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ObjectiveGenome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis.MethodsWe built gene expression predictive models in blood B cells, CD4+and CD8+T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches.ResultsTWAS identified 171 genes for SLE (p–5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association betweenCD83and SLE (p–8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10–9) aroundCD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect onACAP1, and that presence of the SLE risk allele decreasedACAP1expression.ConclusionsCell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Objectives. The aim of our study was to investigate the association of single-nucleotide polymorphism (SNP) and mRNA expression profile of single immunoglobulin IL-1-related receptor (SIGIRR) in rheumatoid arthritis (RA) in a Chinese population. Methods. SIGIRR rs7396562 polymorphism was genotyped using TaqMan allelic discrimination assay in 517 RA patients and 601 healthy controls. Simultaneously, the SIGIRR mRNA expression levels of 79 RA patients and 76 healthy controls were examined by real-time quantitative polymerase chain reaction (RT-qPCR). Results. The frequency of SIGIRR rs7396562 T allele was significantly higher in RA patients compared with healthy controls (T versus G:OR=1.277,95%CI=1.079−1.511,P=0.004). The TT genotype of SIGIRR rs7396562 was more frequent in RA patients than in healthy controls (OR=1.547,95%CI=1.107−2.163,P=0.011). Moreover, we also found a significant difference in the recessive model (TT versus TG+GG:OR=1.439,95%CI=1.122−1.847,P=0.004). However, no significant evidence was observed for the association of the SIGIRR rs7396562 with RA in dominant model (TT+TG versus GG:OR=1.275,95%CI=0.947−1.717,P=0.109). Further analysis showed no association between SIGIRR rs7396562 polymorphism and laboratory parameters of RA patients (allP>0.05). The mRNA expression of SIGIRR was decreased in PBMCs of patients with RA when compared to healthy controls (Z=−2.459,P=0.014). No significant differences in SIGIRR mRNA expression levels were observed in patients with RA with different genotypes (P=0.280). Conclusions. Our findings demonstrated that the dysregulation of SIGIRR might be associated with the pathogenesis of RA, and SIGIRR rs7396562 polymorphism might contribute to RA susceptibility in the Chinese population.

To investigated the association between single nucleotide polymorphisms (SNPs) in microRNA-146a (miR-146a) gene and susceptibility of rheumatoid arthritis (RA). We systemically extracted the genetic data of miR-146a from previous genome-wide association studies (GWASs) of RA. Subsequently, we performed a replication study in an independent Chinese cohort for selected variant. A meta-analysis combined the previous GWASs with the replication study was also conducted. The epigenetic annotation and cytokine assay were used for exploring potential variant function. The extracted genetic association data from three previous GWASs showed that the allele T of functional SNP rs2431697 increased RA susceptibility. The significant association for the SNP was also found in the Chinese replication cohort (OR = 1.24, 95% CI = 1.06–1.46, p = 8.69E-03). The estimated effect size for this SNP was larger in Asian population than that in European population (Asian meta-analysis: OR = 1.15, 95% CI = 1.09–1.22, p = 4.37E-07; Tran-ethnic meta-analysis: OR = 1.07, 95% CI = 1.04–1.10, p = 1.79E-06). The cytokine assay also showed that the risk allele T of the SNP rs2431697 is inversely associated with plasma TNF-α levels in health controls (p = .016). In summary, this study supports that genetic variant in miR-146a gene is associated with RA risk.KEY MESSAGESThe association between SNPs in miR-146a gene and susceptibility of RA was unclear.We investigated the genetic association using GWASs data and a replication study.The SNP rs2431697 in miR-146a gene is associated with RA risk. The association between SNPs in miR-146a gene and susceptibility of RA was unclear. We investigated the genetic association using GWASs data and a replication study. The SNP rs2431697 in miR-146a gene is associated with RA risk.

ObjectiveSystemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.MethodsWe newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.ResultsWe identified 113 genetic regions including 46 novel loci at genome-wide significance (p−8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=−0.242) and non-albumin protein (rg=0.238).ConclusionThis study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

ObjectivesThe present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA).MethodsWe performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA cases and 2879 controls) and further conducted an expanded meta-analysis with previous GWAS summary data and replication studies. The functional roles of the associated loci were interrogated using publicly available databases. Dual-luciferase reporter and cytokine assay were also used for exploring variant function.ResultsWe identified five new susceptibility loci (IL12RB2, BOLL-PLCL1, CCR2, TCF7 and IQGAP1; pmeta IQGAP1 have significantly increased reporter activity in HEK293T cells. In addition, the cytokine assay found that the risk allele of rs244672 in TCF7 was most significantly associated with increased plasma IL-17A levels in healthy controls. Finally, identified likely causal genes in these loci significantly interacted with RA drug targets.ConclusionThis study identified novel RA risk loci and highlighted that comprehensive genetic study can provide important information for RA pathogenesis and drug therapy.

