Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese

NeuroD/BETA2, a transcription factor of the insulin gene, also plays an imp ortant role in the development of pancreatic beta-cells. Recently, the Neur oD/BETA2 gene has been mapped to the long arm of human chromosome 2 (2q32) where the IDDM7 gene has previously been mapped, implying its involvement i n diabetes. To identify mutations in the NeuroD/BETA2 gene that may predisp ose patients to develop diabetes, we studied the gene in 50 Japanese subjec ts with diabetes (4 with type 1 and 46 with type 2) by the polymerase chain reaction (PCR) followed by single-strand conformation polymorphism and seq uencing analyses. Further analysis was performed in 392 Japanese subjects ( 60 with type 1 and 158 with type 2 diabetes and 174 healthy control subject s) by mismatch PCR restriction fragment length polymorphism. We found a DNA polymorphism of the NeuroD/BETA2 gene. A nucleotide G-Lo-A transition resu lts in the substitution of alanine to threonine at codon 45 (Ala45Thr). The frequencies of heterozygotes for the Ala45Thr variant were 9.8% in the con trol subjects, 9.5% in the patients with type 2 diabetes, and 25.0% in the patients with type 1 diabetes, a significant difference (P = 0.006). Becaus e the variant of the NeuroD/BETA2 gene (Ala45Thr) is associated with type 1 but not type 2 diabetes, it may be implicated in the loss of pancreatic be ta-cells in type 1 diabetes.