Mendelian randomization analysis suggests no associations of herpes simplex virus infections with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) characterized by immune dysfunction is possibly more vulnerable to herpes simplex virus (HSV) infection. The infection has been intensively considered a common onset and exacerbation of SLE. This study is aimed at elucidating the causal association between SLE and HSV. A bidirectional two-sample Mendelian Randomization (TSMR) analysis was systematically conducted to explore the causal effect of SLE and HSV on each other. The causality was estimated by inverse variance weighted (IVW), MR-Egger and weighted median methods based on the summary-level genome-wide association studies (GWAS) data from a publicly available database. Genetically proxied HSV infection exhibited no causal association with SLE in the forward MR analysis using IVW method (odds ratio [OR] = 0.987; 95% confidence interval [CI]: 0.891-1.093; p = 0.798), nor did HSV-1 IgG (OR = 1.241; 95% CI: 0.874-1.762; p = 0.227) and HSV-2 IgG (OR = 0.934; 95% CI: 0.821-1.062; p = 0.297). Similar null results with HSV infection (OR = 1.021; 95% CI: 0.986-1.057; p = 0.245), HSV-1 IgG (OR = 1.003; 95% CI: 0.982-1.024; p = 0.788) and HSV-2 IgG (OR = 1.034; 95% CI: 0.991-1.080; p = 0.121) were observed in the reverse MR where SLE served as the exposure. Our study demonstrated no causal association between the genetically predicted HSV and SLE.

Deep stratification by transcriptome molecular characters for precision treatment of patients with systemic lupus erythematosus.

OBJECTIVES: To leverage the high clinical heterogeneity of systemic lupus erythematosus (SLE), we developed and validated a new stratification scheme by integrating genome-scale transcriptomic profiles to identify patient subtypes sharing similar transcriptomic markers and drug targets. METHODS: A normalized compendium of transcription profiles was created from peripheral blood mononuclear cells (PBMCs) of 1046 SLE patients and 86 healthy controls (HCs), covering an intersection of 13 689 genes from six microarray datasets. Upregulated differentially expressed genes were subjected to functional and network analysis in which samples were grouped using unsupervised clustering to identify patient subtypes. Then, clustering stability was evaluated by the stratification of six integrated RNA-sequencing datasets using the same method. Finally, the Xgboost classifier was applied to the independent datasets to identify factors associated with treatment outcomes. RESULTS: Based on 278 upregulated DEGs of the transcript profiles, SLE patients were classified into three subtypes (subtype A-C) each with distinct molecular and cellular signatures. Neutrophil activation-related pathways were markedly activated in subtype A (named NE-driving), whereas lymphocyte and IFN-related pathways were more enriched in subtype B (IFN-driving). As the most severe subtype, subtype C [NE-IFN-dual-driving (Dual-driving)] shared functional mechanisms with both NE-driving and IFN-driving, which was closely associated with clinical features and could be used to predict the responses of treatment. CONCLUSION: We developed the largest cohesive SLE transcriptomic compendium for deep stratification using the most comprehensive microarray and RNA sequencing datasets to date. This result could guide future design of molecular diagnosis and the development of stratified therapy for SLE patients.

Specific enterotype of gut microbiota predicted clinical effect of methotrexate in patients with rheumatoid arthritis.