Human immunodeficiency virus (HIV) infection results in gut microbiota alteration and this is associated with immune activation and chronic inflammation. The gastrointestinal tract is a primary site of viral replication and thus HIV-induced loss of T-helper (Th) cells in the gut causes impairments in intestinal barriers, resulting in disruptions in intestinal immunity and precipitating into gut dysbiosis. Here, we show that late HIV diagnosis can negatively affect the immunological, virological, and clinical prognosis of the patients with its higher implication at an older age. Further, the review indicates that antiretroviral therapy affects the gut microbiota. We discussed the use of probiotics and prebiotics that have been indicated to play a promising role in reversing gut microbiota alteration in HIV patients. Though there are several studies reported with regard to such alterations in gut microbiota regarding HIV infection, there is a need to provide comprehensive updates. It is, therefore, the objective of this review to present most recently available evidence on the alteration of gut microbiota among HIV patients.

Previous studies are inconclusive on the relationships between BLK gene polymorphisms and clinical features of systemic lupus erythematosus (SLE). The present study aimed to estimate association between BLK loci and SLE clinical features in Chinese population. Associations between BLK single-nucleotide polymorphisms (SNPs) and susceptibility to SLE in this study were estimated using data of 1205 health controls previously reported in the same population. And a total of 814 SLE patients recruited from two different sources according with ACR criteria were analyzed for genotype–phenotype associations. A meta-analysis was conducted of the associations between BLK loci and renal disorder in SLE. The expression quantitative trait locus (eQTL) data were also extracted from the public databases for the selected SNPs. Significant associations were observed between these SNPs and susceptibility to SLE. In addition, the data showed that rs2618479 and rs7812879 were associated with renal disorder [OR = 1.51 (95% CI: 1.15, 1.99) and 1.61 (95% CI: 1.21, 2.14), Pcorr = 0.033 and 0.011, respectively] and proteinuria [OR = 1.47 (95% CI: 1.12, 1.95) and 1.52 (95% CI: 1.14, 2.03), Pcorr = 0.048 and 0.040, respectively]. The consistent associations were observed in two independent centers as well as new cases group. The result of meta-analysis for rs2618479 was also significant [OR = 1.35 (95% CI: 1.12, 1.62)]. In addition, bioinformatics analysis demonstrated that the two SNPs were significantly associated with the expression of BLK in whole blood and several immune cells. Our data support that variant loci of BLK are associated with presence of renal disorder in patients with SLE.

Background: N6-methyladenosine (m6A) modification is widespread in eukaryotic mRNA, regulated by m6A demethylase, AlkB homolog 5 (ALKBH5). However, the role of m6A in systemic lupus erythematosus (SLE) is still obscure. We explored ALKBH5 expression in SLE patients and its effects on T cells. Methods: 100 SLE patients and 110 healthy controls were recruited to investigate the expression of ALKBH5 in peripheral blood mononuclear cells (PBMCs). An additional 32 SLE patients and 32 health controls were enrolled to explore the expression of ALKBH5 in T cells. Then we explored the function of ALKBH5 in T cells by lentivirus. Results: The expressions of ALKBH5 were downregulated in both PBMCs and T cells in SLE patients (all P Conclusion: Conclusion: ALKBH5 expression is downregulated in SLE patients and could affect the apoptosis and proliferation of T cells, but the exact mechanism still needs to be further explored.

Background and Objectives: The 3’ repair exonuclease 1 (TREX1) gene is the major DNA-specific 3’–5 ’exonuclease of mammalian cells which reduces single- and double-stranded DNA (ssDNA and dsDNA) to prevent undue immune activation mediated by the nucleic acid. TREX1 is also a crucial suppressor of selfrecognition that protects the host from inappropriate autoimmune activations. It has been revealed that TREX1 function is necessary to prevent host DNA accumulating after cell death which could actuate an autoimmune response. In the manuscript, we will discuss in detail the latest advancement to study the role of TREX1 in autoimmune disease. Methods: As a pivotal cytoprotective, antioxidant, anti-apoptotic, immunosuppressive, as well as an antiinflammatory molecule, the functional mechanisms of TREX1 were multifactorial. In this review, we will briefly summarize the latest advancement in studying the role of TREX1 in autoimmune disease, and discuss its potential as a therapeutic target for these diseases. Results: Deficiency of TREX1 in human patients and murine models is characterized by systemic inflammation and the disorder of TREX1 functions drives inflammatory responses leading to autoimmune disease. Moreover, much more studies revealed that mutations in TREX1 have been associated with a range of autoimmune disorders. But it is also unclear whether the mutations of TREX1 play a causal role in the disease progression, and whether manipulation of TREX1 has a beneficial effect in the treatment of autoimmune diseases. Conclusion: Integration of functional TREX1 biology into autoimmune diseases may further deepen our understanding of the development and pathogenesis of autoimmune diseases and provide new clues and evidence for the treatment of autoimmune diseases.

