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

  1. Claudia Langenberg2
  1. 1Steno Diabetes Center, Gentofte, Denmark
  2. 2Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K.
  3. 3Department of Epidemiology and Public Health, University College London, London, U.K.
  4. 4Department of Medicine, Semmelweis University, Budapest, Hungary
  1. Corresponding authors: Claudia Langenberg, claudia.langenberg{at}; Daniel R. Witte, drw{at}; or Adam G. Tabák, a.tabak{at}
  1. A.C.J. and A.B. contributed equally to this study.


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.


  • Received October 1, 2010.
  • Accepted February 27, 2011.

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