No confirmation of extreme genetic risk for type 1 diabetes (T1D) in DR3/4-DQ8 siblings sharing both extended HLA haplotypes with their diabetic proband

Transplantation and autoimmunit

No extreme genetic risk for type 1 diabetes among DR3/4-DQ8 siblings sharing both extended HLA haplotypes with their diabetic proband

An extreme genetic risk for type 1 diabetes (T1D) was reported for DR3/4-DQ8 siblings sharing both extended human leukocyte antigen (HLA) haplotypes identical-by-descent (IBD) with their diabetic proband. We attempted to replicate this finding in our prospective Dutch T1D cohort and in families from the Type 1 Diabetes Genetics Consortium (T1DGC). Only 2 of the 14 Dutch siblings, sharing both DR3-DQ2/DR4-DQ8 haplotypes IBD with their diabetic proband, developed T1D in a 12-year follow-up period. No differential sharing of HLA haplotypes or significant transmission distortion in parents homozygous for HLA risk alleles was found in T1DGC material. Therefore, we could not confirm the reported extreme risk for T1D, suggesting that the risk conferred by other HLA complex loci is moderate

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 trans-molecules composed of α and β chains from DQ2 and DQ8 express unique β-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis- and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.Transplantation and autoimmunit

Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes

RANTES ( regulated on activation, normal T-cell expressed and secreted) is a T-helper type 1 (Th1) chemokine that promotes T-cell activation and proliferation. RANTES is genetically associated with asthma, sarcoidosis and multiple sclerosis. The concentration of RANTES is increased at inflammation sites in different autoimmune diseases. Type 1 diabetes (T1D) is a Th1-mediated disease with complex genetic predisposition. We tested RANTES as a candidate gene for association with T1D using three single-nucleotide polymorphism ( SNP) variants (rs4251719, rs2306630 and rs2107538) to capture haplotype information. The minor alleles of all SNPs were transmitted less frequently to T1D offspring (transmission rates 37.3% (P = 0.002), 38.7% (P = 0.007) and 41.0% ( P = 0.01)) and were less frequently present in patients compared to controls (P = 0.009, 0.03 and 0.04, respectively). A similar protective effect was observed for the haplotype carrying three minor alleles (transmission disequilibrium test (TDT): P = 0.003; odds ratio (OR) = 0.55; confidence interval (CI): 0.37 - 0.83; case/control: P 0.03; OR 0.74; CI: 0.55 - 0.98). Both patients and controls carrying the protective haplotype express significantly lower serum levels of RANTES compared to non-carriers. Subsequently, we tested a cohort of 310 celiac disease patients, but failed to detect association. RANTES SNPs are significantly associated with RANTES serum concentration and development of T1D. The rs4251719* A-rs2306630* A-rs2107538* A haplotype associated with low RANTES production confers protection from T1D. Our data imply that RANTES is associated with T1D both genetically and functionally, and contributes to diabetes-prone Th1 cytokine profile

Association analysis of myosin IXB and type 1 diabetes

To date, seven studies have provided evidence for an association between the gene encoding for myosin IXB (MYO9B) and celiac disease (CD), and inflammatory bowel diseases, including single nucleotide polymorphisms (SNPs) rs2305767, rs1457092, and rs2305764. We investigated whether MYO9B is associated with T1D. The three SNPs were genotyped in Dutch samples from 288 T1D patients and 1615 controls. The A allele of SNP rs2305767A>G showed some evidence of association with T1D (nominal p for genotype = 0.06; OR carrier = 1.51,95% CI = 1.04-2.19), but not in British samples from 4301 case patients and 4706 controls (p = 0.53), or when the Dutch and UK data were pooled (N patients = 4582, N controls = 6224; Mantel-Hansel p=0.83). Furthermore, the nonsynonymous rs1545620 C>A SNP that has been associated with the inflammatory bowel disease, showed no association with T1D in British case-control set (p = 0.57). We conclude that MYO9B might not be a strong determinant of T1D, although there was some association in our initial Dutch study. Further studies are needed to evaluate the role of MYO9B in T1D. (C) 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.Transplantation and autoimmunit

MICA marks additional risk factors for Type 1 diabetes on extended HLA haplotypes: An association and meta-analysis