LncRNAs are potential biomarkers for SLE, but the epigenetic regulatory mechanisms of N6-methyladenosine (m6A) modification in SLE remain largely unclear.In this study, we established m6A modification profile and investigated the potential roles of m6A-related lncRNAs in SLE. The m6A modification profile of SLE was established using MeRIP-seq. Four potential m6A related-lncRNAs (linc02446, linc01410, Xist, and PSMB8-AS1) were selected for validation using qRT-PCR, and their expression and association with clinical characteristics with SLE were evaluated.Overall, m6A level was lower in patients with SLE than in controls. Compared with controls, the expression of the two m6A related-lncRNAs (Xist and PSMB8-AS1) was downregulated in patients with SLE (all P0.05); the linc02446 was up-regulated in PBMCs of patients with SLE (Z=-2.738, P = 0.006), while it was not differentially expressed in T cells (Z=-0.387, P = 0.699). No significant alteration in linc01410 expression was observed in patients (Z=-0.940, P = 0.347). The lower expression levels of Xist and PSMB8-AS1 were associated with many clinical manifestations in patients with SLE (all P0.05). Additionally, mRNAs co-expressed with m6A related-lncRNAs (Xist, linc02446, and PSMB8-AS1) also participated in SLE.These results suggest that m6A methylation and m6A related-lncRNAs might be involved in the pathogenesis of SLE. Thus, our findings provide some clues on the potential function of lncRNAs that m6A modification may target in novel therapeutic or diagnostic strategies for SLE.

Aim: To derive a precise estimation on plasma/serum level of SOD, GPx, CAT and GSH levels in systemic lupus erythematosus (SLE) patients. Methods: A total of 36 articles from electronic databases were finally included with 1120 SLE patients and 1024 healthy controls considered for antioxidant levels. Results: The levels of CAT and GSH were significantly lower, while SOD and GPx levels were slightly lower in patients with SLE compared with healthy controls. Subgroup analysis indicated that Arabs, ages ≥40 and SLE diseases activity index

Anti-keratin antibody (AKA) is a serum antibody for patients with rheumatoid arthritis (RA), and it has a high specificity. Diagnostic role of AKA in RA was evaluated in this study. PubMed, EMBASE, and Web of Science were searched to acquire eligible studies. Articles published before 15 March 2018 were considered to be included. Quality Assessment of Diagnostic Accuracy Studies 2 was used to evaluate the risk of bias and application concern of the included articles. Pooled analysis of diagnostic indicators of AKA for RA was conducted by using a random effects model. Subgroup analysis was employed to explore the potential influencing factors. RevMan 5.3, Stata 11.0, and Meta-DiSc 1.4 software were used in this study. A total of 15 studies (2350 positive and 2067 negative participants) were included. The pooled sensitivity was 0.46 (95% CI 0.44–0.48), pooled specificity was 0.94 (95% CI 0.93–0.95), and pooled diagnostic odds ratio was 15.86 (95% CI 9.48–26.52). In addition, the area under the curve was 0.7194. The current evidence indicated that AKA has high diagnostic specificity in RA and may be useful for RA diagnostic application in clinic.

It has been reported that circRNAs are diff ;erentially expressed in many diseases and can be used as new biomarker to facilitate disease diagnosis. Circular RNAs (circRNAs) microarray were used to identify dysregulated circRNAs in plasma of systemic lupus erythematosus (SLE) patients. Then, we confirmed the microarray data by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in both plasma and peripheral blood mononuclear cells (PBMCs) of SLE. One hundred and twelve circRNAs were identified to dysregulated expressed in plasma of SLE as compared to healthy controls. The results of qRT-PCR showed that the levels of hsa_circRNA_407176 and hsa_circRNA_001308 were decreased in both plasma and PBMCs of SLE when compared with healthy controls. The receiver operating characteristic (ROC) curve area of hsa_circRNA_407176 and hsa_circRNA_001308 in plasma were 0.599 and 0.662, respectively. The area under the ROC curves of hsa_circRNA_407176, hsa_circRNA_406567 and hsa_circRNA_001308 in PBMCs were 0.806, 0.744, and 0.722, respectively. Our study illustrated that hsa_circRNA_407176 and hsa_circRNA_001308 in plasma and PBMCs could be potential biomarkers for SLE.

Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci1-8. Nevertheless, these loci only partially explain SLE heritability and provide limited biological insight. We report the largest study of SLE in East Asians (13,377 cases and 194,993 controls), identifying 233 association signals within 113 (46 novel) genetic loci. We detect six new lead missense variants and prioritize ten most likely putative causal variants, one of which we demonstrate exhibits allele-specific regulatory effect on ACAP1 in vitro. We suggest 677 effector genes with potential for drug repurposing, and provide evidence that two distinct association signals at a single locus act on different genes (NCF2 and SMG7). We demonstrate that SLE-risk variants overlap with cell-specific active regulatory elements, notably EBNA2-mediated super-enhancers in Epstein-Barr Virus-transformed B cells, and implicate the role for non-immune cells in SLE biology. These findings shed light on genetic and biological understandings of SLE.

