Genetic association between the interleukin-2 receptor-alpha gene and mode of onset of type 1 diabetes in the Japanese population.

CONTEXT/OBJECTIVE: The IL-2 receptor-alpha (IL2RA), also known as CD25, is expressed on the regulatory T cells, which play an important role in the control of immune responses and the maintenance of immune homeostasis. Our objective was to determine whether variants in the IL2RA gene are associated with type 1 diabetes in the Japanese population. DESIGN/PATIENTS: We genotyped the four single-nucleotide polymorphisms (rs706778, rs3118470, ss52580101, and rs11594656) of the IL2RA in 885 patients with type 1 diabetes and 606 control subjects of Japanese origin. The allele and genotype frequencies were examined in the patient groups stratified by their mode of onset in a case-control study. RESULTS: We found evidence of association with acute-onset, but not slow-onset and fulminant, type 1 diabetes for two of the four single-nucleotide polymorphisms genotyped (rs706778 and rs3118470). The rs706778 A allele and the rs3118470 G allele were associated with an increased disease risk [odds ratio (OR) for rs706778 AA genotype 1.54, P = 4.2 x 10(-4) and OR for rs3118470 GG genotype 1.50, P = 0.0019, respectively]. Furthermore, the A-G haplotype was associated with increased type 1 diabetes risk in the acute-onset form (OR 1.30, P = 0.002). CONCLUSIONS: The present data confirm the type 1 diabetes association with IL2RA and provide evidence that the different contributions of the IL2RA in the susceptibility to acute-onset and other forms of type 1 diabetes in the Japanese population.

Association of type 1 diabetes with two Loci on 12q13 and 16p13 and the influence coexisting thyroid autoimmunity in Japanese.

CONTEXT: Recent genome-wide association studies have identified several novel type 1 diabetes (T1D) loci in white populations. OBJECTIVE: In line with recent findings, we conducted a replication study of two loci on chromosome 12p13 and 16p13 and assessed their potential associations with thyroid autoimmunity in a Japanese population. SUBJECTS AND METHODS: Two single-nucleotide polymorphisms (SNPs), rs2292399 in ERBB3 on 12q13 and rs2903692 in CLEC16A (or KIAA0350) on 16p13, were analyzed in Japanese subjects consisting of 735 T1D patients, 330 patients with autoimmune thyroid disease (AITD), and 621 control subjects. RESULTS: According to a case-control study and logistic regression adjusting for sex and age, we observed that these SNPs in ERBB3 and CLEC16A were both significantly associated with T1D, with the risk alleles being consistent with those in white populations [adjusting odds ratio by multiplicative model: 1.37 (1.13-1.67), P = 0.001; and 1.28 (1.02-1.60), P = 0.030, respectively]. In both SNPs, the association was suggested to be stronger in T1D complicated with AITD (Graves' disease, Hashimoto's thyroiditis, or thyroid autoantibodies). Furthermore, a joint analysis, with the INS and CTLA4 SNPs, revealed that CTLA4 rs3087243, ERBB3 rs2292399, and CLEC16A rs2903692, but not INS rs689, were significant risk factors for the cooccurrence of AITD in Japanese T1D. CONCLUSION: We confirmed two loci on 12q13 and 16p13 that were identified by the independent genome-wide association studies in white populations, thus suggesting that these loci contribute to T1D susceptibility across different ethnic groups. In addition, these loci may also be associated with the cooccurrence of thyroid autoimmunity in T1D.

Differences in the contribution of the CTLA4 gene to susceptibility to fulminant and type 1A diabetes in Japanese patients.

OBJECTIVE: To examine the contribution of the CTLA4 gene in the susceptibility to fulminant type 1 diabetes and compare it with classic type 1A diabetes. RESEARCH DESIGN AND METHODS: We genotyped the +49G>A and CT60G>A variants of the CTLA4 gene in fulminant type 1 diabetic patients (n = 55), classic type 1A diabetic patients (n = 91), and healthy control subjects (n = 369). We also assessed serum levels of the soluble form of CTLA4 (sCTLA4). RESULTS: The +49GG and CT60GG genotypes were associated with type 1A diabetes (P < 0.001). In contrast, the CT60AA genotype, but not the +49G>A variation, was associated with fulminant type 1 diabetes (P < 0.05), especially in patients carrying HLA-DR4 (P < 0.01). Serum levels of sCTLA4 were significantly decreased in patients with fulminant type 1 diabetes (P < 0.05). CONCLUSIONS: These results suggest that CTLA4 CT60 affects the genetic susceptibility to fulminant type 1 diabetes. Furthermore, the contribution of CTLA4 to disease susceptibility is distinct between fulminant type 1 diabetes and classic type 1A diabetes.

