UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor–Induced NF-κB Signaling

Ge, Yan; Paisie, Taylor; Newman, Jeremy R.B.; McIntyre, Lauren; Concannon, Patrick

doi:10.2337/db16-1023

Cited by 56 publications

(98 citation statements)

References 40 publications

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“…The UBASH3A gene, also on chromosome 21, has been associated (and the association replicated) with T1D and has a role in the regulation of T cells (34). UBASH3A downregulates T-cell receptor-induced NFкB signaling (35). NFкB signaling regulates multiple aspects of the innate and adaptive immune system including the expression of IL2 (36), a pleiotropic cytokine whose roles include the regulation of self-tolerance (37).…”

Section: Discussionmentioning

confidence: 99%

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

et al. 2019

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Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis <6 months) provides important insights into b-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are four times more likely to have childhood diabetes with an intermediate HLA association. It is not known whether DS can cause PNDM. We found that trisomy 21 was seven times more likely in our PNDM cohort than in the population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected) and none of the 13 DS-PNDM patients had a mutation in the known PNDM genes that explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4 of 9 DS-PNDM patients, but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes (T1D). We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental T1D that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated.Permanent neonatal diabetes (PNDM) is diagnosed before the age of 6 months, and a genetic diagnosis is possible for .82% of cases (1). Twenty-four causative PNDM genes have been identified (1-4), and four of these cause monogenic autoimmune PNDM that results from destruction of the b-cells very early in life (FOXP3, IL2RA, LRBA, and STAT3). Identifying novel causes of autoimmune neonatal diabetes can provide key insights into the development of autoimmunity and can provide new targets for therapeutic intervention.Down syndrome (DS) is caused by trisomy of chromosome 21 and has an incidence of 1:700 to 1:1,100 live births (5). Large studies have shown childhood-onset autoimmune diabetes is four times more common in DS than in the general population and has an intermediate HLA association (6). There have been three reported cases of DS with diabetes diagnosed before 6 months (DS-PNDM) (7,8). However, it is not known whether DS was the cause of PNDM or a coincidental finding in these patients. The aim of our study was to use our large international cohort of PNDM patients to assess whether DS can aetiologically cause PNDM. We assessed clinical phenotype, islet autoantibodies, and polygenic risk of T1D in patients with monogenic PNDM and DS-PNDM. RESEARCH DESIGN AND METHODS Study PopulationWe defined PNDM as diabetes diagnosed before the age of 6 months, which is treated with continual insulin treatment. We studied 1,522 DNA samples from two international collections of PNDM patients, 1,360 recruited in Exeter and 162 recruited in Chicago. These either had a confirmed monogenic etiology (82.9% [n = 1,262]) or had been tested (and were negative) for all 24 known genes (17.1% [n = 260]). Clinical information was provided by the referring physician via a comprehensive referral form. This includes a section for the reporting of extra pancreatic clinical features. Genetic Testing Testing of the Known GenesAll individuals diagnosed in the first 6 months of life were tested for mutations either by rapid Sanger sequencing of

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Section: Discussionmentioning

confidence: 99%

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

et al. 2019

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“…However, few GWAS regions in autoimmune diseases have yet converged on a causal gene. An exception is UBASH3A, encoding ubiquitin-associated and SH3 domain containing protein A, which functions as a negative regulator of NF-kB signaling in T cells on stimulation of the antigen T cell receptor (36). Noncoding susceptibility alleles within UBASH3A are associated with several autoimmune diseases, including type 1 diabetes and RA, and are also associated with increased transcription, thereby leading to reduced transcription of interleukin-2 (IL2) in effector T cells (36).…”

Section: Discussionmentioning

confidence: 99%

“…An exception is UBASH3A, encoding ubiquitin-associated and SH3 domain containing protein A, which functions as a negative regulator of NF-kB signaling in T cells on stimulation of the antigen T cell receptor (36). Noncoding susceptibility alleles within UBASH3A are associated with several autoimmune diseases, including type 1 diabetes and RA, and are also associated with increased transcription, thereby leading to reduced transcription of interleukin-2 (IL2) in effector T cells (36). An association study by Liu et al identified one SNP (rs1893592) in UBASH3A that was significantly related to DAS28, CRP level and bone erosion in RA patients (37).…”