Long noncoding RNAs (lncRNAs) widely participate in human diseases by regulating gene transcription, modulating protein function, or acting as ceRNAs. Yet, their roles in rheumatoid arthritis (RA) remain obscure. In this study, the expression of three lncRNAs (H19, GAS5, and linc0597) in peripheral blood mononuclear cells (PBMCs) were detected in 77 RA patients and 78 controls using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The association of lncRNAs related gene polymorphisms with RA were evaluated in 828 RA patients and 780 controls using TaqMan single nucleotide polymorphism (SNP) genotyping assays. We observed that the expression levels of H19, GAS5 and linc0597 were down-regulated in PBMCs of RA patients, of which GAS5 level decreased in patients with hypocomplementemia, and negatively correlated with C-reactive protein (CRP) level in RA patients. Moreover, we highlighted two related potential functional SNPs, GAS5 rs6790 and linc0597 rs2680700 for associations with RA susceptibility. The precise roles of these lncRNAs in mechanism of RA remain to be further explored.

OBJECTIVE: Th17 cell and IL-17 mediated autoimmunity has been implicated in the development of organ damage in Systemic Lupus Erythematosus (SLE). New evidence suggests that hypoxia-inducible factor 1α (HIF-1α) enhances Th17 differentiation and promotes IL-17 production. However, the role of HIF-1α in the pathogenesis of lupus has not been examined. The aim of this study was to investigate the role of HIF-1α in lupus development. METHODS: Female lupus mice (MRL/lpr) received tail vein injections of HIF1α-shRNA or control treatments, and were sacrificed at 24h, 2 weeks, or 4 weeks after the administration. HIF-1α expression was measured in splenocytes and sera obtained from the mice. The proportion of Th17 cells in splenocytes and serum IL-17 level were determined. Urine protein, serum ANA and anti-dsDNA antibody levels were compared among the groups. We also scored renal pathology, IgG and C3 depositions in glomeruli. RESULTS: Administration of HIF1α-shRNA suppressed HIF-1α expression in lupus mice. The serum IL-17 level decreased significantly following the HIF-1α silencing. Decreased ANA level, reduced urinary protein concentrations, ameliorated pathological damage and remarkably reduced renal IgG and C3 depositions were also observed in HIF1α-shRNA treated group compared to those in the controls. CONCLUSION: Our results provide the first evidence for a role of HIF-1α in the pathogenesis of lupus and suggest a potential new therapeutic avenue for the treatment of lupus patients through reducing the HIF-1α level.

The field of m6A modification and epitranscriptomics has recently attracted much attention. More methods allowing for precise m6A site profiling and location are developed and crucial players of m6A modification machinery are increasingly identified. Although some challenges remain, m6A modification is found to modulate almost all aspects of RNA metabolism, such as splicing, stability, structure, translation, and export. Thus, m6A modification adds a new layer of post-transcriptional gene expression regulation, and it is implicated in T cell response to HIV infection, type I interferon production, and T cell differentiation and homeostasis. Moreover, evidence supporting its involvement in various human diseases including cancers is accumulating. Given the role of m6A modification in gene expression regulation and immune response, it invites the speculation that m6A modification may justify the pathogenesis of systemic lupus erythematosus (SLE) and take part in the initiation and progression of SLE. In this review, we introduce the widespread existence of m6A modification and briefly discuss components of m6A modification machinery in mammals. We mainly summarize the studies reporting the mechanisms of m6A modification in gene expression regulation through modulating pre-mRNA splicing, mRNA stability, RNA structure, translation, and pri-miRNA processing. Biological functions related to immune response of m6A modification and the implication of m6A modification in cancers are highlighted. In the end, we surmise the potential link between m6A modification and SLE.

Increasing evidence has demonstrated the association between long noncoding RNAs (lncRNAs) and multiple autoimmune diseases. To explore four lncRNAs (GAS5, lnc-DC, linc0597 and linc0949) expression levels and gene polymorphisms in systemic lupus erythematosus (SLE), a two stage design was applied. In the first stage, 85 SLE patients and 71 healthy controls were enrolled to investigate the lncRNAs expression levels. Then, 1260 SLE patients and 1231 healthy controls were included to detect the single nucleotide polymorphisms (SNPs) in the differentially expressed lncRNAs identified in the first stage. Linc0597, lnc-DC and GAS5 expression levels were significantly lower in SLE patients than healthy controls (P P P = 0.003 respectively). Association of five SNPs (rs10515177, rs2070107, rs2632516, rs2877877, rs2067079) with SLE risk were analyzed. No significant association was observed between these gene polymorphisms and susceptibility to SLE (all P > 0.010), and we did not find significant association between any genotypes at five SNPs and their respective lncRNAs expression in SLE (all P > 0.010). In summary, the expression levels of linc0597, lnc-DC and GAS5 are decreased in SLE patients, but their gene polymorphisms are not associated with SLE risk, and do not influence their expression levels.

