%0 Journal Article %J Diabetologia %D 2012 %T Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism. %A Walford, G A %A Green, T %A Neale, B %A Isakova, T %A Rotter, J I %A Grant, S F A %A Fox, C S %A Pankow, J S %A Wilson, J G %A Meigs, J B %A Siscovick, D S %A Bowden, D W %A Daly, M J %A Florez, J C %K Adult %K Aged %K Blood Glucose %K Cohort Studies %K Diabetes Mellitus, Type 2 %K Disease Progression %K Fasting %K Female %K Genetic Variation %K Genotype %K Humans %K Male %K Middle Aged %K Models, Genetic %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Regression Analysis %K Risk %X

AIMS/HYPOTHESIS: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes.

METHODS: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n = 16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype.

RESULTS: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p = 1 × 10(-4)), nominally greater at GCK and SLC30A8 (p < 0.05) and nominally smaller at IGF2BP2 (p = 0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings.

CONCLUSIONS/INTERPRETATION: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.

%B Diabetologia %V 55 %P 331-9 %8 2012 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22038522?dopt=Abstract %R 10.1007/s00125-011-2353-8