Interrelationship of the rs7903146 TCF7L2 gene variant with measures of glucose metabolism and adiposity: The NEO study

Background and aims We investigated the interrelationship of rs7903146-T in TCF7L2 with measures of glucose metabolism and measures of adiposity. Methods and results This cross-sectional analysis was conducted in 5744 middle-aged participants (mean (standard deviation [SD]) age is 55.9 (6.0) years) from the Netherlands Epidemiology of Obesity (NEO) Study. Associations between rs7903146-T and Type 2 diabetes mellitus (T2D) were assessed with logistic regression. Additive (per-allele) associations with measures of glucose metabolism (e.g., fasting insulin) and adiposity (e.g., body mass index [BMI]) were examined with multivariable linear regression. In the total study population, rs7903146-T was associated with a higher risk of T2D (additive odds ratio: 1.42; 95% confidence interval: 1.17; 1.72), and specifically with T2D treated with insulin analogs (2.31 [1.19; 4.46]). After exclusion of participants treated with glucose-lowering medication, rs7903146-T was associated with lower mean insulin concentration (additive mean difference: −0.07 SD [−0.14; 0.00]), but not with higher mean glucose concentration (0.03 SD [−0.01; 0.07]). Furthermore, rs7903146-T was associated with, among other measures of adiposity, a lower mean BMI (−0.04 SD [−0.09; −0.00]), and a lower mean total body fat (−0.04 SD [−0.08; −0.00]). The association between rs7903146-T and T2D increased after adjustment for BMI (odds ratio: 1.51 [1.24; 1.86]); the association between rs7903146-T and fasting insulin diminished after adjustment (−0.05 SD [−0.11; 0.02]). Conclusion rs7903146-T is associated with a decreased insulin concentration and increased risk of T2D with opposing effects of adjustment for adiposity.