Association of Common Genetic Variation in the FOXO1 Gene with β-Cell Dysfunction, Impaired Glucose Tolerance, and Type 2 Diabetes

Context: The transcription factor forkhead box protein (FOX) O1A plays a crucial role in regulation of beta-cell function and metabolic effects of insulin in the liver. Objective: The objective of the study was to investigate whether common genetic variation within the FOXO1 gene encoding FOXO1A contributes to prediabetic phenotypes, such as insulin resistance or beta-cell dysfunction, and to risk of type 2 diabetes. Design and Settings: Study I was a study enrolling thoroughly phenotyped subjects from Germany at increased risk for type 2 diabetes. Study II was a population-based study of Finnish men for the assessment of the prevalence of type 2 diabetes and metabolic syndrome. Participants: Study I included 941 nondiabetic subjects (353 males, 588 females, aged 39 +/- 1 yr, body mass index 29.2 +/- 0.3 kg/m(2)). Study II included 5957 middle-agedmen(870 type 2 diabetic and 5087 nondiabetic subjects). Interventions: Genotyping for 10 single-nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency >= 10%) within the FOXO1 gene (r(2) >= 0.8) based on HapMap data, oral glucose tolerance test, and in a subset additionally a hyperinsulinemic-euglycemic clamp. Main Outcome Measurements: Parameters of insulin secretion, insulin resistance, and glucose tolerance status were measured. Results: In the German subjects at increased risk for type 2 diabetes, SNPs rs2721068 and rs17446614 were significantly (P = 0.0045 and P = 0.0018, respectively) and SNPs rs17446593 and rs2297627 were nominally (P = 0.0091 and P = 0.0387, respectively) associated with beta-cell dysfunction. rs2721068, rs17446614, and rs2297627 were also nominally associated with impaired glucose tolerance (P = 0.0264, P = 0.0162, and P = 0.0221, respectively). Minor allele carriers showed reduced insulin secretion and elevated glucose levels during an oral glucose tolerance test. Investigating the relevance of our findings in a separate cohort, we found that SNP rs2721068 was significantly associated with type 2 diabetes in the additive (P = 0.002) and dominant model (P = 0.009) in Finnish men. Conclusions: Common genetic variation within the FOXO1 gene affects insulin secretion and glucose tolerance and associates with an increased risk of type 2 diabetes. (J Clin Endocrinol Metab 94: 1353-1360, 2009)