Associations of Common Genetic Variants With Age-Related Changes in Fasting and Postload Glucose: Evidence From 18 Years of Follow-Up of the Whitehall II Cohort

OBJECTIVE: In the general, nondiabetic population, fasting glucose increases only slightly over time, whereas 2-h postload glucose shows a much steeper age-related rise. The reasons underlying these different age trajectories are unknown. We investigated whether common genetic variants associated with fasting and 2-h glucose contribute to age-related changes of these traits. RESEARCH DESIGN AND METHODS: We studied 5,196 nondiabetic participants of the Whitehall II cohort (aged 40–78 years) attending up to four 5-yearly oral glucose tolerance tests. A genetic score was calculated separately for fasting and 2-h glucose, including 16 and 5 single nucleotide polymorphisms, respectively. Longitudinal modeling with age centered at 55 years was used to study the effects of each genotype and genetic score on fasting and 2-h glucose and their interactions with age, adjusting for sex and time-varying BMI. RESULTS: The fasting glucose genetic score was significantly associated with fasting glucose with a 0.029 mmol/L (95% CI 0.023–0.034) difference (P = 2.76 × 10(−21)) per genetic score point, an association that remained constant over time (age interaction P = 0.17). Two-hour glucose levels differed by 0.076 mmol/L (0.047–0.105) per genetic score point (P = 3.1 × 10(−7)); notably, this effect became stronger with increasing age by 0.006 mmol/L (0.003–0.009) per genetic score point per year (age interaction P = 3.0 × 10(−5)), resulting in diverging age trajectories by genetic score. CONCLUSIONS: Common genetic variants contribute to the age-related rise of 2-h glucose levels, whereas associations of variants for fasting glucose are constant over time, in line with stable age trajectories of fasting glucose.