Association of Common Genetic Variation in theFOXO1Gene with β-Cell Dysfunction, Impaired Glucose Tolerance, and Type 2 Diabetes

Abstract

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. 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. 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. 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-aged men (870 type 2 diabetic and 5087 nondiabetic subjects). Genotyping for 10 single-nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency >or=10%) within the FOXO1 gene (r(2) >or= 0.8) based on HapMap data, oral glucose tolerance test, and in a subset additionally a hyperinsulinemic-euglycemic clamp. Parameters of insulin secretion, insulin resistance, and glucose tolerance status were measured. 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. Common genetic variation within the FOXO1 gene affects insulin secretion and glucose tolerance and associates with an increased risk of type 2 diabetes.