Telomere erosion in Sjögren's syndrome: A multi‐tissue comparative analysis

Noll, Braxton; Mougeot, Farah Bahrani; Brennan, Michael T.; Mougeot, Jean-Luc

doi:10.1111/jop.12961

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…For parts of IMIDs, our findings were similar to those from some previous studies, while for other IMIDs, they were the opposite. The results from the MR study based on data from the FinnGen Biobank corroborate the findings of retrospective studies that show shorter LTL is a risk factor for RA ( Blinova et al, 2016 ; Gamal et al, 2018 ; Lee and Bae, 2018 ), SS ( Kawashima et al, 2011 ; Noll et al, 2020 ), sarcoidosis ( Maeda et al, 2009 ; Afshar et al, 2021 ), IPF ( McDonough et al, 2018 ; Ley et al, 2020 ), and psoriasis ( Liu et al, 2008 ). Furthermore, our results are also similar to previously reported MR studies of LTL and the risk of RA ( Zeng et al, 2020 ) and IPF ( Duckworth et al, 2021 ).…”

Section: Discussionsupporting

confidence: 74%

Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study

et al. 2023

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Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study.Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn’s disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran’s Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction.Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66–0.89, and p = 3.66 × 10−4), SS (OR: 0.75, CI: 0.58–0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68–0.88, and p = 9.85 × 10−5), hypothyroidism (OR: 0.84, 95% CI: 0.78–0.91, and p = 7,08 × 10−6), hyperthyroidism (OR: 0.60, 95% CI: 0.44–0.83, and p = 1.90 × 10−3), sarcoidosis (OR: 0.67, 95% CI: 0.54–0.83, and p = 2.60 × 10−4), and IPF (OR: 0.41, 95% CI: 0.29–0.58, and p = 4.11 × 10−7) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18–1.94, and p = 9.66 × 10−4). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62–1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37–2.54, and p = 8.01 × 10−5).Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs.

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Section: Discussionsupporting

confidence: 74%

Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study

et al. 2023

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“…In addition, age, gender, and associated hormonal changes account for possible factors affecting expression profiles of iSGECs, impacting their biological properties. Moreover, acinar cells of lacrimal glands, acinar progenitor cells of salivary glands, and saliva DNA of pSS patients may have shortened telomeres, which could be more prominent with older age [ 3 , 49 , 50 ]. Extensive cell passaging due to age combined with chronically shortened telomeres could lead to chromosomal instability and changes in DNA expression.…”

Section: Limitationsmentioning

confidence: 99%

Immortalization of Salivary Gland Epithelial Cells of Xerostomic Patients: Establishment and Characterization of Novel Cell Lines

Noll

Grdzelishvili

Mougeot

et al. 2020

JCM

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Primary Sjögren’s Syndrome (pSS) is an autoimmune disease mainly affecting salivary and lacrimal glands. Previous pSS studies have relied on primary cell culture models or cancer cell lines with limited relevance to the disease. Our objective was to generate and characterize immortalized salivary gland epithelial cells (iSGECs) derived from labial salivary gland (LSG) biopsies of pSS patients (focus score > 1) and non-Sjögren’s Syndrome (nSS) xerostomic (i.e., sicca) female patients. To characterize iSGECs (n = 3), mRNA expression of specific epithelial and acinar cell markers was quantified by qRT-PCR. Protein expression of characterization markers was determined by immunocytochemistry and Western blot. Secretion of α-amylase by iSGECs was confirmed through colorimetric activity assay. Spheroid formation and associated alterations in expression markers were determined using matrigel-coated cell culture plates. Consistent mRNA and protein expressions of both epithelial and pro-acinar cell markers were observed in all three iSGEC lines. When cultured on matrigel medium, iSGECs formed spheroids, secreted α-amylase after β-adrenergic stimulation, and expressed multiple acinar cell markers at late passages. One iSGEC line retained adequate cell morphology without a loss of SV40Lt expression and proliferation potential after over 100 passages. In conclusion, our established iSGEC lines represent a viable model for salivary research due to their passaging capacity and maintenance of pro-acinar cell characteristics.

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“…Although the relationship between leukocyte telomere length and disease is complex, LTL has been proposed as a marker of biological age and is associated with a high risk of multiple age-related diseases: including cardiovascular disease and cancer (4)(5)(6). In recent years, the involvement of telomere length, telomerase and protein complex systems in the pathogenesis of autoimmune diseases has become a hot research topic (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Assessing the association of leukocyte telomere length with ankylosing spondylitis and rheumatoid arthritis: A bidirectional Mendelian randomization study

et al. 2023

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BackgroundTelomere length shortening can cause senescence and apoptosis in various immune cells, resulting in immune destabilization and ageing of the organism. In this study, we aimed to systematically assess the causal relationship of leukocyte telomere length (LTL) with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) using a Mendelian randomization study.MethodsLTL (n=472174) was obtained from the UK Biobank genome-wide association study pooled data. AS (n=229640), RA (n=212472) were obtained from FinnGen database. MR-Egger, inverse variance weighting, and weighted median methods were used to estimate the effects of causes. Cochran’s Q test, MR Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots were used to look at sensitivity, heterogeneity, and multiple effects. Forward MR analysis considered LTL as the exposure and AS, RA as the outcome. Reverse MR analysis considered AS, RA as the exposure and LTL as the outcome.ResultsIn the forward MR analysis, inverse variance-weighted and weighted median analysis results indicated that longer LTL might be associated with increased risk of AS (IVW: OR = 1.55, 95% CI: 1.14-2.11, p = 0.006). MR Egger regression analysis showed no pleiotropy between instrumental variables (IVs) (Egger intercept= 0.008, p = 0.294). The leave-one-out analysis showed that each single nucleotide polymorphism (SNP) of AS was robust to each outcome. No significant causal effects were found between AS, RA and LTL in the reverse MR analysis.ConclusionLonger LTL may be related with an increased risk of developing AS, and these findings provide a foundation for future clinical research on the causal association between LTL and AS.

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Telomere erosion in Sjögren's syndrome: A multi‐tissue comparative analysis

Cited by 5 publications

References 26 publications

Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study

Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study

Immortalization of Salivary Gland Epithelial Cells of Xerostomic Patients: Establishment and Characterization of Novel Cell Lines

Assessing the association of leukocyte telomere length with ankylosing spondylitis and rheumatoid arthritis: A bidirectional Mendelian randomization study

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