OBJECTIVE: The most used drug for the treatment of rheumatoid arthritis (RA) remains methotrexate (MTX). Unfortunately, up to 50% of patients do not achieve a clinically adequate outcome. Here we study whether the gut microbiota patterns can aid in the prediction of MTX efficacy for RA. METHOD: To dissect gut microbiome profiles of RA patients (n = 145), 16S rRNA gene sequencing was performed. Dirichlet multinomial mixture (DMM) clustering was used to identify enterotypes at genus level. The relationships between enterotypes and clinical measures (such as lymphocyte subsets and cytokines detected by flow cytometry) were explored. Then, enterotype stability was evaluated by the stratification of the RA patient cohort (n = 66) in Shanghai, China, using the same method. Finally, the enterotype-based gut microbial human index classifier was applied to another independent RA patient cohort (n = 27) to identify the factors associated with MTX clinical response. RESULTS: Our analysis revealed that the RA patients always displayed two different dysbiotic microbiota patterns: RA E1 comprised predominantly Prevotella and RA E2 comprised predominantly Bacteroides. Among all of the lymphocyte subsets and cytokines, only the number of CD8+ T cells showed a significant difference between RA E1 and RA E2. These results were validated in the RA patient cohort in Shanghai, China. Significant associations of RA E1 with clinical response to subsequent MTX treatment were confirmed by another independent RA patient cohort. CONCLUSION: Together, the enterotype-based gut microbial human index (EGMI) classifier was useful to precisely and effectively identify enterotypes of individual RA patients, which could effectively evaluate MTX clinical responses.

Reduced circulating Tregs and positive pANCA were robustly associated with the occurrence of antiphospholipid syndrome in patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a typical chronic immune disorder with clinical heterogeneity. The systemic abnormal immune response not only challenges the diagnosis and treatment of the disease itself but also the secondary antiphospholipid syndrome (APS), characterized by recurrent arterial or venous thrombosis, recurrent spontaneous abortion, or stillbirth. Clinical interest has primarily focused on primary APS's pathological and clinical features. However, differences in clinical features and laboratory indicators between SLE with or without APS are still lacking, especially differences between circulating lymphocytes, which are critical in the pathogenesis of SLE and its complications. METHODS: In this retrospective study, we collected and analyzed clinical characteristics, general laboratory indicators, immunological indicators, and circulating lymphocyte subsets of SLE with or without APS. RESULTS: Systemic lupus erythematosus with APS (SLE-APS) had elevated SLEDAI scores, hospitalization costs and time, and frequencies of central nervous system symptoms and spontaneous abortion compared with those without APS. SLE-APS had higher positive anti-Cardiolipin antibodies, anti-ß2 Glycoprotein 1 antibodies, and perinuclear antineutrophil cytoplasmic antibody (pANCA) than none-APS patients. Compared with healthy controls (HCs), the circulating lymphocyte subsets were altered to some extent in all patients, especially in patients with SLE-APS. Reduced Tregs and positive pANCA were independent risk factors for SLE secondary APS. CONCLUSION: The present study revealed a robust association between APS secondary to SLE and reduced Tregs and positive pANCA, which provides essential information regarding the diagnosis and therapeutic possibilities of APS secondary to SLE.

Identifying cellular senescence associated genes involved in the progression of end-stage renal disease as new biomarkers.

BACKGROUND: Cellular senescence plays an essential role in the development and progression of end-stage renal disease (ESRD). However, the detailed mechanisms phenomenon remains unclear. METHODS: The mRNA expression profiling dataset GSE37171 was taken from the Gene Expression Omnibus (GEO) database. The cell senescence-associated hub genes were selected by applying protein-protein interaction (PPI), followed by correlation analysis, gene interaction analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. We next explored the relationships of hub genes with miRNAs, TFs, and diseases. The absolute abundance of eight immune cells and two stromal cells were calculated by MCPcount and the correlation of hub genes with these ten cells was analyzed. Lasso was used to selecting for trait genes. ROC curves and DCA decision curves were used to assess the accuracy and predictive power of the trait genes. RESULTS: A total of 65 cellular senescence signature genes were identified among patients and controls. The PPI network screened out ten hub genes. GO and KEGG indicated that ten hub genes were associated with ESRD progression. Transcription factor gene interactions and common regulatory networks of miRNAs were also identified in the datasets. The hub genes were significantly correlated with immune cells and stromal cells. Then the lasso model was constructed to screen out the five most relevant signature genes (FOS, FOXO3, SIRT1, TP53, SMARCA4). The area under the ROC curve (AUC) showed that these five characteristic genes have good resolving power for the diagnostic model. CONCLUSIONS: Our findings suggested that cellular senescence-associated genes played an important role in the development of ESRD and immune regulation.

Potential new therapeutic target for Alzheimer's disease: Glucagon-like peptide-1.

Increasing evidence shows a close relationship between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Recently, glucagon-like peptide-1 (GLP-1), a gut incretin hormone, has become a well-established treatment for T2DM and is likely to be involved in treating cognitive impairment. In this mini review, the similarities between AD and T2DM are summarised with the main focus on GLP-1-based therapeutics in AD.

Identification of novel hub genes associated with gastric cancer using integrated bioinformatics analysis.

BACKGROUND: Gastric cancer (GC) is one of the most common solid malignant tumors worldwide with a high-recurrence-rate. Identifying the molecular signatures and specific biomarkers of GC might provide novel clues for GC prognosis and targeted therapy. METHODS: Gene expression profiles were obtained from the ArrayExpress and Gene Expression Omnibus database. Differentially expressed genes (DEGs) were picked out by R software. The hub genes were screened by cytohubba plugin. Their prognostic values were assessed by Kaplan-Meier survival analyses and the gene expression profiling interactive analysis (GEPIA). Finally, qRT-PCR in GC tissue samples was established to validate these DEGs. RESULTS: Total of 295 DEGs were identified between GC and their corresponding normal adjacent tissue samples in E-MTAB-1440, GSE79973, GSE19826, GSE13911, GSE27342, GSE33335 and GSE56807 datasets, including 117 up-regulated and 178 down-regulated genes. Among them, 7 vital upregulated genes (HMMR, SPP1, FN1, CCNB1, CXCL8, MAD2L1 and CCNA2) were selected. Most of them had a significantly worse prognosis except SPP1. Using qRT-PCR, we validated that their transcriptions in our GC tumor tissue were upregulated except SPP1 and FN1, which correlated with tumor relapse and predicts poorer prognosis in GC patients. CONCLUSIONS: We have identified 5 upregulated DEGs (HMMR, CCNB1, CXCL8, MAD2L1, and CCNA2) in GC patients with poor prognosis using integrated bioinformatical methods, which could be potential biomarkers and therapeutic targets for GC treatment.

Absolute reduction of peripheral regulatory T cell in patients with relapsing polychondritis.

OBJECTIVES: Although relapsing polychondritis (RP) is considered as an immune-mediated systemic disease, the levels of peripheral lymphocyte subpopulations are rarely studied in patients with RP. In this study, we focused on changes of peripheral CD4+T cell subsets in patients with RP. METHODS: Absolute numbers and percentages of CD4+T cell subsets including helper T(Th)1, Th2, Th17 cells and regulatory T (Treg) cells in peripheral blood (PB) from 19 RP patients, healthy controls and RA patients respectively were assessed by flow cytometry combined a microbead-based single-platform method. We compared the CD4+T cell levels in all RP patients and healthy controls. In addition, we analysed the difference of the absolute number and percentage of Treg cells between RP and RA patients. RESULTS: Compared with healthy controls, all RP patients had significantly both lower absolute number and proportion of Treg cells (absolute number, 45.10/µl vs. 22.48/µl, p<0.001; proportion, 5.19% vs. 3.78%, p<0.001) no matter whether they had received treatment or not. Similarly, the absolute number of Th2 cells in all RP patients was decreased (10.19/µl vs. 7.44/µl, p=0.030). However, there were no significant differences in percentages and absolute numbers of Th1 and Th17 cells between RP patients and healthy controls. The above results led to increased ratios of Th1/Treg (3.68 vs. 2.06, p=0.020), Th2/Treg (0.29 vs. 0.21, p=0.037) and Th17/Treg (0.25 vs. 0.14, p<0.001) in RP patients, and untreated RP patients were mainly characterised by the imbalance of Th17/Treg (0.25 vs. 0.14, p<0.01). There was no significant difference in Treg cells between RP and RA patients (p>0.05). CONCLUSIONS: Our data suggest that the reduction of Treg cells and its imbalance with Th cells play an important role in the pathogenesis of RP.

