Genetic predisposition to long-term non-diabetic deteriorations in glucose homeostasis: ten-year follow-up of the GLACIER Study

To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits. Methods: Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the GLACIER Study, a population-based prospective cohort study from Northern Sweden. Genotypes were tested for association with baseline fasting and 2-hr post-challenge glycemia (N=16,398), and with change in 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 12/16 variants; nine variants also associated with impaired fasting glucose (IFG) and seven were independently associated with 2-hr post-challenge glucose concentrations. In prospective analyses corrected for multiple testing, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, G6PC2 rs560887) were statistically associated with worsening fasting glucose concentrations during 10-years follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on post-challenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-hr glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80(th) vs. 20(th) centiles) was associated with a 0.16mmol/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 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 endpoints will help establish whether the magnitude of these changes is clinically relevant.