We have searched the human genome for genes that predispose to type 1 (insulin-dependent) diabetes mellitus using semi-automated fluorescence-based technology and linkage analysis. In addition to IDDM1 (in the major histocompatibility complex on chromosome 6p21) and IDDM2 (in the insulin gene region on chromosome 11p15), eighteen different chromosome regions showed some positive evidence of linkage to disease. Linkages to chromosomes 11q (IDDM4) and 6q (IDDM5) were confirmed by replication, and chromosome 18 may encode a fifth disease locus. There are probably no genes with large effects aside from IDDM1. Therefore polygenic inheritance is indicated, with a major locus at the major histocompatibility complex.

The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1-kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By 'cross-match' haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent-of-origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.

It has been reported that an increased population of regulatory T cells (Tregs) is one of the reasons for impaired anti-tumor immunity. Recently, Foxp3 has been reported as a reliable marker of Tregs. The authors investigated the frequency of Foxp3 1 Tregs within CD4 1 cells in TILs, regional lymph nodes and PBLs of gastric cancer patients (n 5 45). Furthermore, to elucidate the mechanisms behind Treg accumulation within tumors, they evaluated the relationship between CCL17 or CCL22 expression and the frequency of Foxp3 1 Tregs in gastric cancer. CD4 1 CD25 1 Foxp3 1 Tregs as a percentage of CD4 1 cells were counted by flow cytometry and evaluated by immunohistochemistry. Moreover, an in vitro migration assay using Tregs derived from gastric cancers was performed in the presence of CCL17 or CCL22. As a result, the frequency of Foxp3 1 Tregs in TILs was significantly higher than that in normal gastric mucosa (12.4% 6 7.5% vs. 4.1% 6 5.3%, p < 0.01). Importantly, the increase in Tregs in TILs occurred to the same extent in early and advanced disease. Furthermore, the frequency of CCL17 1 or CCL22 1 cells among CD14 1 cells within tumors was significantly higher than that of normal gastric mucosa, and there was a significant correlation between the frequency of CCL17 1 or CCL22 1 cells and Foxp3 1 Tregs in TILs. In addition, the in vitro migration assay indicated that Tregs were significantly induced to migrate by CCL17 or CCL22. In conclusion, CCL17 and CCL22 within the tumor are related to the increased population of Foxp3 1 Tregs, with such an observation occurring in early gastric cancer. ' 2008 Wiley-Liss, Inc.Key words: CCL17; CCL22; Foxp3; regulatory T cells; gastric cancer It has been reported that regulatory T cells (T regs) play important roles in immunological self-tolerance, 1-4 and are functionally immune-suppressive subsets of T cells. T regs are identified as a small population of CD4 1 cells that constitutively express CD25 (IL-2 receptor a chain) on their surface, and several other markers, including CD45RO, glucocorticoid-induced tumor-necrosis factor receptor-related protein (GITR), or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), are also known to be expressed on T regs. [3][4][5] Recently, it has been reported that Foxp3, forkhead/ winged helix transcription factor, is the most reliable marker of T regs 6,7 ; therefore, it is possible to define T regs more strictly as CD4 1 CD25 1 Foxp3 1 cells.In mice, it is known that auto-immune diseases such as ulcerative colitis or Crohn's disease occur due to the depletion of T regs. 6,8 Also in humans, immune dysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is an auto-immune disease developed from a deficiency of T regs. [8][9][10][11] These observations indicate that T regs play important roles in immunological homeostasis. Although the mechanisms of suppression by T regs are still unclear, it has been reported that T regs can inhibit the function of effector T cells directly by cell to cell contact or indirectly via the se...

To assess the effect of Asian-specific HLA haplotypes on susceptibility to type 1 diabetes, we investigated the association of genotypic combinations of DRB1-DQB1 haplotypes with susceptibility to type 1 diabetes. We studied 132 Japanese patients with type 1 diabetes and 157 control subjects, along with 67 Korean patients and 109 control subjects. DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 were confirmed to be two major susceptible HLA haplotypes in the Japanese population. The frequencies of heterozygotes and homozygotes with DRB1*0405-DQB1*0401 were similarly higher in patients than in control subjects (homozygotes, 5.3% vs. 3.8%; heterozygotes, 48.5% vs. 26.1%). In contrast, homozygotes, but not heterozygotes, with DRB1*0901-DQB1*0303 were more frequent in patients with type 1 diabetes than in control subjects (homozygotes, 12.9% vs. 0.6%; heterozygotes, 22.0% vs. 24.8%). A similar tendency was also observed in the Korean population. In multiple logistic regression analysis, DRB1*0405-DQB1*0401 fitted a dominant model and DRB1*0901-DQB1*0303 fitted a recessive model. These data, which indicate that the contribution of HLA haplotypes to the genetic susceptibility to type 1 diabetes differs depending on the genotypic combination of HLA haplotypes, suggest the importance of extensive analysis of genotypes in studies on HLA and disease association in general. Diabetes 51:545-551, 2002

The allele frequencies for a Pro 12 3 Ala substitution in peroxisome proliferator-activated receptor-␥ differ among ethnic groups, and its relationship with diabetes and associated diseases is controversial. The prevalence of this polymorphism and its effects on clinical characteristics have now been evaluated with a large number of Japanese individuals with type 2 diabetes (n ‫؍‬ 2,201) and normal control subjects (n ‫؍‬ 1,212) recruited by 10 institutions located in seven different cities in Japan. The allele frequency for the Ala 12 variant was significantly lower in the type 2 diabetic group than in the control group (2.39 vs. 4.13%, P ‫؍‬ 0.000054). However, compared with subjects without the Ala 12 variant, the diabetic subjects with this variant exhibited a significantly higher serum concentration of total cholesterol (P ‫؍‬ 0.001), manifested a reduced capacity for insulin secretion as evaluated by homeostasis model assessment (P ‫؍‬ 0.007), and tended to possess a higher level of HbA 1c . These data suggest that the Ala 12 variant is associated with a reduced risk for the development of diabetes in the general population, but that it may be also a risk factor for insulin deficiency and disease severity in individuals with type 2 diabetes. Diabetes 50:891-894, 2001

To facilitate large-scale genetic mapping of the human genome, we have developed chromosome-specific sets of microsatellite marker loci suitable for use with a fluorescence-based automated DNA fragment analyser. We present 254 dinucleotide repeat marker loci (80% from the Généthon genetic linkage map) arranged into 39 sets, covering all 22 autosomes and the X chromosome. The average distance between adjacent markers is 13 centiMorgans, and less than 4% of the genome lies more than 20 cM from the nearest marker. Each set of microsatellites consists of up to nine marker loci, with allele size ranges that do not overlap. We selected marker loci on the basis of their reliability in the polymerase chain reaction, polymorphism content, map position and the accuracy with which alleles can be scored automatically by the Genotyper program.

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We previously identified three novel HLA-A24-restricted epitope peptides, which were derived from three cancer-testis antigens, TTK protein kinase (TTK), lymphocyte antigen 6 complex locus K (LY6K), and insulin-like growth factor (