Long non-coding RNA MEG3 inhibits M2 macrophage polarization by activating TRAF6 via microRNA-223 down-regulation in viral myocarditis.

Viral myocarditis (VMC) commonly triggers heart failure, for which no specific treatments are available. This study aims to explore the specific role of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) in VMC. A VMC mouse model was induced by Coxsackievirus B3 (CVB3). Then, MEG3 and TNF receptor-associated factor 6 (TRAF6) were silenced and microRNA-223 (miR-223) was over-expressed in the VMC mice, followed by determination of ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). Dual-luciferase reporter assay was introduced to test the interaction among MEG3, TRAF6 and miR-223. Macrophages were isolated from cardiac tissues and bone marrow, and polarization of M1 or M2 macrophages was induced. Then, the expressions of components of NLRP3 inflammatory body (NLRP3, ASC, Caspase-1), M1 markers (CD86, iNOS and TNF-α) and M2 markers (CD206, Arginase-1 and Fizz-1) were measured following MEG3 silencing. In the VMC mouse model, MEG3 and TRAF6 levels were obviously increased, while miR-223 expression was significantly reduced. Down-regulation of MEG3 resulted in the inhibition of TRAF6 by promoting miR-223. TRAF6 was negatively correlated with miR-223, but positively correlated with MEG3 expression. Down-regulations of MEG3 or TRAF6 or up-regulation of miR-223 was observed to increase mouse weight, survival rate, LVEF and LVFS, while inhibiting myocarditis and inflammation via the NF-κB pathway inactivation in VMC mice. Down-regulation of MEG3 decreased M1 macrophage polarization and elevated M2 macrophage polarization by up-regulating miR-223. Collectively, down-regulation of MEG3 leads to the inhibition of inflammation and induces M2 macrophage polarization via miR-223/TRAF6/NF-κB axis, thus alleviating VMC.

Cetuximab for esophageal cancer: an updated meta-analysis of randomized controlled trials.

BACKGROUND: Increasing evidence indicates that cetuximab (CET) combined with chemoradiotherapy may be effective for patients with esophageal cancer. However, the recent results are still contradictory and no consensus has yet been reached on this issue. To evaluate the clinical effects and safety of CET, we conducted an updated meta-analysis by retrieving published data up to June 2018. METHODS: A comprehensive literature search was performed in several electronic databases, including PubMed, Embase, the Cochrane Library, CNKI database and Chinese Biomedicine Database using subject terms and free terms. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to determine the efficiency and safety of CET. RESULTS: This meta-analysis included 10 randomized controlled trials (RCTs). Five RCTs reported localized esophageal cancer and other five RCTs reported metastatic esophageal cancer. For these patients with localized esophageal cancer, CET could not significantly improve the response rate, overall survival and progression-free survival (PFS, 1-5 years). But CET treatment might increase the incidences of diarrhea (OR = 2.07; CI = 1.01-4.25) and rash (OR = 16.91; CI = 3.20-89.42). For other patients with metastatic esophageal cancer, the addition of CET significantly increased the response rate (OR = 3.34; CI = 1.90-5.88), disease control rate (OR = 2.92; CI = 1.49-5.71) and 2-year overall survival (OR = 2.78; CI = 1.20-6.46) compared with the control group. However, CET could not improve the 1-year overall survival and might make patients with metastatic esophageal cancer more susceptible to rash (OR = 5.50; CI = 2.14-14.14). No significant differences in other adverse effects were found between the two groups. CONCLUSIONS: Our findings suggested that adding CET to multimodal therapy significantly improved response rate and disease control rate for patients with metastatic esophageal cancer rather than patients with localized esophageal cancer. CET might be a safe therapeutic choice, but CET failed to significantly improve the overall survival and PFS for patients with localized or metastatic esophageal cancer.

