Association of distal chromosome 2q with IDDM in Japanese subjects

Abstract

Insulin-dependent diabetes mellitus (IDDM) is caused by autoimmune destruction of insulin-producing beta cells of the pancreas in genetically susceptible individuals [1]. Inheritance of IDDM is polygenic with a major locus (IDDM1) in the major histocompatibility complex (MHC) [2,3]. Several additional loci have recently been mapped to the human genome by whole genome scanning with random markers [4±8] and/or a candidate gene approach [9±14]. Most reports, however, are based on data in Caucasian populations, and it is yet to be determined whether loci mapped in one population universally contribute to IDDM susceptibility in other populations.The Japanese population is unique in studies on the genetics of IDDM not only because they are genetically distinct from Caucasian populations, but also because the incidence of IDDM is very low in this population [15]. We have previously reported that two IDDM loci, IDDM1 in HLA region [15,16] and IDDM2 in the insulin gene (INS) region [17], both of which were identified by the candidate gene approach, contribute to IDDM susceptibility in Japanese in the same way as in Caucasians. The contribution of other loci, however, to IDDM susceptibility in Japanese is largely unknown due to their low incidence and, as a consequence, the limited number of multiplex families with IDDM. Diabetologia (1998) Summary An insulin-dependent diabetes mellitus (IDDM)-susceptibility gene (IDDM13) has recently been mapped to a region of distal chromosome 2q, which is syntenic to the region of mouse chromosome 1 containing a murine susceptibility gene for IDDM, Idd5. To determine the contribution of this region to IDDM disease susceptibility further and to narrow the region for positional cloning of susceptibility genes, we have studied the association of distal chromosome 2q with IDDM in the genetically distinct Japanese population. A 137 mobility unit (mu) allele at D2S137 locus was significantly associated with IDDM (odds ratio 1.92, p = 0.0016). Other markers, D2S301 and D2S143, located in the same region were not associated with IDDM, indicating that IDDM13 is in linkage disequilibrium with D2S137, but not with D2S301 or D2S143. The association of D2S137 with IDDM was observed in patients lacking one of two high risk HLA alleles, DQB1*0303 and DQB1*0401, but not in patients with either of these alleles. The frequency of high risk HLA alleles was significantly lower in patients with the susceptible allele at D2S137, suggesting that IDDM13 contributes to IDDM susceptibility in subjects without high risk genotypes at IDDM1. Demonstration of allelic association of D2S137 with IDDM localizes IDDM13 in the close vicinity (< 2 centiMorgans) of D2S137, greatly facilitating fine structure mapping and positional cloning of IDDM13. [Diabetologia (1998) 41: 228±232]

Promoter polymorphism of SLC11A1 (formerly NRAMP1) confers susceptibility to autoimmune type 1 diabetes mellitus in Japanese

“…It is noteworthy that this polymorphism showed much stronger association with type 1 diabetes in the subpopulation of those lacking one of two diabetes‐susceptibility HLA haplotypes and those possessing at least one protective allele. This observation is similar to previous findings on IDDM13 in Caucasian (17) and Japanese (34) subjects; a stronger association of type 1 diabetes with the IDDM13 gene was observed in subjects without the major susceptibility HLA alleles. This may explain why we detected a significant contribution of SLC11A1 in a case‐control study in Japanese.…”

Genetic control of autoimmunity in Type I diabetes and associated disorders

“…Putative IDDM loci with their chromosomal localization and candidate genes in that region are summarized (Table 2). For some of these loci, such as D2S137 or D14S67, the association seems to be stronger in patients lacking the high risk HLA alleles, DQ2 or DQ8 [96,97]. Some studies have found that age of diagnosis, sex of affected subjects, and parental origin of shared alleles modify the influence of loci on diabetes risk [98,99].…”

Definition of polymorphisms in the gene encoding the interleukin-12 receptor B1 subunit: testing linkage disequilibrium with Type I diabetes susceptibility

“…Stratification of sib pairs by factors such as sex and HLA status has proven useful in revealing linkage in multipoint analysis, for example, allowing a clear definition of the susceptibility locus IDDM13. [13][14][15] Applying stratification to the 19p13.1-13.2 data revealed a difference between sib pairs sharing HLA haplotypes, A, B and DR, and those differing at HLA. The HLA identical and mismatched sibs showed weak linkage in these families to IL12RB1 with maximised LOD ¼ 1.4.…”