LCK rs10914542-G allele associates with type 1 diabetes in children via T cell hyporesponsiveness

Zhu, Qi; Wang, Jing; Zhang, Lingli; Bian, Wen‐Jun; Lin, Mengsi; Xu, Xiaoning; Zhou, Xiang

doi:10.1038/s41390-019-0436-2

Cited by 12 publications

(10 citation statements)

References 18 publications

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“…ITGAL and UPF3A were selected as two of the most biologically plausible genes linked to T1DM-ESKD, as discussed previously. CD247 [113] and LCK [114] have both been previously linked to diabetes and which could warrant further investigation. Furthermore, two interactions scored 0.999 from both Analyses 2 and 4: ITGAL-ITGB2 and BRE-UIMC1.…”

Section: Discussionmentioning

confidence: 99%

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study

et al. 2021

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Background A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10–8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Results Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Conclusions Epigenetic alterations provide a dynamic link between an individual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

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Section: Discussionmentioning

confidence: 99%

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study

et al. 2021

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“…The lymphocyte-specific protein tyrosine kinase (Lck) and zeta-associated protein 70 (ZAP70), which are involved in the PTK signaling pathway, play important roles in T cell activation. Animal experiments show that IgD activates the phosphorylation of Lck and phospholipase C-γ (PLC-γ) in T cell hybridomas [ 16 ]. Lck mainly exists in T cells and participates in signal transduction that is involved in T cell development, differentiation, and activation [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

IgD-Fc-Ig fusion protein, a new biological agent, inhibits T cell function in CIA rats by inhibiting IgD-IgDR-Lck-NF-κB signaling pathways

et al. 2020

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IgD-Fc-Ig fusion protein, a new biological agent, is constructed by linking a segment of human IgD-Fc with a segment of human IgG1-Fc, which specifically blocks the IgD-IgDR pathway and selectively inhibits the abnormal proliferation, activation, and differentiation of T cells. In this study we investigated whether IgD-Fc-Ig exerted therapeutic effects in collagen-induced arthritis (CIA) rats. CIA rats were treated with IgD-Fc-Ig (1, 3, and 9 mg/kg) or injected with biological agents etanercept (3 mg/kg) once every 3 days for 40 days. In the PBMCs and spleen lymphocytes of CIA rats, both T and B cells exhibited abnormal proliferation; the percentages of CD3 + total T cells, CD3 + CD4 + Th cells, CD3 + CD4 + CD25 + -activated Th cells, Th1(CD4 + IFN-γ + ), and Th17(CD4 + IL-17 + ) were significantly increased, whereas the Treg (CD4 + CD25 + Foxp3 + ) cell percentage was decreased. IgD-Fc-Ig administration dose-dependently decreased the indicators of arthritis; alleviated the histopathology of spleen and joint; reduced serum inflammatory cytokines levels; decreased the percentages of CD3 + total T cells, CD3 + CD4 + Th cells, CD3 + CD4 + CD25 + -activated Th cells, Th1 (CD4 + IFN-γ + ), and Th17(CD4 + IL-17 + ); increased Treg (CD4 + CD25 + Foxp3 + ) cell percentage; and down-regulated the expression of key molecules in IgD-IgDR-Lck-NF-κB signaling (p-Lck, p-ZAP70, p-P38, p-NF-κB65). Treatment of normal T cells with IgD (9 μg/mL) in vitro promoted their proliferation. Co-treatment with IgD-Fc-Ig (0.1–10 μg/mL) dose-dependently decreased IgD-stimulated T cell subsets percentages and down-regulated the IgD-IgDR-Lck-NF-κB signaling. In summary, this study demonstrates that IgD-Fc-Ig alleviates CIA and regulates the functions of T cells through inhibiting IgD-IgDR-Lck-NF-κB signaling.

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“…From these studies, the AID/RAD51, and SNP rs10914542 of LCK gene have been suggested as appropriate candidates for CRISPR-Cas9 treatment. Zhu et al attempted to reveal the role of SNPs of the Lymphocytespecific protein tyrosine kinase (LCK) gene [59]. They gained blood samples from type 1 DM patients and used CRISPR-Cas9 to find the role of LCK SNP [59].…”

Section: Crispr-cas9 and Type 1 Diabetes Mellitusmentioning

confidence: 99%

Genome Editing Using CRISPR-Cas9 and Autoimmune Diseases: A Comprehensive Review

Lee

Smıth

Yang

et al. 2022

IJMS

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Autoimmune diseases are disorders that destruct or disrupt the body’s own tissues by its own immune system. Several studies have revealed that polymorphisms of multiple genes are involved in autoimmune diseases. Meanwhile, gene therapy has become a promising approach in autoimmune diseases, and clustered regularly interspaced palindromic repeats and CRISPR-associated protein 9 (CRISPR-Cas9) has become one of the most prominent methods. It has been shown that CRISPR-Cas9 can be applied to knock out proprotein convertase subtilisin/kexin type 9 (PCSK9) or block PCSK9, resulting in lowering low-density lipoprotein cholesterol. In other studies, it can be used to treat rare diseases such as ornithine transcarbamylase (OTC) deficiency and hereditary tyrosinemia. However, few studies on the treatment of autoimmune disease using CRISPR-Cas9 have been reported so far. In this review, we highlight the current and potential use of CRISPR-Cas9 in the management of autoimmune diseases. We summarize the potential target genes for immunomodulation using CRISPR-Cas9 in autoimmune diseases including rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes mellitus (DM), psoriasis, and type 1 coeliac disease. This article will give a new perspective on understanding the use of CRISPR-Cas9 in autoimmune diseases not only through animal models but also in human models. Emerging approaches to investigate the potential target genes for CRISPR-Cas9 treatment may be promising for the tailored immunomodulation of some autoimmune diseases in the near future.

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LCK rs10914542-G allele associates with type 1 diabetes in children via T cell hyporesponsiveness

Cited by 12 publications

References 18 publications

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study

IgD-Fc-Ig fusion protein, a new biological agent, inhibits T cell function in CIA rats by inhibiting IgD-IgDR-Lck-NF-κB signaling pathways

Genome Editing Using CRISPR-Cas9 and Autoimmune Diseases: A Comprehensive Review

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