Abstract
Variation in FTO is the most important common genetic determinant of body weight. Altered energy metabolism could underlie this association. We hypothesized that higher circulating glucose or triglycerides can amplify the FTO impact on BMI. In 2671 subjects of the TUEF study, we investigated the interaction effect of fasting glucose and triglyceride levels with rs9939609 in FTO on BMI. We analysed the same interaction effect by longitudinally utilizing mixed effect models in the prospective Whitehall II study. In TUEF, we detected an interaction effect between fasting glucose and fasting triglycerides with rs9939609 on BMI (p = 0.0005 and p = 5 × 10−7, respectively). The effect size of one risk allele was 1.4 ± 0.3 vs. 2.2 ± 0.44 kg/m² in persons with fasting glucose levels below and above the median, respectively. Fasting triglycerides above the median increased the per-allele effect from 1.4 ± 0.3 to 1.7 ± 0.4 kg/m2. In the Whitehall II study, body weight increased by 2.96 ± 6.5 kg during a follow-up of 13.5 ± 4.6 yrs. Baseline fasting glucose and rs9939609 interacted on weight change (p = 0.009). Higher fasting glucose levels may amplify obesity-risk in FTO carriers and lead to an exaggerated weight gain over time. Since weight gain perpetuates metabolic alterations, this interplay may trigger a vicious circle that leads to obesity and diabetes.
Highlights
Due to its increasing global prevalence, obesity has become a major health problem worldwide
To determine whether glycemia or triglycerides modulate the effect of the single nucleotide polymorphisms (SNPs) on body weight and BMI, linear regression modelling was performed with the least squares method, including the interaction term SNP × environmental factor
Using a linear mixed model, we modelled the BMI change between consecutive visits as a function of the FTO SNP and the fasting glucose levels assessed during the previous visit
Summary
Due to its increasing global prevalence, obesity has become a major health problem worldwide. We hypothesized that higher plasma levels of energy substrates, namely glucose and triglycerides, could intensify this increased lipid storage, thereby causing excessive weight gain, in subjects carrying the risk allele in FTO. To determine whether glycemia or triglycerides modulate the effect of the SNP on body weight and BMI, linear regression modelling was performed with the least squares method, including the interaction term SNP × environmental factor.
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