The association of the HLA complex on chromosome 6 does not explain total linkage of the HLA region to Type 1 Diabetes (T1D), leading to the hypothesis that there may be additional causal genes in the HLA region for immune-related disorders. Reports on the MHC Class I chain-related A (MICA) gene as candidate for association with T1D are contradicting. We investigated whether variation in MICA is associated to T1D in a cohort of 350 unrelated individuals with juvenile-onset T1D and 540 control subjects, followed by a meta-analysis of 14 studies. We also investigated an HLA-independent association for MICA with T1D. In our case-control study, we found that the MICA*A5 variant was significantly associated with an increased risk for T1D, while MICA*A6 was significantly associated with a decreased risk that was confirmed by our meta-analysis. However, the meta-analysis did not show an association of MICA*A5 T1D. Analysis of MICA alleles conditional on T1D-associated high-risk MHC class II haplotypes revealed that MICA*A6 was associated with an increased risk for T1D when this marker co-occurred with HLA DQ2DR17 T1D risk-haplotypes. In contrast, MICA*A6 reduced the risk from the HLA DQ8DR4 T1D-risk haplotype. Moreover, MICA*A9 showed a significant association to increased risk for T1D on DQ8DR4 haplotypes. Co-inheritance of MICA*A6 with the HLA DQ2DR17 haplotype in T1D indicates this haplotype may carry the additional genetic factors for T1D, but our study does not support an independent association between MICA variants and T1D. (c) 2007 Elsevier Ltd. All rights reserved

Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population.

Contains fulltext : 49092.pdf (publisher's version ) (Closed access)Protein tyrosine phosphatase PTPN22 is involved in the negative regulation of T-cell responsiveness. Recently, the association of a coding variant of the PTPN22 gene-R620W(1858C>T) with a number of autoimmune diseases has been described. Therefore, we tested the association of PTPN22 1858*T allele in Dutch early onset type 1 diabetes (T1D) and rheumatoid arthritis (RA) patients, as well as celiac disease (CD) patients, for which no previous study of PTPN22 has been reported. The PTPN22 variant was strongly associated with T1D in cases vs controls (P=2 x 10(-7), OR=2.3, 95% CI=1.7-3.1) as well as in a transmission disequilibrium test in nuclear trio's (P=9 x 10(-9), OR=3.3, CI=2.1-5.0), RA (case/control: P=0.003, OR=1.8 CI =1.2-2.6), but not CD, in spite of a trend of increased homozygosity (P=0.05) and early age at onset (P=0.01). PTPN22 is not generally associated with T-cell mediated autoimmune diseases, although it might play a role in the CD patients with early clinical manifestation

Early Onset of Diabetes in the Proband Is the Major Determinant of Risk in HLA DR3-DQ2/DR4-DQ8 Siblings

Islet autoimmunity is initiated in infancy, and primary prevention trials require children at high genetic risk to be identified before autoantibodies appear. To inform screening strategies, we evaluated risks of autoimmunity and diabetes associated with HLA DR3-DQ2/DR4-DQ8 in UK families. Extended HLA haplotypes were determined in 2,134 siblings from the Bart's-Oxford Study followed to median age 22 years. Risks of diabetes and islet autoimmunity (≥ 2 antibodies) were estimated by survival analysis. Of 138 informative DR3-DQ2/DR4-DQ8 siblings, 63% shared both haplotypes with their diabetic proband, 29% shared one and 8% neither. In HLA-identical DR3-DQ2/DR4-DQ8 siblings, the cumulative risk of diabetes by age 15 was 17% (vs. 6% in those sharing one haplotype or none, p=0.095). Risk varied, however, with diabetes age-at-onset in the proband; the cumulative risk of autoimmunity and/or diabetes by age 15 was 61% in siblings of probands diagnosed below age 10 years compared with only 4.7% in those diagnosed after age 10 years (

Association analysis of myosin IXB and type 1 diabetes

To date, seven studies have provided evidence for an association between the gene encoding for myosin IXB (MYO9B) and celiac disease (CD), and inflammatory bowel diseases, including single nucleotide polymorphisms (SNPs) rs2305767, rs1457092, and rs2305764. We investigated whether MYO9B is associated with T1D. The three SNPs were genotyped in Dutch samples from 288 T1D patients and 1615 controls. The A allele of SNP rs2305767A>G showed some evidence of association with T1D (nominal p for genotype = 0.06; OR carrier = 1.51,95% CI = 1.04-2.19), but not in British samples from 4301 case patients and 4706 controls (p = 0.53), or when the Dutch and UK data were pooled (N patients = 4582, N controls = 6224; Mantel-Hansel p=0.83). Furthermore, the nonsynonymous rs1545620 C>A SNP that has been associated with the inflammatory bowel disease, showed no association with T1D in British case-control set (p = 0.57). We conclude that MYO9B might not be a strong determinant of T1D, although there was some association in our initial Dutch study. Further studies are needed to evaluate the role of MYO9B in T1D. (C) 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved