Genetic Predisposition to Long-Term Nondiabetic Deteriorations in Glucose Homeostasis

Ten-Year Follow-Up of the GLACIER Study

  1. Paul W. Franks1,2,7
  1. 1Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden;
  2. 2Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts;
  3. 3Department of Odontology, Umeå University Hospital, Umeå, Sweden;
  4. 4Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, U.K.;
  5. 5Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
  6. 6Department of Public Health and Clinical Medicine, Section for Nutritional Research, Umeå University Hospital, Umeå, Sweden;
  7. 7Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.
  1. Corresponding author: Paul W. Franks, paul.franks{at}


OBJECTIVE To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits.

RESEARCH DESIGN AND METHODS Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk (GLACIER) Study, a population-based prospective cohort study from northern Sweden. Genotypes were tested for association with baseline fasting and 2-h postchallenge glycemia (N = 16,330), and for changes in these glycemic traits during a 10-year follow-up period (N = 4,059).

RESULTS Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12 of 16 variants; 10 variants were also associated with impaired fasting glucose (IFG) and 7 were independently associated with 2-h postchallenge glucose concentrations. In prospective analyses, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, and G6PC2 rs560887) were nominally associated with worsening fasting glucose concentrations during 10-years of follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on postchallenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-h glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80th vs. 20th centiles) was associated with a 0.16 mmol/l (P = 2.4 × 10−6) greater elevation in fasting glucose and a 64% (95% CI: 33–201%) higher risk of developing IFG during 10 years of follow-up.

CONCLUSIONS Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant.


  • *A complete list of the MAGIC Investigators can be found in the online appendix, available at

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  • Received July 5, 2010.
  • Accepted September 14, 2010.

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