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

Abstract

OBJECTIVE—The majority of type 1 diabetes is considered to be autoimmune with, for the most part, abrupt development. However, type 1 diabetes with slow onset, or the so-called slowly progressive type 1 diabetes or latent autoimmune diabetes in adults, has been recently recognized and is considered to be autoimmune-related. Although some investigators tried to explain the difference in onset pattern by the genetic background, including HLA type, it has not been established thus far. We hypothesized that the difference in onset pattern may relate to regeneration or differentiation of pancreatic β-cells, and we therefore focused on the NeuroD/BETA2 gene, which encodes a transcription factor for the insulin gene and β-cell differentiation. RESEARCH DESIGN AND METHODS—We examined the NeuroD/BETA2 gene polymorphism in 105 Japanese type 1 diabetic patients and in 122 nondiabetic Japanese subjects in a case-control study, and we stratified the patients according to their onset pattern and islet-associated autoantibody positivity. RESULTS—Regardless of the existence of islet-associated autoantibody, we found a significant difference in A allele frequency between type 1 diabetic patients with acute-onset type and control subjects. However, no difference was found between type 1 slow-onset diabetic patients and control subjects. CONCLUSIONS—These results support our hypothesis that NeuroD/BETA2 may affect the ability of regeneration of β-cells, leading to a difference in the onset pattern and clinical course of type 1 diabetes.

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.…”

Ala45Thr polymorphism of the NEUROD1 gene and diabetes susceptibility: a meta-analysis

“…However, provided that the ethnic background is similar among patients and controls, the lack of such matching should not have introduced bias in the estimates. Finally, in some studies, the extent of testing to exclude diabetes mellitus or impaired glucose intolerance was not described in detail (Iwata et al 1999;Awata et al 2000;Yamada et al 2001;Mockizuki et al 2002), and several of the healthy controls may subsequently develop diabetes (in particular T2D) in their lifetime. Such misclassification errors would tend to decrease the observed association compared with the true one, but it is unlikely that the bias would be large.…”

“…The latter type is a heterogeneous group of non-autoimmune-mediated insulin-deficient diabetes with extensive pancreatic islet beta-cell destruction (Abiru et al 2002). The majority of T1D is immune-mediated; only one study of those included in this meta-analysis specified that auto-antibody-negative T1D patients were also included, and separate data were provided for them (Yamada et al 2001). In these patients, the observed association with the Thr allele was very strong (Yamada et al 2001).…”

“…The majority of T1D is immune-mediated; only one study of those included in this meta-analysis specified that auto-antibody-negative T1D patients were also included, and separate data were provided for them (Yamada et al 2001). In these patients, the observed association with the Thr allele was very strong (Yamada et al 2001).…”

“…Several studies to date have focused on whether a single base-pair substitution G fi A in codon 45 of exon 2 resulting in an Ala to Thr substitution confers susceptibility to diabetes. Results from molecular epidemiological studies concerning the significance of the Ala45Thr polymorphism in T1D (Owerbach et al 1997;Iwata et al 1999;Dupont et al 1999a;Awata et al 2000;Hansen et al 2000;Yamada et al 2001;Cinek et al 2003;Malecki et al 2003b) and T2D (Dupont et al 1999b;Kanatsuka et al 2002;Ye et al 2002;Malecki et al 2003a;Jackson et al 2004) have been seemingly contradictory. Given the amount of the accumulated data, a quantitative synthesis of the evidence has been deemed important.…”