Genetic predisposition to long-term nondiabetic deteriorations in glucose homeostasis: Ten-year follow-up of the GLACIER study.

• Published in: Diabetes
• Main Authors: Renström, F., Shungin, D., Johansson, I, MAGIC Investigators (Grallert, H., Gieger, C., Meisinger, C., Thorand, B., Wichmann, H.-E., Illig, T.), Florez, J.C, Hallmans, G., Hu, F.B., Franks, P.W.
• Format: Article in Journal/Newspaper
• Language: English
• Published: Amer Diabetes Assoc 2011
• Subjects: Genome-Wide Association; Type-2 diabetes risk; Impaired fasting glucose; Melatonin-receptor; Northern Sweden; Popurlation; Variants; Insulin; Polymorphism; Mellitus
• Online Access: https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=6902; https://doi.org/10.2337/db10-0933

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 ...