Efficacy, safety and the lymphocyte subsets changes of low-dose IL-2 in patients with systemic lupus erythematosus: A systematic review and meta-analysis.

INTRODUCTION: Existing therapies of systemic lupus erythematosus (SLE) are efficacious only in certain patients. Developing new treatment methods is urgent. This meta-analysis aimed to evaluate the efficacy and safety of low-dose IL-2 (LD-IL-2). METHODS: According to published data from PubMed, Web of Science, Embase, ClinicalTrials.gov, MEDLINE, MEDLINE, Web of Knowledge, Cochrane Library, and FDA.gov, eight trials were included. RESULTS: After the LD-IL-2 treatment, 54.8% of patients had distinct clinical remission. The SRI-4 response rates were 0.819 (95% confidence interval [CI]: 0.745-0.894), and the SELENA-SLEDAI scores were significantly decreased (SMD = -2.109, 95% CI: [-3.271, -0.947], p < .001). Besides, the proportions of CD4+ T (SMD = 0.614, 95% CI: [0.250, 0.979], p = .001) and Treg cells (SMD = 1.096, 95% CI: [0.544, 1.649], p < .001) were increased dramatically after LD-IL-2 treatment, while there were no statistical differences in the proportions of CD8+ T cells, Th1 cells, Th2 cells, and Th17 cells (p > .05). Besides, the proportions of Th17 (SMD = 1.121, 95% CI: [0.709, 1.533], p < .001) and Treg (SMD = 0.655, 95% CI: [0.273, 1.038], p = .001) were significantly increased after receiving subcutaneously 0.5 million IU of LD-IL-2 treatment per day for 5 days, but there were no statistical differences in the proportions of Treg after receiving 1 million IU every other day subcutaneously of LD-IL-2 treatment. Injection site reaction and fever were common side effects of IL-2, which occurred in 33.1% and 14.4% of patients. No serious adverse events were reported. CONCLUSION: LD-IL-2 was promising and well-tolerated in treating SLE, which could promote Treg's proliferation and functional recovery. Injecting 0.5 million IU of IL-2 daily can better induce the differentiation of Treg cells and maintain immune homeostasis than injecting 1 million IU every other day.

Efficacy, Safety and the Lymphocyte Subset Changes of Low-Dose IL-2 in Patients with Autoimmune Rheumatic Diseases: A Systematic Review and Meta-Analysis.

INTRODUCTION: Current therapies for autoimmune rheumatic diseases (ARDs) have limited efficacy in certain patients, highlighting the need for the development of novel treatment approaches. This meta-analysis aims to assess the efficacy and safety of low-dose interleukin-2 (LD-IL-2) and evaluate the alterations in lymphocyte subsets in various rheumatic diseases following administration of different dosages of LD-IL-2. METHODS: A comprehensive search was conducted in PubMed, Web of Science, the Cochrane Library, Embase databases and CNKI to identify relevant studies. A total of 31 trials were included in this meta-analysis. The review protocols were registered on PROSPERO (CRD42022318916), and the study followed the PRISMA guidelines. RESULTS: Following LD-IL-2 treatment, patients with ARDs exhibited a significant increase in the number of Th17 cells and Tregs compared to their pre-treatment levels [standardized mean difference (SMD) = 0.50, 95% confidence interval (CI) (0.33, 0.67), P < 0.001; SMD = 1.13, 95% CI (0.97, 1.29), P < 0.001]. Moreover, the Th17/Tregs ratio showed a significant decrease [SMD = - 0.54, 95% CI (- 0.64, - 0.45), P < 0.001]. In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), LD-IL-2 injection led to a significant increase in Treg numbers, and the Th17/Tregs ratio and disease activity scores, including Disease Activity Score-28 joints (DAS28), Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), were all significantly reduced. No serious adverse events were reported in any of the included studies. Additionally, 54.8% of patients with lupus nephritis achieved distinct clinical remission following LD-IL-2 treatment. Injection site reactions and fever were the most common side effects of LD-IL-2, occurring in 33.1% and 14.4% of patients, respectively. CONCLUSION: LD-IL-2 treatment showed promise and was well tolerated in the management of ARDs, as it effectively promoted the proliferation and functional recovery of Tregs. TRIAL REGISTRATION: Retrospectively registered (CRD42022318916, 21/04/2022).

