A Human Type 1 Diabetes Susceptibility Locus Maps to Chromosome 21q22.3

Concannon, Patrick; Önengüt-Gümüşcü, Suna; Todd, John A.; Smyth, Deborah J.; Pociot, Flemming; Bergholdt, Regine; Akolkar, Beena; Erlich, Henry A.; Hilner, Joan E.; Julier, Cécile; Morahan, Grant; Nerup, Jørn; Nierras, Concepcion R.; Chen, Weimin; Rich, Stephen S.

doi:10.2337/db08-0753

Cited by 104 publications

(92 citation statements)

References 34 publications

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“…Currently 15 loci have been identified that have convincing evidence for association with T1D. [1][2][3][4] Interestingly, several of these T1D susceptibility loci are shared with other immune-mediated diseases, namely PTPN22, CTLA4, IL2RA, IL2, IL7R and SH2B3 (see Table 1 for full gene names). 1,5,6 Therefore, we sought to test newly identified rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis, ankylosing spondylitis (AS) and Crohn's disease (CD) loci for association in T1D [7][8][9][10][11][12][13][14][15][16][17] with the assumption of an increased prior probability of association based on the previous evidence of overlapping risk alleles across autoimmune diseases.…”

mentioning

confidence: 99%

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

et al. 2008

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mentioning

confidence: 99%

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

et al. 2008

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mentioning

confidence: 99%

“…In humans, particular HLA alleles are also associated with T1D, explaining more than 50% of the genetic risk for disease development (14). For example, the HLA-DQ8 (DQB*03:02) and DQ2 (DQB*02:01 and DQB*02:02) alleles greatly increase the risk of disease development, with ∼90% of all T1D individuals having one or both alleles (14)(15)(16).…”

mentioning

confidence: 99%

“…For example, the HLA-DQ8 (DQB*03:02) and DQ2 (DQB*02:01 and DQB*02:02) alleles greatly increase the risk of disease development, with ∼90% of all T1D individuals having one or both alleles (14)(15)(16). Strikingly, the polymorphic HLA-DQ6 (DQB*06:02) allele provides dominant protection from diabetes development (14). DQ is the homolog of mouse IA, and the β-chains of DQ2 and DQ8 share with IA g7 the unique non-D amino acid polymorphism at position 57 that favors an acidic amino acid at the p9 position of their binding grooves (17).…”

mentioning

confidence: 99%

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Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

Nakayama

McDaniel

Fitzgerald-Miller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA g7 , in an unfavorable position or register. Because of the similarities between IA g7 and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulinspecific therapies to prevent diabetes onset.T ype 1 diabetes (T1D), the autoimmune form of diabetes, results from T cell-mediated destruction of insulin-producing β-cells within pancreatic islets (1). The disease is dramatically increasing in incidence, doubling in the last two decades (2, 3), and now predictable with the measurement of antibodies directed against insulin and other proteins found in β-cells (4). Major efforts at disease prevention have been undertaken using preparations of insulin (s.c., oral, and intranasal) to induce tolerance and delay the onset of clinical symptoms (5-7). Measuring insulin-specific T-cell responses from the peripheral blood has been challenging but would allow for assessment of therapeutic response, which has been a major obstacle in these trials. In our study, we sought to detect peripheral T-cell responses to insulin in T1D patients and nondiabetic controls using a modified insulin B-chain peptide.Insulin is a major self-antigen for both T and B cells in murine and human T1D, with insulin B-chain amino acids 9-23 (B:9-23) being a key epitope presented by major histocompatibility complex class II (MHCII) molecules to CD4 T cells targeting pancreatic β-cells (8-10). There is strong evidence from the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes that the NOD MHCII molecule, IA g7 , is required for development of T1D and that pathogenic CD4 T cells recognize insulin B:9-23 presented in an unfavorable position or register (Reg3) in the IA g7 peptide binding groove (9, 11,...

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“…Several IFIH1 polymorphisms were associated with T1DM, with the rs1990760 (G/A) polymorphism, which substitutes an alanine to valine in codon 946 of exon 15, being most strongly associated with protection against development of the disease (odds ratio [OR] = 0.86, P = 1.42 x 10 -10 for the G allele) (50). Associations between IFIH1 polymorphisms and T1DM have been replicated in some populations (29,(51)(52)(53)(54)(55), but not in others (56)(57)(58) (Table 1). Jermendy and cols.…”

Section: Ifih1 Gene Polymorphisms and Their Association With T1dmmentioning

confidence: 92%

The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus

Bouças

Oliveira

Canani

et al. 2013

Arq Bras Endocrinol Metab

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Type 1 diabetes mellitus (T1DM) is a chronic, progressive, autoimmune disease characterized by metabolic decompensation frequently leading to dehydration and ketoacidosis. Viral pathogens seem to play a major role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, enteroviruses have been consistently associated with T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The IFIH1 gene encodes a cytoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, playing a role in the innate immune response triggered by viral infection. Binding of dsRNA to this PRR triggers the release of proinflammatory cytokines, such as interferons (IFNs), which exhibit potent antiviral activity, protecting uninfected cells and inducing apoptosis of infected cells. The IFIH1 gene appears to play a major role in the development of some autoimmune diseases, and it is, therefore, a candidate gene for T1DM. Within this context, the objective of the present review was to address the role of IFIH1 in the development of T1DM. Arq Bras Endocrinol Metab. 2013;57(9):667-76 Keywords Autoimmunity; type 1 diabetes mellitus; viral infection; IFIH1 RESUMO O diabetes melito tipo 1 (T1DM) é uma doença autoimune crônica e progressiva caracterizada por descompensações metabólicas frequentemente acompanhadas por desidratação e cetoacidose. Os agentes virais parecem ter um papel importante no desencadeamento da destruição autoimune que leva ao desenvolvimento do T1DM. Entre as cepas virais estudadas até agora, a família dos enterovírus foi consistentemente associada ao surgimento da doença em humanos. Um dos mediadores do dano viral é o RNA fita dupla (RNAfd) gerado durante a replicação e transcrição de RNA e DNA viral. O gene IFIH1 codifica um receptor citoplasmático pertencente à família dos pattern-recognition receptors (PRRs) que reconhece o RNAfd, tendo um papel importante na resposta imune inata desencadeada por infecção viral. A ligação do RNAfd a essa PRR desencadeia a liberação de citocinas pró-inflamatórias como interferons (IFNs), os quais exibem uma potente ação antiviral e têm como objetivo proteger as células não infectadas e induzir apoptose naquelas já contaminadas. O gene IFIH1 parece ter uma participação importante no desenvolvimento de algumas doenças autoimunes. Por isso, esse gene é um candidato ao desenvolvimento do T1DM. Dentro desse contexto, o objetivo da presente revisão foi abordar o papel do IFIH1 no desenvolvimento do T1DM. Arq Bras Endocrinol Metab.2013;57(9):667-76 Descritores Autoimunidade; diabetes melito tipo 1; infecção viral; IFIH1

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A Human Type 1 Diabetes Susceptibility Locus Maps to Chromosome 21q22.3

Cited by 104 publications

References 34 publications

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus

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