Evidence for Association Between the Class I Subset of the Insulin Gene Minisatellite (IDDM2 Locus) and IDDM in the Japanese Population

Abstract

Although the shortest (class I) minisatellite (i.e., variable number of tandem repeats [VNTR]) alleles in the 5' region of the insulin gene are positively associated with IDDM in Caucasians, the majority of Japanese are homozygous for class I alleles. Here, we determined the exact length, in number of repeat units (RUs), of class I alleles in Japanese subjects. The distribution of class I alleles in Japanese was trimodal, with peaks located at 32/33, 41, and 44 RUs. The shortest component (i.e., 1S [25-38 RUs]) alleles were significantly increased in the IDDM group compared with the control group (54 vs. 46%; P = 0.040). The 1S/1S genotype was significantly increased in the IDDM patients (34 vs. 20%; P = 0.005; relative risk 2.1). Furthermore, the transmission disequilibrium test of Japanese families with 1S/1M or 1S/1L heterozygous parents confirmed the association of 1S alleles; 17 alleles of 1S and 6 alleles of 1M (39-41 RUs) or 1L (42-44 RUs) were transmitted to affected offspring (P = 0.022). In addition, we found tight linkage of 1S with allele 9 of the tyrosine hydroxylase gene microsatellite and allele (-) of the IGF-II gene Apa I polymorphism, but neither 9 nor (-) alleles were significantly associated with IDDM. The present study suggests that a class I subset may have a role in IDDM susceptibility in Japan. It was revealed that the difference between 1S alleles and 1M or 1L alleles is almost consistently characterized by a sequence variation generated by deletion of two copies of an ACAGGGGTCC CGGGG repeat element, implying that sequence variation of class I alleles may influence disease susceptibility.

CTLA4 gene polymorphism contributes to the mode of onset of diabetes with antiglutamic acid decarboxylase antibody in Japanese patients: genetic analysis of diabetic patients with antiglutamic acid decarboxylase antibody

“…In INS‐VNTR, the shortest (class I) minisatellite alleles are positively associated with Type 1 diabetes in Caucasians [8]. Although the majority of people in Japan are homozygous for class I alleles [9], it has been reported that the class I allele is of variable length (1S, 25–38 repeat units; 1M, 39–41 repeat units; 1L, 42–44 repeat units) and that the frequency of 1S alleles is significantly higher in those with Type 1 diabetes than in controls [10]. An A–G transition polymorphism at position 49 in exon 1 of the CTLA4 gene is also associated with Type 1 diabetes [11–13].…”

Noninsulin-Dependent Diabetes Mellitus as a Mitochondrial Genomic Disease

“…For example, more than 44 different mutations in MODY-2 patients have been reported (54)(55)(56). Mutation in the gene for insulin (59), the genes for insulin processing enzymes (60), and the genes for the insulin receptor (61) have also been detected and associated with the early onset forms of the disease. The maternal inheritance pattern of diabetes has led researchers to look for genetic defects in the mitochondrial genome.…”

The association of variable number of tandem repeats of the insulin gene with susceptibility to type 1 diabetes among Korean subjects

“…The INS VNTRs show ethnic variations [16], and their effects on the susceptibility to T1D have been studied extensively in Caucasians, whereas among Asians this has been studied only among Japanese [21][22][23]. Thus, the effect of INS VNTR on the development of T1D has not yet been clarified for Koreans.…”