// Dao-Jun Chen 1, 2 , Lan-Ju Li 1, 2 , Xiao-Ke Yang 1, 2 , Tao Yu 1, 2 , Rui-Xue Leng 1, 2 , Hai-Feng Pan 1, 2 and Dong-Qing Ye 1, 2 1 Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China 2 Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, Anhui, China Correspondence to: Dong-Qing Ye, email: ydqahmu@gmail.com , ydq@ahmu.edu.cn Keywords: microRNA, vitamin D, SLE, T cells Received: August 15, 2016 Accepted: May 31, 2017 Published: July 07, 2017 ABSTRACT Vitamin D has been recognized as a potent immunomodulator and its deficiency is common in different population groups including patients with SLE. As miRNAs regulation plays a significant role in SLE, the present study aimed to evaluate the association between vitamin D status and miRNAs levels in patients with SLE. The serum concentrations of vitamin D (25-hydroxyvitamin D) and the levels of six miRNAs in T cells from patients with SLE were measured in 42 SLE cases and 48 healthy controls. Vitamin D treatment was also performed in isolated and cultured T cells from SLE patients in different times and doses. Vitamin D insufficiency (25-hydroxyvitamin D concentration

BACKGROUND This study aimed to estimate the point prevalence of myositis and identify associated variables of myositis in systemic lupus erythematosus (SLE). MATERIAL AND METHODS Clinical date of patients hospitalized with lupus at the First Affiliated Hospital of Anhui Medical University and Anhui Provincial Hospital were collected. Patients were defined as having myositis if they reported the presence of persistent invalidating muscular weakness combined with increased levels of creatine phosphokinase (CPK) and abnormal electromyography (EMG). RESULTS The study sample comprised 1701 lupus patients, of which 44 had myositis. Patients with SLE-associated myositis are more likely to have skin rash, alopecia, pericarditis, vasculitis, anti-Sm, anti-RNP, anti-dsDNA, thrombocytopenia, leukopenia, low C3, low C4, high erythrocyte sedimentation rate (ESR), high D-dimer, and active disease. Multivariate logistic regression found positive associations between leukopenia, alopecia, and active disease with myositis. Negative associations between myositis with the use of corticosteroids or immunosuppressive drugs were revealed in univariate and multivariate analysis. CONCLUSIONS The point prevalence of myositis was 2.6% in SLE patients. The significant association of alopecia, leukopenia, and active disease with myositis suggests that organ damage, hematological abnormality, and high disease activity promote the progression of myositis in lupus patients.

To explore the association of LEP and leptin receptor (LEPR) gene single‐nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese population. Four LEP SNPs (rs11761556, rs12706832, rs2071045 and rs2167270) and nine LEPR SNPs (rs10749754, rs1137100, rs1137101, rs13306519, rs8179183, rs1805096, rs3790434, rs3806318 and rs7518632) were genotyped in a cohort of 633 patients with SLE and 559 healthy controls. Genotyping of SNPs was performed with improved multiple ligase detection reaction (iMLDR). No significant differences were detected for the distribution of allele and genotype frequencies of all 13 SNPs between patients with SLE and controls. The genotype effects of recessive, dominant and additive models were also analysed, but no significant evidence for association was detected. However, further analysis in patients with SLE showed that the TT genotype and T allele frequencies of the LEP rs2071045 polymorphism were nominally significantly higher in patients with pericarditis (P = 0.012, P = 0.011, respectively). In LEPR, the GA/AA genotype and A allele frequencies of the rs1137100 polymorphism were both nominally associated with photosensitivity in patients with SLE (P = 0.043, P = 0.018, respectively). Moreover, the genotype and allele distribution of rs3806318 were also nominally associated with photosensitivity in patients with SLE (P = 0.013, P = 0.008, respectively). No significant differences in serum leptin levels were observed in patients with SLE with different genotypes. In summary, LEP and LEPR SNPs are not associated with genetic susceptibility to SLE, but may contribute to some specific clinical phenotype of this disease; further studies are necessary to elucidate the exact role of LEP and LEPR genes in the pathogenesis of SLE.

