Aim: The human protein encoded by the FOXO1A gene functions as a transcription factor of insulin signaling key genes. In this study we investigated the role of genetic variation in the FOXO1A gene in susceptibility to type 2 diabetes (T2D) and relevant metabolic traits.
Methods: We genotyped six haplotype tagging single nucleotide polymorphisms (SNPs) for association analyses in German Caucasians (593 patients with T2D and 760 non-diabetics, who included 594 normoglycemics and 166 individuals with impaired glucose tolerance).
Results: In a case control study involving all type 2 diabetics and healthy controls with normal glucose tolerance, none of the FOXO1A SNPs showed any association with T2D. However, the frequency of the [C-C-G-A-A-A] haplotype comprising six FOXO1A SNPs was 36.5% in normoglycemic non-diabetic controls compared to 31.0% in type 2 diabetic patients (P=0.004). Consistent with this, the same haplotype was significantly associated with lower fasting plasma insulin, BMI, HbA(1C), free fatty acids and % body fat in all non-diabetic subjects (all adjusted P<0.05).
Conclusion: In conclusion, our study suggests a protective effect of FOXO1A haplotype [C-C-G-A-A-A] on T2D development and relevant intermediate phenotypes which predispose for T2D.