Relative predispositional effects of HLA class II DRB1‐DQB1 haplotypes and genotypes on type 1 diabetes: a meta‐analysis

Thomson, Glenys; Valdes, Ana M.; Noble, Janelle A.; Kockum, Ingrid; Grote, Mark N.; Najman, Jackob M.; Erlich, Henry A.; Cucca, Francesco; Pugliese, Alberto; Steenkiste, Ann R.; Js, Dorman; Caillat‐Zucman, Sophie; Hermann, Róbert; Ilonen, Jorma; Lambert, Aude; Bingley, Polly J.; Gillespie, K. M.; Lernmark, Åke; Sanjeevi, Carani B.; Rønningen, Kjersti S.; Undlien, Dag E.; Thorsby, E.; Petrone, Antonio; Buzzetti, Raffaella; Koeleman, Bobby P. C.; Roep, Bart O.; Saruhan‐Direskeneli, Güher; Uyar, Fatma; Günöz, Hülya; Gorodezky, Clara; Aláez, C.; Boehm, Bernhard O.; Młynarski, Wojciech; Ikegami, Hiroshi; Berrino, M.; Fasano, Maria Edvige; Dametto, Ennia; Israel, S. Leon; Brautbar, Chaim; Santiago-Cortes, A.; Llado, Teresa Frazer de; She, Jin Xiong; Bugawan, Teodorica L.; Rotter, J. I.; Raffel, Leslie J.; Zeidler, Adina; Leyva-Cobián, Francisco; Hawkins, B. R.; Chan, Ssc; Castaño, Luís; Pociot, Flemming; Nerup, Jørn

doi:10.1111/j.1399-0039.2007.00867.x

Cited by 158 publications

(179 citation statements)

References 69 publications

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“…8,14,[29][30][31][32] Earlier studies derived a HLA DR-DQ haplotype-based risk strategy, which showed a statistically significant risk hierarchy, ranging from highly predisposing to highly protective. 33,34 The need for at least three HLA DQ-DRbased risk groups was noticed by other groups, as well. 31,35,36 As this study focused exclusively on the HLA DQ region, which shows a high density of polymorphisms, a grouping based only on HLA DQ risk status was applied (see Supplementary data).…”

Section: Discussionmentioning

confidence: 99%

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

et al. 2009

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Type 1 diabetes (T1D) has a strong genetic component and the major locus lies in the HLA DQB1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4 þ CD25 þ high T-cell subset (Treg) in human subjects with recent-onset T1D and in multiple autoantibody-positive, high at-risk individuals. Tregs normally inhibit or delay onset of T1D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DQB1 genotypes are associated with increased CD4 þ CD25 þ high T-cell apoptosis. HLA DQ-based genetic risk status was significantly associated with CD4 þ CD25 þ high T-cell apoptosis, after adjustment for age, gender and phenotypic status (n ¼ 83, F ¼ 4.04 (d.f. ¼ 3), P ¼ 0.01). Unaffected, autoantibody-negative high risk HLA DQB1 control subjects showed increased CD4 þ CD25 þ high apoptosis levels compared with low risk HLA DQB1 control subjects (n ¼ 26, P ¼ 0.002), confirming that the association precedes disease. The association of specific HLA DQB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DQB1*0302, DQB1*0201 and HLA DQB1*0602 alleles. Our study shows an association of HLA DQB1 genotypes with CD4 þ CD25 þ high T-cell apoptosis, which implicates CD4 þ CD25 þ high T-cell apoptosis as a new intermediate trait for T1D.

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Section: Discussionmentioning

confidence: 99%

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

et al. 2009

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“…The most important susceptibility factors reside within the major histocompatibility complex (MHC) where particular human leukocyte antigen (HLA) class II DRB1-DQA1-DQB1 haplotypes confer high disease risk. 1,2 However, numerous studies have strongly implicated additional T1D risk loci within the MHC. [3][4][5][6][7][8][9][10][11][12] This complex contains an unusually high density of genes involved in immunological responses, 13 of which many are good candidates for involvement in autoimmune processes.…”

Section: Introductionmentioning

confidence: 99%

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

et al. 2008

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The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex.

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“…T1D is genetically strongly associated with HLA-DQ2 and HLA-DQ8 (13,14). HLA-DQ2/8 heterozygous individuals carry the highest odds ratio (OR) for T1D, exceeding that of HLA-DQ2 or HLA-DQ8 homozygous individuals (13,15).…”

Section: Posttranslational Modification Of Hla-dq Binding Islet Autoamentioning

confidence: 99%

Posttranslational Modification of HLA-DQ Binding Islet Autoantigens in Type 1 Diabetes

et al. 2013

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Posttranslational modification (PTM) of islet autoantigens can cause lack of central tolerance in type 1 diabetes (T1D). Tissue transglutaminase (tTG), involved in PTM of gluten antigens in celiac disease, creates negatively charged peptides favored by T1D-predisposing HLA-DQ molecules, offering an attractive candidate modifying islet autoantigens in T1D. The highly predisposing HLA-DQ8cis/trans molecules share preferences for negatively charged peptides, as well as distinct peptide-binding characteristics that distinguish their peptide-binding repertoire. We screened islet autoantigens with the tTG substrate motif for candidate-modified epitopes binding to HLA-DQ8cis/trans and identified 31 candidate islet epitopes. Deamidation was confirmed for 28 peptides (90%). Two of these epitopes preferentially bound to HLA-DQ8cis and six to HLA-DQ8trans upon deamidation, whereas all other peptides bound equally to HLA-DQ8cis/trans. HLA-DQ8cis-restricted T cells from a new-onset T1D patient could only be generated against a deamidated proinsulin peptide, but cross-reacted with native proinsulin peptide upon restimulation. The rate of T-cell autoreactivity in recent-onset T1D patients extended from 42% to native insulin to 68% adding responses to modified proinsulin, versus 20% and 37% respectively, in healthy donors. Most patients responded by interferon-g, whereas most healthy donors produced interleukin-10 only. Thus, T-cell autoreactivity exists to modified islet epitopes that differs in quality and quantity between patients and healthy donors.

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Relative predispositional effects of HLA class II DRB1‐DQB1 haplotypes and genotypes on type 1 diabetes: a meta‐analysis

Cited by 158 publications

References 69 publications

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

Posttranslational Modification of HLA-DQ Binding Islet Autoantigens in Type 1 Diabetes

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