Objectives Air pollution ranks high among risk factors for the global burden of disease. The associations of air pollution and rheumatoid arthritis (RA) are controversial. This systematic review and meta-analyses has analyzed the association between outdoor air pollution and the development of RA. Methods PubMed, Embase and Web of science (last search, May 21, 2019) were searched. A meta-analysis was performed with a random-effects model, and summarized syntheses effects were expressed as relative risks (RRs). Results Eight studies were identified from among 1296 articles. The pooled RR for the association between ozone (O3) exposure and RA was 1.16 (95% CI: 1.15, 1.18). The pooled RR for the association of RA risk with proximity to traffic road was 1.34 (95% CI: 1.11, 1.62) for residence ≤ 50 m from a traffic road compared with residence more far away. In contrast, there was an inverse effect between PM2.5 exposure and incident RA, and similar result of PM10 was found by subgroup analysis in seropositive RA. In addition, there was no clear evidence between exposing to PM10, CO, NO2 and NO2 (tenth year prior) and RA risk. Conclusion Existing evidence indicated significant associations between some markers (ozone, proximity to traffic road and PM2.5) of air pollution and RA. For generalizability of evidence, that research should be extended to developing countries where air pollution (including indoor) is high may provide more complete insight into risk factors for RA.

Recent evidence has demonstrated that UBASH3A play a pivotal role in multiple autoimmune diseases. In this study, we explored the association between UBASH3A gene single-nucleotide polymorphisms (SNPs) and rheumatoid arthritis (RA) in a Chinese Han population. We also comparatively evaluated the UBASH3A expression profile in peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy controls.Four UBASH3A polymorphisms (rs1893592, rs11203203, rs2277798, and rs3788013) were studied in 553 patients with RA and 587 controls in a Chinese population. Genotyping was performed using the Fluidigm 192.24 Dynamic Array Integrated Fluidic Circuit (IFC). For gene expression study, UBASH3A mRNA levels of 30 RA patients and 31 healthy individuals were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Data were analyzed by SPSS 19.0 software.A significant association between rs1893592 polymorphism and RA was found under all genetic models (all p.05). We also discovered a significant association between rs3788013 polymorphism and RA in the allele and genotype distributions, as well as the recessive model (all p.05). Moreover, we found the genotype distribution and allele frequency of rs1893592 were significantly associated with RF phenotype in the RA patients (χOur observations suggested that the dysregulation of UBASH3A might be associated with the pathogenesis of RA, and UBASH3A gene polymorphisms (rs1893592 and rs3788013) might contribute to RA susceptibility in Chinese Han population.

Recent large-scale genetic association studies have identified that several single nucleotide polymorphisms (SNPs) on X chromosome are correlated with risk of systemic lupus erythematosus (SLE) in Chinese population. The aim of this study was to estimate association between these loci and clinical features in female patients with SLE. Six SNPs identified in previous studies were genotyped. Odds ratio (OR) was calculated with adjusting for potential confounding factors. A total of 772 SLE patients were included in the final analysis. The data showed that 3 SNPs (rs5914778, rs3853839 and rs1059702) were marginally associated with several clinical subphenotypes. Furthermore, consistent associations were also found in two independent cohorts. However, the cumulative genetic risk score (GRS) was not associated with clinical manifestations as well as the disease activity index at disease diagnosis. In summary, genetic variants in X-linked genes may be potentially associated with presence of specific clinical feature. Further studies in distinct ethnical populations are required to clarify the association between these loci and presence of SLE clinical features.

Autoimmune diseases contain a large number of pathologies characterized by various factors that contribute to a breakdown in self-tolerance. Cytokine-mediated immunity plays an essential role in the pathogenesis of varieties of autoimmune diseases. Recent studies reveal that interleukin-35 (IL-35), a newly identified cytokine of IL-12 family, is implicated in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), etc. In this review, we will discuss the biological features of IL-35 and summarize recent advances in the role of IL-35 in the development and pathogenesis of autoimmune diseases; the discoveries gained from these findings might translate into future therapies for these diseases.

Objective To evaluate the plasma levels of six adipokines, including chemerin, omentin-1, lipocalin-2, cathepsin-S, cathepsin-L and adipsin, in patients with SLE. Methods Ninety SLE patients and ninety control subjects were recruited, plasma adipokines levels were measured by enzyme-linked immunosorbent assay, and their associations with major clinical and laboratory indexes were analyzed. Results There were no significant differences in plasma chemerin, omentin-1, lipocalin-2, cathepsin-S, cathepsin-L and adipsin levels between SLE patients and controls. Further subgroup analyses by major clinical and laboratory indexes showed that plasma omentin-1 level was significantly lower in SLE patients without nephritis when compared with those patients with nephritis ( P = 0.002). Plasma chemerin, cathepsin-S levels in SLE patients without nervous system disorder were significantly lower in comparison with SLE patients with nervous system disorder ( P = 0.035, P = 0.029). No significant associations of other adipokines with any major clinical and laboratory indexes were observed. Conclusions Plasma levels of chemerin, omentin-1, lipocalin-2, cathepsin-S, cathepsin-L and adipsin in SLE patients were not markedly different from the normal controls. The presence of nephritis was connected with higher plasma omentin-1 levels in SLE patients, and the presence of nervous system disorder was associated with higher plasma chemerin, cathepsin-S levels in SLE patients. However, functional studies are awaited to further explore the potential roles of these cytokines in SLE.

