Genetically Predicted Circulating Omega-3 Fatty Acids Levels Are Causally Associated With Increased Risk for Systemic Lupus Erythematosus.

BACKGROUND: Accumulating evidence has demonstrated the associations of omega-3 or omega-6 polyunsaturated fatty acids (PUFAs) with the disease activity and inflammatory mediators of systemic lupus erythematosus (SLE), but the evidence of causal links of omega-3 or omega-6 PUFAs on the risk for SLE remains inconclusive. OBJECTIVES: This study was conducted to evaluate the causal relationships between omega-3/omega-6 PUFAs and SLE by performing the Mendelian randomization (MR) analysis. METHODS: Genome-wide significant single-nucleotide polymorphisms (SNPs) were obtained from genome-wide association studies (GWASs) of circulating omega-3/omega-6 levels (n = up to 13,544) and GWAS meta-analyses of SLE (n = 14,267), respectively. The bidirectional two-sample MR (TSMR) analysis was conducted to infer the causality. RESULTS: The inverse-variance weighted (IVW) method revealed that genetically determined per SD increase in omega-3 levels were causally associated with an increased risk for SLE (odds ratios [ORs] = 1.49, 95% CI: 1.07, 2.08, p = 0.021), but no causal effect of omega-6 on the risk SLE was observed (IVW OR = 1.06, 95% CI: 0.72, 1.57, p = 0.759). In addition, there were no significantly causal associations in genetic predisposition to SLE with the changes of omega-3 and omega-6 levels, respectively (IVW beta for omega-3: 0.007, 95% CI: -0.006, 0.022, p = 0.299; IVW beta for omega-6: -0.008, 95% CI: -0.023, 0.006, p = 0.255). CONCLUSION: The present study revealed the possible causal role of omega-3 on increasing the risk for SLE, it could be the potential implications for dietary recommendations.

Therapeutic Potential of Galectin-1 and Galectin-3 in Autoimmune Diseases.

Galectins are a highly conserved protein family that binds to ß-galactosides. Different members of this family play a variety of biological functions in physiological and pathological processes such as angiogenesis, regulation of immune cell activity, and cell adhesion. Galectins are widely distributed and play a vital role both inside and outside cells. They can regulate homeostasis and immune function in vivo through mechanisms such as apoptosis. Recent studies have indicated that galectins exhibit pleiotropic roles in inflammation. Furthermore, emerging studies have found that galectins are involved in the occurrence and development of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D), and systemic sclerosis (SSc) by regulating cell adhesion, apoptosis, and other mechanisms. This review will briefly discuss the biological characteristics of the two most widely expressed and extensively explored members of the galectin family, galectin-1 and galectin-3, as well as their pathogenetic and therapeutic roles in autoimmune diseases. This information may provide a novel and promising therapeutic target for autoimmune diseases.

Elevated Circulating Thrombomodulin Levels in Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis.

OBJECTIVES: Thrombomodulin (TM) is closely related to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). However, current evidence on circulating TM levels in SLE patients is contradictory. We conducted this meta-analysis to more accurately assess circulating TM levels in patients with SLE and lupus nephritis (LN) and to analyze related influencing factors. METHODS: Systematic search of relevant documents was conducted in PubMed, Embase, and The Cochrane Library databases (up to 28 February 2021). Studies on the comparison of circulating TM between SLE patients and controls were screened and evaluated for inclusion. Random-effects model analysis was applied to calculate the combined standardized mean difference (SMD) with a 95% confidence interval (CI). Heterogeneity was estimated by Q statistics and I2. RESULTS: A total of 353 articles were identified, 14 provided adequate information for this study finally. The results illustrated that SLE patients had higher TM levels than healthy controls (SMD=0.38, 95% CI: 0.02 to 0.74, p=0.04). Circulating TM levels were increased in patients with active SLE compared to inactive SLE patients (SMD=1.12, 95% CI: 0.03 to 2.20, p=0.04). In addition, circulating TM levels of SLE patients with LN were higher than those without LN (SMD=4.55, 95% CI: 1.97 to 7.12, p=0.001). CONCLUSION: The circulating TM levels in SLE patients are enhanced. In addition, circulating TM levels may be practical in reflecting the disease activity and nephritis involvement of SLE patients.