Section: Discussionmentioning

confidence: 99%

Rheumatoid Arthritis Patients, Both Newly Diagnosed and Methotrexate Treated, Show More DNA Methylation Differences in CD4+ Memory Than in CD4+ Naïve T Cells

et al. 2020

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Background: Differences in DNA methylation have been reported in B and T lymphocyte populations, including CD4 + T cells, isolated from rheumatoid arthritis (RA) patients when compared to healthy controls. CD4 + T cells are a heterogeneous cell type with subpopulations displaying distinct DNA methylation patterns. In this study, we investigated DNA methylation using reduced representation bisulfite sequencing in two CD4 + T cell populations (CD4 + memory and naïve cells) in three groups: newly diagnosed, disease modifying antirheumatic drugs (DMARD) naïve RA patients (N = 11), methotrexate (MTX) treated RA patients (N = 18), and healthy controls (N = 9) matched for age, gender and smoking status. Results: Analyses of these data revealed significantly more differentially methylated positions (DMPs) in CD4 + memory than in CD4 + naïve T cells (904 vs. 19 DMPs) in RA patients compared to controls. The majority of DMPs (72%) identified in newly diagnosed and DMARD naïve RA patients with active disease showed increased DNA methylation (39 DMPs), whereas most DMPs (80%) identified in the MTX treated RA patients in remission displayed decreased DNA methylation (694 DMPs). Interestingly, we also found that about one third of the 101 known RA risk loci overlapped (±500 kb) with the DMPs. Notably, introns of the UBASH3A gene harbor both the lead RA risk SNP and two DMPs in CD4 + memory T cells. Conclusion: Our results suggest that RA associated DNA methylation differences vary between the two T cell subsets, but are also influenced by RA characteristics such as disease activity, disease duration and/or MTX treatment.

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“…It can be activated by multiple extracellular stimulations. In addition, it can participate in gene regulation under apoptosis and inflammation (22). Meanwhile, it has important physiological and pathological actions (23).…”

Section: Discussionmentioning

confidence: 99%

Ursolic acid alleviates inflammation and against diabetes‑induced nephropathy through TLR4‑mediated inflammatory pathway

Yan

et al. 2018

Mol Med Report

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Ursolic acid (UA) is a triterpenoid isolated from Chinese herbal medicine. It is extensively distributed in the plant kingdom in at least 63 Chinese herbal medicines of 26 families. UA has multiple bioactivities, including anti‑viral hepatitis, antitumor, anti‑oxidation, anti‑bacterium and anti‑inflammation. The aim of this in vitro study was to examine the effects of UA on diabetes‑induced nephropathy and its possible mechanism. In mice with diabetes‑induced nephropathy, UA increased the body weight, reduced kidney/body weight index, protected kidney cells, alleviated inflammation [tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, IL‑6 and IL‑18 levels] and kidney cell damage. It was also indicated that UA suppressed Toll‑like receptor 4 (TLR4), myeloid differentiation factor 88 and nuclear factor‑κB protein expression in mice with diabetes‑induced nephropathy. The inhibition of TLR4 increased the anti‑inflammation of UA on inflammation in rat with diabetes‑induced nephropathy through the TLR4 signaling pathway. In conclusion, UA alleviates inflammation and inhibits diabetes‑induced nephropathy through a TLR4‑mediated inflammatory pathway. The present findings indicated that UA may be a possible therapeutic agent against diabetic nephropathy.

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UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor–Induced NF-κB Signaling

Cited by 56 publications

References 40 publications

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

Rheumatoid Arthritis Patients, Both Newly Diagnosed and Methotrexate Treated, Show More DNA Methylation Differences in CD4+ Memory Than in CD4+ Naïve T Cells

Ursolic acid alleviates inflammation and against diabetes‑induced nephropathy through TLR4‑mediated inflammatory pathway

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