OBJECTIVE A recent genome-wide association study identified that genetic variants in DPP4 and CCR6 are connected with a risk of RA in the Han Chinese population. The aim of this study was to estimate the epistatic interaction between DPP4 and CCR6 in RA. METHODS Two single-nucleotide polymorphisms identified in a Han Chinese genome-wide association study (rs12617656 in DPP4, rs1854853 in CCR6) were genotyped. Logistic regression was used to estimate the multiplicative interaction and the additive interaction was analysed by 2 × 2 factorial design. RESULTS A total of 1224 subjects (377 RA patients, 847 healthy controls) were included in the initial analysis. Additionally, 600 patients with lupus arthritis were included for comparison. Significant multiplicative interaction between DPP4 and CCR6 was observed in RA [codominant model: odds ratio (OR) = 1.49, P = 0.003]. The epistatic effect seems to be stronger in ACPA-positive RA (codominant model: OR = 1.66, P = 0.001). However, no significant multiplicative interactions were observed in ACPA-negative RA or lupus arthritis. Additive interaction analysis showed a significant epistatic effect, but only in ACPA-positive RA [attributable proportion due to interaction = 0.48 (95% CI 0.10, 0.85)]. A further replication study of an independent cohort (476 subjects) found similar results. Pooled results confirmed that there was significant interaction between DPP4 and CCR6 on both the multiplicative and additive scales. CONCLUSION The study suggests that a genetic interaction between DPP4 and CCR6 is involved in RA susceptibility. Furthermore, these findings highlight Th17 cell response as an important contributor in the pathogenesis of RA.

MicroRNAs (miRNAs) are a set of small single-stranded noncoding RNAs with diverse biological functions. As a prototypical hypoxamir, human microRNA-210 (hsa-miR-210) is one of the most widely studied miRNAs thus far. In addition to its involvement in sophisticated regulation of numerous biological processes, miR-210 has also been shown to be associated with the development of different human diseases including various types of cancers, cardiovascular and cerebrovascular diseases, and immunological diseases. Given its multi-faceted functions, miR-210 may serve as a novel and promising theranostic target for prevention and treatment of diseases. Areas covered: This review aims to provide a comprehensive overview of miR-210, the regulation of its expression, biological functions and molecular mechanisms, with particular emphasis on its diagnostic and therapeutic potential. Expert opinion: Although the exact roles of miR-210 in various diseases have not been fully clarified, targeting miR-210 may be a promising therapeutic strategy. Further investigations are also needed to facilitate therapeutic-clinical applications of miR-210 in human diseases.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by multisystem organ involvement and unclear pathogenesis. Several adipokines synthesized in the adipose tissue, including leptin, adiponectin, resistin, and chemerin, have been explored in autoimmune rheumatic diseases, especially SLE, and results suggest that these mediators may be implicated in the pathogenesis of SLE. However, the current results are controversial. In this review, we will briefly discuss the expression and possible pathogenic role of several important adipokines, including leptin, adiponectin, resistin, and chemerin in SLE.

Recent evidence has demonstrated that CD3ζ (also called CD247) play a vital role in multiple autoimmune diseases. In this study, we explored the association between CD247 gene single-nucleotide polymorphisms (SNPs) and rheumatoid arthritis (RA) in a Chinese Han population. We also evaluated the CD3ζ expression profile in peripheral blood mononuclear cells (PBMCs) from patients with RA and health controls.Three CD247 polymorphisms (rs704853, rs1214611 and rs858554) were studied in 612 patients with RA and 848 controls in a Chinese population. Genotyping was performed using the Fluidigm 192.24 Dynamic Array™ Integrated Fluidic Circuit (IFC). For gene expression study, CD3ζ mRNA levels of 36 patients with RA and 39 healthy individuals were assessed by real-time polymerase chain reaction (RT-PCR). Data were analyzed by SPSS 11.5 software.A significant association between rs858554 polymorphism and RA was found under all genetic models (all p 0.05). Moreover, we found the genotype distribution and allele frequency of rs858554 were significant associated with ACCPOur results, the first reported for distinct Chinese populations, support a role of the CD247 gene in the susceptibility to RA. Further studies with more sample size are necessary to clarify the exact role of CD247 gene in the pathogenesis of RA.

