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

Abstract

NeuroD/BETA2, a transcription factor of the insulin gene, also plays an important role in the development of pancreatic beta-cells. Recently, the NeuroD/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 in diabetes. To identify mutations in the NeuroD/BETA2 gene that may predispose patients to develop diabetes, we studied the gene in 50 Japanese subjects with diabetes (4 with type 1 and 46 with type 2) by the polymerase chain reaction (PCR) followed by single-strand conformation polymorphism and sequencing analyses. Further analysis was performed in 392 Japanese subjects (60 with type 1 and 158 with type 2 diabetes and 174 healthy control subjects) by mismatch PCR restriction fragment length polymorphism. We found a DNA polymorphism of the NeuroD/BETA2 gene. A nucleotide G-to-A transition results in the substitution of alanine to threonine at codon 45 (Ala45Thr). The frequencies of heterozygotes for the Ala45Thr variant were 9.8% in the control 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). Because 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 beta-cells in type 1 diabetes.

NeuroD/BETA2 Gene G→A Polymorphism May Affect Onset Pattern of Type 1 Diabetes in Japanese

“…Dupont et al (17) suggested an ethnic difference between Caucasians and Japanese because no AA homozygote was found in a previous study in Japanese (11). However, in our study, we did find AA homozygotes in both type 1 diabetes and control subjects (10.5 and 3.3%, respectively) in the Japanese population.…”

“…It is known that there is a G3 A transition polymorphism in codon 45 of the NeuroD/BETA2 gene, leading to an Ala/Thr substitution in the NH 2 -terminus, although the functional difference between the G and A alleles is unknown. Previously, several studies showed no association between this gene and type 1 diabetes (16,17), whereas one study showed a significant association (11). Therefore, the role of this gene in type 1 diabetes is controversial and inconclusive.…”

“…The G3 A transition polymorphism in codon 45 of the NeuroD/BETA2 gene, leading to an Ala/Thr substitution in the NH 2 -terminus, was determined by polymerase chain reaction-restriction fragment-length polymorphism method (11). HLA typing was performed by the hybridization protection assay as previously described (6).…”

Neuronatin, a Downstream Target of BETA2/NeuroD1 in the Pancreas, Is Involved in Glucose-Mediated Insulin Secretion

“…The importance of BETA2 is highlighted by the discovery that it is the sixth maturity-onset diabetes of the young (MODY6) gene identified (24). In addition, many genetic studies in various populations have linked mutations in BETA2 to susceptibility to type 1 (25)(26)(27) and type 2 (28,29) diabetes. Consequently, target genes of BETA2 will likely affect the etiology of diabetes linked to BETA2.…”

Genetics of type 1 diabetes mellitus

“…These include genes of the interleukin-1 gene cluster (ie IL1R1, [144][145][146] IL1B, 130,147,148 and IL1RN 130,149 ) HOXD8, 150 GAD1, 151 GALNT3, 141 and NEUROD. [152][153][154] However, linkage or association has not been convincingly demonstrated for any of these candidate genes.…”