Genetic Predisposition to Long-Term Nondiabetic Deteriorations in Glucose Homeostasis Ten-Year Follow-Up of the GLACIER Study

摘要

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 post-challenge 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 rsl0885122, dgkb-tmem195 rs2191349, and g6pc2 rs560887) were nominally associated with worsening fasting glucose concentrations during 10-years of follow-up. Mtnr1b rsl0830963, 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/1 (p = 2.4 x 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. Diabetes 60:345-354, 2011