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

ABSTRACT

Context: The transcription factor FOXO1A (forkhead box protein O1A) plays a crucial role in regulation of β-cell function and of metabolic effects of insulin in the liver.

Objective: To investigate whether common genetic variation within the FOXO1 gene encoding FOXO1A contributes to prediabetic phenotypes, such as insulin resistance or β-cell dysfunction, and to risk of type 2 diabetes.

Design and Settings: Study I: Study enrolling thoroughly phenotyped subjects from Germany at increased risk for type 2 diabetes. Study II: Population-based study of Finnish men for the assessment of the prevalence of type 2 diabetes and metabolic syndrome.

Participants: Study I: 941 non-diabetic subjects (353 males, 588 females, age 39±1 yr, BMI 29.2±0.3 kg/m²). Study II: 5957 middle-aged men (870 type 2 diabetic and 5087 non-diabetic subjects).

Interventions: Genotyping for ten single nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency ≥10%) within the FOXO1 gene (r² ≥0.8) based on HapMap data, oral glucose tolerance test (OGTT), in a subset additionally a hyperinsulinemic-euglycemic clamp.

Main Outcome Measurements: Parameters of insulin secretion, insulin resistance, and glucose tolerance status.

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 -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 OGTT. 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.