The efficacy and safety of short-term and low-dose IL-2 combined with tocilizumab to treat rheumatoid arthritis.

Background: Immunotherapy targeting factors related to immune imbalance has been widely employed for RA treatment. This study aimed to evaluate the efficacy and safety of low-dose interleukin (IL)-2 combined with tocilizumab (TCZ), a biologics targeting IL-6, in RA patients. Methods: Fifty adults with active RA who met the criteria with complete clinical data were recruited, and divided into three groups: control group (n=15), IL-2 group (n=26), and IL-2+TCZ group (n=9). In addition to basic treatment, participants in the IL-2 group received IL-2 (0.5 MIU/day), while participants in the IL-2+TCZ group received IL-2 (0.5 MIU/day) along with one dose of TCZ (8 mg/kg, maximum dose: 800 mg). All subjects underwent condition assessment, laboratory indicators and safety indicators detection, and records before treatment and one week after treatment. Results: Compared with the baseline, all three groups showed significant improvement in disease conditions, as evidenced by significantly reduced disease activity indicators. The low-dose IL-2 and combination treatment groups demonstrated a violent proliferation of Tregs, while the absolute number of Th1, Th2, and Th17 cells in the latter group showed a decreasing trend. The decrease in the Th17/Treg ratio was more pronounced in the IL-2+TCZ groups. No significant adverse reactions were observed in any of the patients. Conclusion: Exogenous low doses of IL-2 combined TCZ were found to be safe and effective in reducing effector T cells and appropriately increasing Treg levels in RA patients with high effector T cell levels. This approach helps regulate immune homeostasis and contributes to the prevention of disease deterioration. Clinical trial registration: https://www.chictr.org.cn/showprojEN.html?proj=13909, identifier ChiCTR-INR-16009546.

Dysbiosis of the Gut Microbiota in Patients with Psoriatic Arthritis is Closely Related to Lymphocyte Subsets and Cytokines.

The purpose of this research was to characterize the microbiota of patients with psoriatic arthritis (PsA) and to compare the relationship between the microbiota and peripheral lymphocyte subsets and cytokines. We collected stool samples from 13 PsA patients and 26 sex- and age-matched healthy controls (HCs) and researched the gut microbiota by sequencing the V3-V4 variable region of the bacterial 16S rRNA gene with the Illumina Miseq PE300 system. Flow cytometry was used to assess the peripheral lymphocyte subsets in these participants. Record measures of disease activity such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Alpha and beta diversity were assessed using results from QIIME2. Panel demonstrated the average relative abundance of the different genera in PsA and HCs. Correlation between clinical parameters and the relative abundance of the genus in samples was assessed by the Pearson correlation analysis using R (version 4.0.1). Compared with HC, the abundance of gut microbiota (Chao 1 and ACE) decreased in patients with PsA, and the diversity of bacteria (Shannon and Simpson indices) also decreased in PsA (Fig. 1a). ß Diversity analysis indicated differences in microbial communities between PsA and HC (Fig. 1b, r = 0.039, p = 0.264, ANOSIM). Furthermore, 18 bacterial groups were significantly different at the genus level in PsA compared to HCs (p < 0.05) (Fig. 2).In the phylum and genus, lymphocyte subsets and cytokines are associated with the microbiota. The gut microbiota of patients with PsA differs from HC, which was closely related to lymphocyte subsets.

Exploring the therapeutic potential of regulatory T cell in rheumatoid arthritis: Insights into subsets, markers, and signaling pathways.