Causal Effects of Gut Microbiome on Systemic Lupus Erythematosus: A Two-Sample Mendelian Randomization Study.

The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. However, whether the association is causal remains unclear. The present study used publicly available genome-wide association study (GWAS) summary data to perform two-sample Mendelian randomization (MR), aiming to examine the causal links between gut microbiome and SLE. Two sets of MR analyses were conducted. A group of single nucleotide polymorphisms (SNPs) that less than the genome-wide statistical significance threshold (5 × 10-8) served as instrumental variables. To obtain a comprehensive conclusion, the other group where SNPs were smaller than the locus-wide significance level (1 × 10-5) were selected as instrumental variables. Based on the locus-wide significance level, the results indicated that there were causal effects of gut microbiome components on SLE risk. The inverse variance weighted (IVW) method suggested that Bacilli and Lactobacillales were positively correlated with the risk of SLE and Bacillales, Coprobacter and Lachnospira were negatively correlated with SLE risk. The results of weighted median method supported that Bacilli, Lactobacillales, and Eggerthella were risk factors for SLE and Bacillales and Coprobacter served as protective factors for SLE. The estimates of MR Egger suggested that genetically predicted Ruminiclostridium6 was negatively associated with SLE. Based on the genome-wide statistical significance threshold, the results showed that Actinobacteria might reduce the SLE risk. However, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) detected significant horizontal pleiotropy between the instrumental variables of Ruminiclostridium6 and outcome. This study support that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk.

Association of MALAT-1 gene single nucleotide polymorphisms with genetic susceptibility to systemic lupus erythematosus.

Background: Abnormal expression and function of long non-coding RNAs (lncRNAs) are closely related to the pathogenesis of systemic lupus erythematosus (SLE). In this study, we aimed to investigate the association of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) gene single-nucleotide polymorphisms (SNPs) with susceptibility and clinical characteristics of SLE patients. Methods: A case-control study including 489 SLE patients and 492 healthy controls was conducted. Four MALAT-1 SNPs (rs4102217, rs591291, rs11227209, and rs619586) were genotyped in all subjects, their correlation with SLE susceptibility and clinical characteristics were also analyzed. Results: Results showed that the rs4102217 locus was associated with the risk of SLE. In recessive models, the GG+CG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC (p = 0.036, OR = 0.348, 95% CI: 0.124-0.975). In additive models, the GG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC (p = 0.040, OR = 0.355, 95% CI: 0.127-0.996). However, no association was found between MALAT-1 gene polymorphism and clinical manifestations of SLE (all p > 0.05). Conclusion: In summary, MALAT-1 rs4102217 is associated with susceptibility to SLE, suggesting that MALAT-1 may play a role in SLE.

Circadian clock genes as promising therapeutic targets for autoimmune diseases.

Circadian rhythm is a natural, endogenous process whose physiological functions are controlled by a set of clock genes. Disturbance of the clock genes have detrimental effects on both innate and adaptive immunity, which significantly enhance pro-inflammatory responses and susceptibility to autoimmune diseases via strictly controlling the individual cellular components of the immune system that initiate and perpetuate the inflammation pathways. Autoimmune diseases, especially rheumatoid arthritis (RA), often exhibit substantial circadian oscillations, and circadian rhythm is involved in the onset and progression of autoimmune diseases. Mounting evidence indicate that the synthetic ligands of circadian clock genes have the property of reducing the susceptibility and clinical severity of subjects. This review supplies an overview of the roles of circadian clock genes in the pathology of autoimmune diseases, including BMAL1, CLOCK, PER, CRY, REV-ERBα, and ROR. Furthermore, summarized some circadian clock genes as candidate genes for autoimmune diseases and current advancement on therapy of autoimmune diseases with synthetic ligands of circadian clock genes. The existing body of knowledge demonstrates that circadian clock genes are inextricably linked to autoimmune diseases. Future research should pay attention to improve the quality of life of patients with autoimmune diseases and reduce the effects of drug preparation on the normal circadian rhythms.

Association between ambient air pollution and tuberculosis risk: A systematic review and meta-analysis.

