06-30.0)) and fasting hyperglycemia (≥100mg/dL) (OR 1.87(95%CI 1.05-40.4)) in middle-aged mothers.
Conclusion: Despite the small sample size, the low average BMI, and the low risk allele frequency, a genetic variation at the FTO locus was related to greater weight gain before age 12 in Japanese women. At age 20, it was related to general adiposity. In midlife, however, it was related to abdominal adiposity in addition to general adiposity, fasting hyperglycemia, higher HbA1c and subtle systemic inflammation. Fasting hyperglycemia associated with higher HbA1c in midlife was independent of its effects on general and abdominal adiposity.