Rheumatoid arthritis (RA) is a complex autoimmune inflammatory rheumatic disease characterized by an imbalance between immunological reactivity and immune tolerance. Regulatory T cells (Tregs), which play a crucial role in controlling ongoing autoimmunity and maintaining peripheral tolerance, have shown great potential for the treatment of autoimmune inflammatory rheumatic diseases such as RA. This review aims to provide an updated summary of the latest insights into Treg-targeting techniques in RA. We focus on current therapeutic strategies for targeting Tregs based on discussing their subsets, surface markers, suppressive function, and signaling pathways in RA.

Genetic evidence reveals a causal relationship between rheumatoid arthritis and interstitial lung disease.

Background/purpose: Previous epidemiological studies have associated interstitial lung disease (ILD) with rheumatoid arthritis (RA), yet the causality of this relationship remains uncertain. This study aimed to investigate the genetic causal link between ILD and RA. Methods: Genome-wide association study (GWAS) statistics for ILD and RA were collected from public datasets. Relevant single-nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. A two-sample bidirectional Mendelian randomization (MR) analysis was performed to assess the causal relationship between the two conditions. The MR analysis primarily used the inverse variance weighting (IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses, including MR-Egger, leave-one-out, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), were conducted to evaluate the heterogeneity and pleiotropy. Replication analyses using Asian datasets were also conducted to enhance the robustness of our findings. Results: In the European population, RA was found to increase the risk of ILD by 9.6% (OR: 1.096, 95% CI: 1.023-1.174, p = 0.009). Conversely, ILD was associated with a 12.8% increased risk of RA (OR: 1.128, 95% CI: 1.013-1.256, p = 0.029). Replication analyses from Asian GWAS further supported these findings, particularly the increased risk of ILD attributable to RA (OR: 1.33, 95% CI: 1.18-1.49, p-value <0.001). Conclusion: Our findings underscore the clinical importance of screening for ILD in RA patients and suggest that effective management of RA could significantly benefit ILD patients. The potential applicability of novel RA treatments to ILD warrants further exploration. Additionally, racial disparities in the manifestation of these diseases should not be overlooked, as they may offer new perspectives for targeted therapies in diverse populations.

Study on the expression changes of lncRNA in patients with systemic lupus erythematosus and its correlation with Treg cells.