There is a growing body of evidence suggesting an association between air pollution exposure and tuberculosis (TB) incidence, but no meta-analysis has assembled all evidence so far. This review and meta-analysis aimed to derive a more reliable estimation on the association between air pollution and TB incidence. PubMed, Embase and Web of Science electronic databases were systemically searched for eligible literature. The PECO framework was used to form the eligibility criteria. Effect estimates and 95% confidence intervals (CIs) published in the included studies were pooled quantitatively. Seventeen articles met the inclusion criteria. The pooled estimates showed that long-term exposure to particulate matter with an aerodynamic diameter ≤10 µm (PM10) was associated with increased incidence of TB (per 10 µg/m3 increase in concentrations of PM10: risk ratios (RR) = 1.058, 95% CI: 1.021-1.095). Besides, long-term exposure to sulfur dioxide (SO2) and nitrogen dioxide (NO2) were significantly associated with TB incidence (per 1 ppb increase, SO2: RR = 1.016, 95% CI: 1.001-1.031; NO2: 1.010, 95% CI: 1.002-1.017). We did not find a significant association of PM2.5, ozone (O3) or carbon monoxide (CO) with TB risk, regardless of long-term or short-term exposure. However, in view of the 2016 ASA Statement and the biological plausibility of PM2.5 damaging host immunity, the association between PM2.5 and TB risk remains to be further established. This meta-analysis shows that long-term exposure to PM10, SO2 or NO2 is associated with increased odds of TB, and the specific biological mechanisms warrant further research.

Association of PER2 gene single nucleotide polymorphisms with genetic susceptibility to systemic lupus erythematosus.

The circadian clock plays a crucial role in the progress of systemic lupus erythematosus (SLE). In this study, we performed a case-control study to explore the association between Period 2 (PER2) gene single nucleotide polymorphisms (SNPs) and the susceptibility of systemic lupus erythematosus (SLE). A total of 492 SLE patients and 493 healthy controls were included. The improved multiple ligase detection reaction (iMLDR) was used for genotyping. The correlations between four SNPs of PER2 (rs10929273, rs11894491, rs36124720, rs934945) and the genetic susceptibility and clinical manifestations of SLE were analyzed. Significant differences were observed in the distributions of allele frequencies and genotype under dominant model in rs11894491 between SLE patients and controls (p = 0.030, p = 022, respectively). We hypothesized that PER2 gene SNPs was related to the genetic susceptibility and clinical manifestations, implying the potential role of PER2 in the pathogenesis of SLE.

Emerging role of Fli1 in autoimmune diseases.

The Ets transcription factor family exerts crucial role in cell proliferation, apoptosis, differentiation and migration. Friend leukemia integration 1 (Fli1), a member of the Ets family, is expressed in fibroblasts, endothelial cells and immune cells. Fli1 gene is participated in the development, proliferation, activation, migration and other processes of immune cells. Fli1 can also affect the function of immune cells by regulating cytokines and chemokines. Emerging evidence has shown that Fli1 is implicated in the etiology of several autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). In this review, we mainly discuss the current evidence for the role of Fli1 in these diseases.

Association between traffic-related air pollution and hospital readmissions for rheumatoid arthritis in Hefei, China: A time-series study.

Air pollution is an important risk factor for autoimmune diseases, but its association with the recurrence of rheumatoid arthritis (RA) remains unclear so far. This study aimed to investigate the short-term association between traffic-related air pollutants and hospital readmissions for RA in Hefei, China. Data on daily hospital readmissions for RA and traffic-related air pollutants, including particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2), and carbon monoxide (CO), from 2014 to 2018 were retrieved. A time-series approach using generalized linear regression model was employed. The analysis was further stratified by sex, age and season. A total of 1153 readmissions for RA were reported during the study period. A significant association between high-concentration PM2.5 (90th percentile) and RA readmissions was observed on lag1 (relative risk (RR) = 1.09, 95% confidence interval (CI): 1.01-1.19) and lasted until lag3 (RR = 1.06, 95%CI: 1.01-1.12). From lag2 to lag5, high-concentration NO2 (90th percentile) was associated with increased risk of RA readmissions, with the highest RR observed at lag 4 (1.11, 95%CI: 1.05-1.17). Stratified analyses indicated that females and the elderly appeared to be more vulnerable to high-concentration PM2.5 and NO2 exposure. High-concentration PM2.5 and NO2 in cold seasons were consistently significantly associated with increased risk of RA readmissions. Exposure to high-concentration PM2.5 and NO2 was associated with increased risk of RA readmissions. Protective measures against the exposure to high-concentration PM2.5 and NO2 should be taken to reduce the recurrence risk in RA patients, especially in females, the elderly and during cold seasons.

