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, Agnes Andersson; Benatti, Elin; Lundgren, Markus; Lernmark, Åke; Maziarz, Marlena; Larsson, Helena Elding

doi:10.4049/immunohorizons.2200039

Cited by 3 publications

(2 citation statements)

References 39 publications

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“…There is also other genetic variation in the HLA region that has been associated with effects on DQ-surface expression. [50][51][52][53] Changes in DQ or DR expression could impact immune responses and predispose individuals to autoimmune diseases. 54,55 Taken together these results indicate that there may be a significant difference in how the immune cells from DR2-DQ6 carriers respond to stimulation, compared to DR3-DQ2 or DR4-DQ8 carriers, and that this difference may be mediated by DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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%

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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Looking back at the TEDDY study: lessons and future directions

Lernmark,

Agardh,

Akolkar

et al. 2024

Nat Rev Endocrinol

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Genetic profile in children with musculoskeletal pathology under conditions of airborne exposure to heavy metals

Otavina,

Kazakova

2024

Hygiene and Sanitation

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Introduction. Diseases of the musculoskeletal system develop largely due to environmental pollution, especially with heavy metals. Lead, manganese, and nickel are the most common and toxic pollutants that affect on the immature bone, immune, and nervous systems in children. Materials and methods. We examined homeostasis and the genetic profile of one hundred eight 7–11 years schoolchildren with dorsopathy from an industrially developed region. The observation group was made of children with dorsalgia (class M54.9). Polymorphic variants of candidate genes, dopamine receptor DRD2 (rs1800497) and the main histocompatibility complex HLA-DRA C/T (rs3135388), were identified by real-time PCR. Results. The average daily dose of exposure to airborne nickel (6.39 µg/(kg ∙ day)), manganese (15.3 µg/(kg ∙ day)), and lead (0.6 µg/(kg ∙ day)) was 35.5, 43.7 and 11.8 times higher in the observation area against the reference one. Schoolchildren with dorsopathy, combined with dorsalgia, had levels of manganese, nickel and lead in blood 1.3, 1.43, and 2 times higher respectively than the reference range. At the same time, the children from the observation group showed increased frequency of the variant T-allele of the DRD2 gene (rs1800497) (OR=3.76; CI: 1.53–9.28, relative risk: RR=1.73; CI: 1.33–2.22; p<0.005) and the C-allele of the HLA-DRA C/T gene (rs3135388) (OR=4.40; CI: 1.30–14.95) associated with excessive levels of dopamine and ionized calcium. Limitations of the study are related to the need to increase the sample and verify the obtained results. Conclusion. Established average daily doses of exposure to airborne nickel, manganese and lead (6.39 µg/(kg ∙ day), 15.3 µg/(kg ∙ day) and 0.6 µg/(kg ∙ day)) were 35.5, 43.7 and 11.8 times respectively higher for the observation group against the reference one. The study reported features of polymorphism of candidate genes DRD2 (rs1800497) and HLA-DRA C/T (rs3135388) in children with dorsopathy complicated by dorsalgia syndrome, associated with disorders of neuroimmune controlling and bone density. They cause additional risk (RR=1.73; CI:1.33–2.22) of pathology of the musculoskeletal system in case biological media are contaminated with lead, manganese, and nickel, which modifies the course of dorsopathy by adding dorsalgia.

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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

Cited by 3 publications

References 39 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

Looking back at the TEDDY study: lessons and future directions

Genetic profile in children with musculoskeletal pathology under conditions of airborne exposure to heavy metals

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