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
- Anders C. Jensen1,
- Adam Barker2,
- Meena Kumari3,
- Eric J. Brunner3,
- Mika Kivimäki3,
- Aroon D. Hingorani3,
- Nicholas J. Wareham2,
- Adam G. Tabák3,4⇓,
- Daniel R. Witte1⇓ and
- Claudia Langenberg2⇓
- 1Steno Diabetes Center, Gentofte, Denmark
- 2Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K.
- 3Department of Epidemiology and Public Health, University College London, London, U.K.
- 4Department of Medicine, Semmelweis University, Budapest, Hungary
- Corresponding authors: Claudia Langenberg, ; Daniel R. Witte, ; or Adam G. Tabák, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1393/-/DC1.
- Received October 1, 2010.
- Accepted February 27, 2011.
- © 2011 by the American Diabetes Association.
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