OBJECTIVES: We initially explored the link between the differentially expressed long non-coding RNAs (lncRNAs) and the number of regulatory T (Treg) cells by detecting the lncRNA expression profiles in patients with systemic lupus erythematosus (SLE), then analyzed the correlation between Treg-related lncRNAs and the clinical features of SLE patients, predicting the mechanism by which lncRNAs regulate the differentiation and development of Treg cells, and provided new ideas for the treatment of SLE. METHODS: Peripheral blood of 9 active SLE patients were collected and mononuclear cells (PBMCs) were extracted; the lncRNA expression profiles of PBMCs were analyzed by whole transcriptome sequencing. Nine healthy people were used as controls to screen the differentially expressed lncRNAs, to analyze the correlation between lncRNAs and Treg cell number. Pearson test was used to analyze the correlation between lncRNAs and the number of Treg cell, and the correlation between Treg-associated lncRNA and SLEDAI score, ESR, C3, and C4 in SLE patients. The targeted genes of Treg-associated lncRNAs were predicted with miRcode and Targetscan databases and coexpression network. RESULTS: There were 240 differentially expressed lncRNAs in SLE patients compared with healthy controls, including 134 highly expressed lncRNAs (p < 0.05) and 106 lowly expressed lncRNAs (p < 0.05). The expression of ANKRD44-AS1 (r = 0.7417, p = 0.0222), LINC00200 (r = 0.6960, p = 0.0373), AP001363.2 (r = 0.7766, p = 0.0138), and LINC02824 (r = 0.7893, p = 0.0114) were positively correlated with the number of Treg cell, and the expression of AP000640.1 (r = - 0.7225, p = 0.0279), AC124248.1 (r = - 0.7653, p = 0.0163), LINC00482 (r = - 0.8317, p = 0.0054), and MIR503HG (r = - 0.7617, p < 0.05) were negatively correlated with the number of Treg cell. Among these Treg-associated lncRNAs, the expression of LINC00482 (r = - 0.7348, p < 0.05) and MIR503 HG (r = - 0.7617, p < 0.05) were negatively correlated with C3. LINC00200, ANKRD44 - AS1, and AP000640.1 related to Treg cells regulate the expression of signal transducer and activator of transcription 5 (STAT5), phospholipase D1 (PLD1), homeodomain-only protein X (HOPX), and runt-related transcription factor 3 (RUNX3) through competitive binding of miRNA or trans-regulatory mechanism, thereby regulating the differentiation and development of Treg cell. CONCLUSIONS: The lncRNA expression profiles were changed in SLE patients, the differentially expressed lncRNAs were associated with abnormal number and function of Treg cells in SLE, and Treg-associated lncRNAs were associated with SLE-disease activity, which may affect the expression of STAT5, PLD1, HOPX, RUNX3 and regulate Treg cell function and participate in the pathogenesis and progression of SLE by competitively binding to miRNAs or trans-regulatory mechanism. Key points • Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and systems. lncRNAs may affect Treg cells function by regulating genes expression, which may be an important pathogenesis of SLE. • This study, taking SLE as an example, preliminarily analyzed the correlation between lncRNA and Treg cells in SLE patients, analyzed the correlation between Treg-related lncRNA and the clinical characteristics of SLE, and speculated that lncRNA could regulate the differentiation and development of Treg cells through competitive combination with miRNA or trans-regulatory mechanisms. • It is possible to target epigenetic therapy for SLE.

Genetically determined type 1 diabetes mellitus and risk of osteoporosis.

BACKGROUND: Observational evidence suggests that type 1 diabetes mellitus (T1DM) is associated with the risk of osteoporosis (OP). Nevertheless, it is not apparent whether these correlations indicate a causal relationship. To elucidate the causal relationship, a two-sample Mendelian randomization (MR) analysis was performed. METHODS: T1DM data was obtained from the large genome-wide association study (GWAS), in which 6683 cases and 12,173 controls from 12 European cohorts were involved. Bone mineral density (BMD) samples at four sites were extracted from the GEnetic Factors for OSteoporosis (GEFOS) consortium, including forearm (FA) (n = 8,143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). The former three samples were from mixed populations and the last one was from European. Inverse variance weighting, MR-Egger, and weighted median tests were used to test the causal relationship between T1DM and OP. A series of sensitivity analyses were then conducted to verify the robustness of the results. RESULTS: Twenty-three independent SNPs were associated with FN-BMD and LS-BMD, twenty-seven were associated with FA-BMD, and thirty-one were associated with eBMD. Inverse variance-weighted estimates indicated a causal effect of T1DM on FN-BMD (odds ratio (OR) =1.033, 95 % confidence interval (CI): 1.012-1.054, p = 0.002) and LS-BMD (OR = 1.032, 95 % CI: 1.005-1.060, p = 0.022) on OP risk. Other MR methods, including weighted median and MR-Egger, calculated consistent trends. While no significant causation was found between T1DM and the other sites (FA-BMD: OR = 1.008, 95 % CI: 0.975-1.043, p = 0.632; eBMD: OR = 0.993, 95 % CI: 0.985-1.001, p = 0.106). No significant heterogeneity (except for eBMD) or horizontal pleiotropy was found for instrumental variables, suggesting these results were reliable and robust. CONCLUSIONS: This study shows a causal relationship between T1DM and the risk of some sites of OP (FN-BMD, LS-BMD), allowing for continued research to discover the clinical and experimental mechanisms of T1DM and OP. It also contributes to the recommendation if patients with T1DM need targeted care to promote bone health and timely prevention of osteoporosis.