Evidence for association between vitamin D receptor BsmI polymorphism and type 1 diabetes in Japanese.

Type 1 diabetes is considered to be T-helper 1 (Th1) type autoimmune disease. Because the vitamin D receptor is expressed on CD4+T cells and is known to affect cytokine responses, several groups have investigated the association between the vitamin D receptor gene BsmI polymorphism and type 1 diabetes. However, this issue is still controversial; therefore, we examined this gene polymorphism in a large number of type 1 diabetic patients as a multi-center collaborative study in Japan. A total of 1,373 subjects, including 774 cases and 599 control subjects of Japanese origin, were studied. The frequency of carriers of the BB genotype in type 1 diabetic patients was significantly higher than that in controls (p<0.01, odds ratio 3.65). Moreover, IFN-gamma production upon anti-CD3 stimulation in the BB genotype group was significantly higher than that in the Bb and bb genotype groups (p<0.05), suggesting that the polyclonal T cell response in BB genotype patients is Th1 dominant. Based upon these results, we propose that it may be worthwhile to focus on subjects with the BB genotype of this gene polymorphism as having high risk for type 1 diabetes.

Insulin gene/IDDM2 locus in Japanese type 1 diabetes: contribution of class I alleles and influence of class I subdivision in susceptibility to type 1 diabetes.

CONTEXT: It is suggested that insulin autoimmunity plays an important role in the development of type 1 diabetes in humans. However, the association between insulin gene (INS) region (IDDM2) and type 1 diabetes has been uncertain in Asians. OBJECTIVE: A multicenter collaboration study was conducted to clarify the role of the IDDM2 region in Japan. SUBJECTS AND METHODS: In total, 661 patients with type 1 diabetes and 706 control subjects were enrolled. The INS variable number of tandem repeat (VNTR) class I/class III status was estimated by genotyping the -23 HphI single nucleotide polymorphism. From surrounding polymorphisms across the insulin gene, we also inferred haplotypes bearing INS VNTR lineages. RESULTS: The frequency of the class I allele was 99.3% in patients and 96.7% in controls (P < 10(-5)), and the class I/III or III/III genotype was found in 1.4% of patients and in 6.4% of controls [odds ratio (OR) 0.20, P < 10(-5)]. The class I subdivision revealed IC to increase significantly in patients with type 1 diabetes (P = 0.002), whereas ID did not; the distribution of IC and ID was significantly different between patients and controls (P = 0.014). CONCLUSION: The present study certainly shows that the IDDM2 region is also a susceptibility locus in the Japanese population. Furthermore, it was revealed that IC may be more susceptible to type 1 diabetes than ID, which could be evidence that the INS VNTR itself confers susceptibility to type 1 diabetes.

Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations.

The protein tyrosine phosphatase, nonreceptor 22 gene (PTPN22) maps to human chromosome 1p13.3-p13.1 and encodes an important negative regulator of T-cell activation, lymphoid-specific phosphatase (Lyp). Recently, the minor allele of a single-nucleotide polymorphism (SNP) at nucleotide position 1858 (rs2476601, +1858C > T) was found to be associated with type 1 diabetes. However, the degree of the association is variable among ethnic populations, suggesting the presence of other disease-associated variants in PTPN22. To examine this possibility, we carried out a systemic search for PTPN22 using direct sequencing of PCR-amplified products in the Japanese population. Association and linkage studies were also conducted in 1,690 Japanese samples, 180 Korean samples, and 472 Caucasian samples from 95 nuclear families. We identified five novel SNPs, but not the +1858C > T SNP. Of these two frequent SNPs, -1123G > C, and +2740C > T were in strong linkage disequilibrium (LD), and the -1123G > C promoter SNP was associated with acute-onset but not slow-onset type 1 diabetes in the Japanese population (odds ratio [OR] = 1.42, 95% CI = 1.07-1.89, P = 0.015). This association was observed also in Korean patients with type 1 diabetes (Mantel-Haenszel chi2= 6.543, P = 0.0105, combined OR = 1.41 95% CI = 1.09-1.82). Furthermore, the affected family-based control (AFBAC) association test and the transmission disequilibrium analysis of multiplex families of European descent from the British Diabetes Association (BDA) Warren Repository indicated that the association was stronger in -1123G > C compared to +1858C > T. In conclusion, the type 1 diabetes association with PTPN22 is confirmed, but it cannot be attributed solely to the +1858C > T variant. The promoter -1123G > C SNP is a more likely causative variant in PTPN22.