Tri-SNP polymorphism in the intron of HLA-DRA1 affects type 1 diabetes susceptibility in the Finnish population

Nygård, Lucas; Laine, Antti; Toppari, Jorma; Härkönen, Taina; Knip, Mikael; Veijola, Riitta; Lempainen, Johanna; Ilonen, Jorma

doi:10.1016/j.humimm.2021.07.010

Cited by 11 publications

(9 citation statements)

References 24 publications

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“…A similar effect was seen in the plasmacytoid dendritic cells (pDCs) extracted from PBMC samples from adolescents. There is also other genetic variation in the HLA region that has been associated with effects on DQ‐surface expression 50–53 . Changes in DQ or DR expression could impact immune responses and predispose individuals to autoimmune diseases 54,55 …”

Section: Discussionmentioning

confidence: 99%

The effect of type 1 diabetes protection and susceptibility associated HLA class II genotypes on DNA methylation in immune cells

Pahkuri,

Katayama,

Valta

et al. 2024

HLA

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The HLA region, especially HLA class I and II genes, which encode molecules for antigen presentation to T cells, plays a major role in the predisposition to autoimmune disorders. To clarify the mechanisms behind this association, we examined genome‐wide DNA methylation by microarrays to cover over 850,000 CpG sites in the CD4+ T cells and CD19+ B cells of healthy subjects homozygous either for DRB1*15‐DQA1*01‐DQB1*06:02 (DR2‐DQ6, n = 14), associated with a strongly decreased T1D risk, DRB1*03‐DQA1*05‐DQB1*02 (DR3‐DQ2, n = 19), or DRB1*04:01‐DQA1*03‐DQB1*03:02 (DR4‐DQ8, n = 17), associated with a moderately increased T1D risk. In total, we discovered 14 differentially methylated CpG probes, of which 10 were located in the HLA region and six in the HLA‐DRB1 locus. The main differences were between the protective genotype DR2‐DQ6 and the risk genotypes DR3‐DQ2 and DR4‐DQ8, where the DR2‐DQ6 group was hypomethylated compared to the other groups in all but four of the differentially methylated probes. The differences between the risk genotypes DR3‐DQ2 and DR4‐DQ8 were small. Our results indicate that HLA variants have few systemic effects on methylation and that their effect on autoimmunity is conveyed directly by HLA molecules, possibly by differences in expression levels or function.

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Section: Discussionmentioning

confidence: 99%

The effect of type 1 diabetes protection and susceptibility associated HLA class II genotypes on DNA methylation in immune cells

Pahkuri,

Katayama,

Valta

et al. 2024

HLA

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“…The DR3-DQ2 and DR4-DQ8 haplotypes of HLA class II genes are well established as major risk factors of T1D [66][67][68], and at least one is present in 90% of individuals with T1D and both in 40% (for apparently healthy controls, these numbers are 30% and 3%, respectively). However, they only partly explain the increased risk for T1D development as they influence seroconversion but not the age of the onset, clinical progression, or C-peptide loss [15].…”

Section: Regulating the Effects Of Cytokines Inside β-Cells For Proap...mentioning

confidence: 99%

Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

Zajec

Podkrajšek

Tesovnik

et al. 2022

Genes

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Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. In this review, we highlight the interplay between genetic predisposition and other non-genetic factors, such as viral infections, diet, and gut biome, which all potentially contribute to the aetiology of T1D. We also discuss a possible active role for β-cells in initiating the pathological processes. Another component in T1D predisposition is epigenetic influences, which represent a link between genetic susceptibility and environmental factors and may account for some of the disease heterogeneity. Accordingly, a shift towards personalized therapies may improve the treatment results and, therefore, result in better outcomes for individuals in the long-run. There is also a clear need for a better understanding of the preclinical phases of T1D and finding new predictive biomarkers for earlier diagnosis and therapy, with the final goal of reverting or even preventing the development of the disease.

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“…The recently reported haplotype of three single-nucleotide polymorphisms (tri-SNP; rs3135394, rs9268645, and rs3129877) in intron 1 of the HLA-DRA1 gene was shown to be strongly associated with type 1 diabetes risk in HLA-DR3 homozygous individuals (18,19). One tri-SNP, AGG, was found to increase the risk for type 1 diabetes in HLA-DR3 homozygous subjects, while another haplotype, GCA, was found to be protective (18).…”

Section: Introductionmentioning

confidence: 98%

“…The aim of this study was to investigate HLA-DQ cellsurface median fluorescence intensity (MFI) in subjects with an increasing number of islet autoantibodies on selected peripheral blood cells (19) in relation to the tri-SNPs. We hypothesize that the HLA-DRA1 tri-SNP may be related to peripheral blood cell HLA-DQ cell-surface expression.…”

Section: Introductionmentioning

confidence: 99%

Possible Relationship between the HLA-DRA1 Intron Haplotype of Three Single-Nucleotide Polymorphisms in Intron 1 of the HLA-DRA1 Gene and Autoantibodies in Children at Increased Genetic Risk for Autoimmune Type 1 Diabetes

Svärd

Benatti²,

Lundgren³

et al. 2022

ImmunoHorizons

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Recently, a haplotype of three single-nucleotide polymorphisms (tri-SNP) in intron 1 of the HLA-DRA1 gene was found to be strongly associated with type 1 diabetes risk in HLA-DR3/3 individuals. The tri-SNP reportedly function as expression quantitative trait loci, modulating HLA-DR and -DQ expression. The aim was to investigate HLA-DRA1 tri-SNPs in relation to extended HLA class II haplotypes and human peripheral blood cell HLA-DQ cell-surface median fluorescence intensity (MFI), the first-appearing islet autoantibody, and autoimmunity burden. A total of 67 healthy subjects (10-15 y) at increased HLA risk for type 1 diabetes and with (n 5 54) or without (n 5 13) islet autoantibodies were followed longitudinally in the Diabetes Prediction in Skåne study. Among four tri-SNPs, AGG (n 5 67), GCA (n 5 47), ACG (n 5 11), and ACA (n 5 9), HLA-DQ cell-surface MFI on CD4 + T cells was lower in AGG than GCA (p 5 0.030) subjects. Cumulative autoimmunity burden was associated with reduced HLA-DQ cell-surface MFI in AGG compared with GCA in CD16 + cells (p 5 0.0013), CD4 + T cells (p 5 0.0018), and CD8 + T cells (p 5 0.016). The results suggest that HLA-DRA1 tri-SNPs may be related to HLA-DQ cell-surface expression and autoimmunity burden. ImmunoHorizons, 2022, 6: 614-629.

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Tri-SNP polymorphism in the intron of HLA-DRA1 affects type 1 diabetes susceptibility in the Finnish population

Cited by 11 publications

References 24 publications

The effect of type 1 diabetes protection and susceptibility associated HLA class II genotypes on DNA methylation in immune cells

The effect of type 1 diabetes protection and susceptibility associated HLA class II genotypes on DNA methylation in immune cells

Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

Possible Relationship between the HLA-DRA1 Intron Haplotype of Three Single-Nucleotide Polymorphisms in Intron 1 of the HLA-DRA1 Gene and Autoantibodies in Children at Increased Genetic Risk for Autoimmune Type 1 Diabetes

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