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}med.lu.se.

Abstract

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.

Footnotes

  • *A complete list of the MAGIC Investigators can be found in the online appendix, available at http://diabetes.diabetesjournals.org/cgi/content/full/db10-0933/DC1.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Diabetes vol. 60 no. 1 345-354
  1. Online Appendix
  2. All Versions of this Article:
    1. db10-0933v1
    2. 60/1/345 most recent