Genetic susceptibility of childhood type 1 diabetes mellitus in Japan

Abstract

Most cases of type 1 diabetes mellitus (T1DM) are caused by an autoimmune reaction, involving genetic and environmental factors, which ultimately disrupt insulin-producing pancreatic beta cells. Several genes, including those encoding human leukocyte antigen (HLA) class II (IDDM1 locus), insulin (IDDM2 locus), and cytotoxic T lymphocyte antigen (CTLA) 4 (IDDM12 locus), are involved in this process. In this paper, I review the studies of Japanese patients with childhood type 1A diabetes mellitus (T1ADM), including the results of the multicenter study conducted by The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT). The JSGIT study analyzed the HLA-DRB1, DQB1, DPB1, A, C, and B genes in Japanese patients with childhood T1ADM to identify candidate genes specific for Japanese individuals. Some of the genes were also involved in diabetes in Caucasian. A comparison of parents and siblings showed that several susceptible DRB1-DQB1 haplotypes and resistant alleles were involved in the development of T1ADM. However, results of transmission disequilibrium tests demonstrated no genomic imprinting of HLA Class I or II genes in Japanese patients. The frequency of the DRB1*09:01 allele was significantly higher in patients who developed the disease at 2-5 years old than in other patients. Identifying HLA gene polymorphisms may help to examine the relationship between antigen-presenting molecule structures and autoantigenic peptides. The JSGIT study also identified single nucleotide polymorphisms in genes other than HLA. Understanding the genetic factors associated with T1ADM that help explain the lower incidence of this disease in Japanese than in Caucasian individuals, will help us to elucidate its pathogenesis.