HLA‐G 14‐bp polymorphism affects the age of onset in Type I Diabetes Mellitus

Gerasimou, Petroula; Skordis, Nicos; Picolos, Michalis; Spyridonidis, Alexandros; Costeas, Paul

doi:10.1111/iji.12259

Cited by 17 publications

(12 citation statements)

References 58 publications

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“…A dataset of previously enrolled consented case (T1D patients) and control (individuals with no history of diabetes) subjects was used [ 19 , 39 ]. The case cohort consisted of 170 Greek Cypriot patients with a cut off age of disease onset set at 39 years (89 females, 81 males, mean age 11 years, age of onset: 0–8 years 59 patients, 9–13 years 60 patients, 14–39 51 patients).…”

Section: Methodsmentioning

confidence: 99%

Combined effect of glutamine at position 70 of HLA-DRB1 and alanine at position 57 of HLA-DQB1 in type 1 diabetes: An epitope analysis

Gerasimou

Nicolaidou

Skordis³

et al. 2018

PLoS ONE

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The contribution of specific HLA Class II alleles in type 1 diabetes is determined by polymorphic amino acid epitopes that direct antigen binding therefore, along with conventional allele frequency analysis, epitope analysis can provide important insights into disease susceptibility. We analyzed the highly heterogeneous Cypriot population for the HLA class II loci of T1DM patients and controls and we report for the first time their allele frequencies. Within our patient cohort we identified a subgroup that did not carry the DRB1*03:01-DQA1*05:01-DQB1*02:01 and DRB1*04:xx-DQA1*03:01-DQB1*03:02 risk haplotypes but a novel recombinant one, DRB1*04:XX-DQA1*03:01-DQB1*02:01 designated DR4-DQ2.3. Through epitope analysis we identified established susceptibility (DQB1 A57, DRB1 H13) and resistance (DQB1 D57) residues as well as other novel susceptibility residues DRB1 Q70, DQB1 L26 and resistance residues DRB1 D70, R70 and DQB1 Y47. Prevalence of susceptibility epitopes was higher in patients and was not exclusively a result of linkage disequilibrium. Residues DRB1 Q70, DQB1 L26 and A57 and a 10 amino acid epitope of DQA1 were the most significant in discriminating risk alleles. An extended haplotype containing these epitopes was carried by 92% of our patient cohort. Sharing of susceptibility epitopes could also explain the absence of risk haplotypes in patients. Finally, many significantly associated epitopes were non-pocket residues suggesting that critical immune functions may exist spanning further from the binding pockets.

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Section: Methodsmentioning

confidence: 99%

Combined effect of glutamine at position 70 of HLA-DRB1 and alanine at position 57 of HLA-DQB1 in type 1 diabetes: An epitope analysis

Gerasimou

Nicolaidou

Skordis³

et al. 2018

PLoS ONE

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“…In autoimmunity and cancer, results on the association of 14-bp INS/DEL genotypes with disease development or with response to therapy reported contradictory and/or inconclusive results. In the context of type 1 diabetes (T1D), the analysis revealed the association of the 14-bp DEL/DEL genotype with the development and the early onset of the disease (27,28). Conversely, in Crohn's disease, a high frequency of the 14-bp INS allele has been associated with an increased risk of early disease onset (29).…”

Section: Hla-g Genetic Footprint and Correlation With Disease Coursementioning

confidence: 99%

HLA-G Genotype/Expression/Disease Association Studies: Success, Hurdles, and Perspectives

Amodio

Gregori

2020

Front. Immunol.

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The non-classical HLA-G is a well-known immune-modulatory molecule. In physiological condition, HLA-G surface expression is restricted to the maternal-fetal interface and to immune-privileged adult tissues, whereas soluble forms of HLA-G are detectable in various body fluids. HLA-G can be de novo expressed in pathological conditions including tumors, chronic infections, or after allogeneic transplantation. HLA-G exerts positive effects modulating innate and adaptive immune responses and promoting tolerance, or detrimental effects inducing immune escape mechanisms. HLA-G locus, in contrast to classical HLA class I gene, is highly polymorphic in the non-coding 3 ′ untranslated region (UTR) and in the 5 ′ upstream regulatory region (5 ′ URR). Variability in these regions influences HLA-G expression by modifying mRNA stability or allowing posttranscriptional regulation in the case of 3 ′ UTR or by sensing the microenvironment and responding to specific stimuli in the case of HLA-G promoter regions (5 ′ URR). The influence of genetic variations on the expression of HLA-G makes it an attractive biomarker to monitor disease predisposition and progression, or response to therapy. Here, we summarize the current knowledge, efforts, and obstacles to generate a general consensus on the correlation between HLA-G genetic variability, protein expression, and disease predisposition. Moreover, we discuss perspectives for future investigation on HLA-G genotype/expression in association with disease predisposition and progression.

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“…Associations between an HLA-G polymorphism and the age of onset of type 1 diabetes have been found [46]. Homozygosity for the deletion of 14 bp of the 3′ untranslated region of HLA-G was associated with an earlier age of type 1 diabetes onset, whereas heterozygotes (carrying only one deletion) had a later age of onset of type 1 diabetes [46]. HLA-G is expressed by pancreatic islet and duct cells, and it is upregulated in response to pro-inflammatory cytokines [37].…”

Section: What Is Known About Non-classical Hla Class I In Type 1 Diabmentioning

confidence: 99%

What the HLA-I!—Classical and Non-classical HLA Class I and Their Potential Roles in Type 1 Diabetes

et al. 2019

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Purpose of ReviewHyperexpression of classical HLA class I (HLA-I) molecules in insulin-containing islets has become a widely accepted hallmark of type 1 diabetes pathology. In comparison, relatively little is known about the expression, function and role of non-classical subtypes of HLA-I. This review focuses on the current understanding of the non-classical HLA-I subtypes: HLA-E, HLA-F and HLA-G, within and outside the field of type 1 diabetes, and considers the possible impacts of these molecules on disease etiology.Recent FindingsEvidence is growing to suggest that non-classical HLA-I proteins are upregulated, both at the RNA and protein levels in the pancreas of individuals with recent-onset type 1 diabetes. Moreover, associations between non-classical HLA-I genotypes and age at onset of type 1 diabetes have been reported in some studies. As with classical HLA-I, it is likely that hyperexpression of non-classical HLA-I is driven by the release of diffusible interferons by stressed β cells (potentially driven by viral infection) and exacerbated by release of cytokines from infiltrating immune cells.SummaryNon-classical HLA-I proteins predominantly (but not exclusively) transduce negative signals to immune cells infiltrating at the site of injury/inflammation. We propose a model in which the islet endocrine cells, through expression of non-classical HLA-I are fighting back against the infiltrating immune cells. By inhibiting the activity and function on NK, B and select T cells, the non-classical HLA-I, proteins will reduce the non-specific bystander effects of inflammation, while at the same time still allowing the targeted destruction of β cells by specific islet-reactive CD8+ T cells.

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HLA‐G 14‐bp polymorphism affects the age of onset in Type I Diabetes Mellitus

Cited by 17 publications

References 58 publications

Combined effect of glutamine at position 70 of HLA-DRB1 and alanine at position 57 of HLA-DQB1 in type 1 diabetes: An epitope analysis

Combined effect of glutamine at position 70 of HLA-DRB1 and alanine at position 57 of HLA-DQB1 in type 1 diabetes: An epitope analysis

HLA-G Genotype/Expression/Disease Association Studies: Success, Hurdles, and Perspectives

What the HLA-I!—Classical and Non-classical HLA Class I and Their Potential Roles in Type 1 Diabetes

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