Circulating Meteorin-like Levels in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis.

BACKGROUND: Meteorin-like (Metrnl) is a newly identified adipokine implicated in the pathogenesis of type 2 diabetes mellitus (T2DM), yet data on the circulating levels of Metrnl in patients with T2DM are controversial. To derive a more precise estimation on circulating Metrnl levels in T2DM patients, we conducted this meta-analysis. METHODS: The existing studies on the circulating levels of Metrnl in patients with T2DM published up to 16 January 2020 were comprehensively retrieved from PubMed, Web of Science, EMBASE, and The Cochrane library database. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated using random-effects model. Heterogeneity was assessed and quantified by Cochrane's Q and I2 statistic. All statistical analyses were performed using Stata 12.0 software. RESULTS: Nine studies with 867 T2DM patients and 831 normal glucose tolerance (NGT) controls were included in the final analysis according to the inclusion criteria. No significant difference in circulating Metrnl levels was found between T2DM patients and NGT individuals (pooled SMD = -0.429, 95% CI = -1.077 to 0.219). Compared to controls, circulating Metrnl levels were significantly higher in the subgroups with BMI <25 kg/m2, using plasma sample and patient sample size ≥100, while circulating Metrnl levels were significantly lower in subgroups with age ≤50 years and homeostatic model assessment for insulin resistance (HOMA-IR) ≥4. CONCLUSION: This meta-analysis indicates no significant change in circulating Metrnl levels in T2DM patients. However, this result may be influenced by age, BMI, sample type, HOMA-IR and patients sample size. Further longitudinal studies are warranted to offer more insights into the relationship between Metrnl and T2DM.

Prevalence and influential factors of thrombocytopaenia in systemic lupus erythematosus patients: a retrospective analysis of 3140 cases in a Chinese population.

INTRODUCTION: The present study aimed to investigate the prevalence and influential factors of thrombocytopaenia in systemic lupus erythematosus (SLE) patients among the Chinese population in order to provide evidence for improving the treatment and nursing of SLE patients. METHODS: A retrospective analysis of 3140 SLE patients admitted to two large tertiary hospitals was conducted in Anhui, China, from 2011 to 2018. In addition, the influential factors related to SLE with thrombocytopaenia were analysed through univariate and multivariate analysis. RESULTS: A total of 804 SLE patients had thrombocytopaenia (25.6%). The top 5 clinical manifestations of SLE inpatients were proteinuria (51.0%), lupus nephritis (45.9%), new rash (38.4%), haematuria (36.7%) and pyuria (32.2%). The incidence of neurological manifestations, oral mucosal ulceration, pleurisy, pericarditis, hyperglycaemia, leucocytopaenia, urinary casts, haematuria, pyuria and high disease activity in the thrombocytopaenia group were higher than those in the non-thrombocytopaenia group (p < 0.05). Multivariate analysis showed age (odds ratio (OR) = 1.009, p = 0.005), neurological manifestations (OR = 1.373, p = 0.048), pericarditis (OR = 1.394, p = 0.048), hyperglycaemia (OR = 1.717, p < 0.001), leucocytopaenia (OR = 2.551, p < 0.001), haematuria (OR = 1.582, p < 0.001), serum C3 level <0.85 g/L (OR = 1.525, p = 0.001), serum C4 concentration <0.10 g/L (OR = 1.287, p = 0.020), serum CRP concentration <8 ng/L (OR = 1.314, p = 0.005), prothrombin time >15.30 seconds (OR = 1.479, p = 0.032), activated partial thromboplatin time >45 seconds (OR = 1.924, p < 0.001) and thrombin time >21 seconds (OR = 1.629, p = 0.015) were associated with thrombocytopaenia. CONCLUSION: Thrombocytopaenia has a high prevalence in SLE patients and is related to some baseline, clinical and laboratory characteristics, affecting multiple organs and systems.