Systemic lupus erythematosus (SLE) is associated with increased risk of cardiovascular disease. Carotid intima media thickness (CIMT) and carotid plaques are both frequently used to identify populations at higher cardiovascular risk. A systematic literature search and meta-analysis were performed to evaluate CIMT and carotid plaques difference between SLE patients and normal controls.The literatures comparing markers of cardiovascular risk (CIMT and prevalence of carotid plaques) in SLE and controls were systematically searched in PubMed, EMBASE and Cochrane databases. The overall mean CIMT difference and pooled odds ratio (OR) for the prevalence of carotid plaques between SLE patients and control groups were calculated by fixed-effects or random-effect model analysis. Meta-regression was performed to explore the potential influencing factors. Publication bias was examined by a funnel plot and Egger's test.A total of 80 studies (6085 SLE patients and 4794 controls) were included in the final analysis, 71 studies with data on CIMT (4814 cases and 3773 controls) and 44 studies reporting on the prevalence of carotid plaques (4417 cases and 3528 controls). As compared to controls, SLE patients showed a higher CIMT (WMD: 0.07 mm; 95%CI: 0.06, 0.09; P0.001), and an increased prevalence of carotid plaques (OR: 2.45; 95%CI: 2.02, 2.97; P0.001). Meta-regression models showed that traditional cardiovascular risk factors (age, HDL and triglyceride of SLE patients) and lupus related risk factors (as expressed by duration, ESR, SLEDAI and steroids) had a significant influence on CIMT, steroids and triglyceride had significant influence on the prevalence of carotid plaques.Our findings support the current evidence base for an increased cardiovascular burden in SLE patients and support the use of CIMT and carotid plaques in observational studies in SLE patients. The findings are of importance to design more specific prevention and treatment strategies.

This study aims to derive a more precise estimation on carotid intima-media thickness (CIMT) level in patients with rheumatoid arthritis (RA) and related factors. Studies published from January 1, 1982 to December 31, 2014 in English, which comparing CIMT between RA group and control group were searched in PubMed, Embase, and Cochrane Library databases. Heterogeneity test was performed, and publication bias was evaluated. Stata software 12.0 was used to perform the meta-analysis. Two-thousand one hundred sixty-three articles were obtained after searching databases, and 47 studies were finally included in the meta-analysis. The result of the analysis in random effect model showed that RA group had significantly higher CIMT than control group, with the standardized mean difference (SMD) of 1.04 and 95% CI (0.81,1.27). To evaluate the stability of our results, sensitivity analyses were performed, and the results showed no significant change when any one study was excluded. Subgroup analyses showed that region, race, age, BMI, and disease duration were associated with CIMT in RA patients. In summary, CIMT in RA patients is thicker than healthy controls, and it is influenced by region, race, age, BMI, and disease duration.

This study was conducted to (1) characterize coagulation cascade and complement system in systemic lupus erythematosus (SLE); (2) evaluate the associations between coagulation cascade, complement system, inflammatory response and SLE disease severity; (3) test the diagnostic value of a combination of D-dimer and C4 for lupus activity. Transcriptomics, proteomics and metabolomics were performed in 24 SLE patients and 24 healthy controls. The levels of ten coagulations, seven complements and three cytokines were measured in 112 SLE patients. Clinical data were collected from 2025 SLE patients. The analysis of multi-omics data revealed the common links for the components of coagulation cascade and complement system. The results of ELISA showed coagulation cascade and complement system had an interaction effect on SLE disease severity, this effect was pronounced among patients with excess inflammation. The analysis of clinical data revealed a combination of D-dimer and C4 provided good diagnostic performance for lupus activity. This study suggested that coagulation cascade and complement system become ‘partners in crime’, contributing to SLE disease severity and identified the diagnostic value of D-dimer combined with C4for lupus activity.

OBJECTIVES The aim of our study was to evaluate two lncRNAs (lnc0640 and lnc5150) expressions and gene single-nucleotide polymorphisms (SNPs) in rheumatoid arthritis (RA) patients. METHODS The expressions of lncRNAs in peripheral blood mononuclear cells (PBMCs) were examined by quantitative real-time reverse transcription polymerase chain reaction from 65 RA patients and 54 controls. Simultaneously, three SNPs (rs13039216, rs6085189, and rs6085190) of lnc0640, three SNPs (rs1590666, rs141561256, and rs144047453) of lnc5150 were genotyped using TaqMan SNP-genotyping assays in 627 RA patients and 590 controls. RESULTS The lnc0640 level in PBMCs from RA patients was significantly increased (P = 0.001), whereas the lnc5150 level was significantly reduced (P

This study was performed to systematically summarize the results on the association of HLA-DQB1 polymorphisms with pemphigus vulgaris (PV) and other related factors.A comprehensive literature search of PubMed, The Cochrane Library, Embase, and Google Scholar database was conducted to identify relevant articles in English, with the last report up to November 1, 2016. Heterogeneity test was performed, and publication bias was evaluated. Stata software 12.0 was used to perform the meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CI) were used to describe the correlation by random-effects model.18 studies were obtained after searching databases: 10 studies were about Caucasian, and 8 articles were about non-Caucasian. Meta-analysis revealed that the allele and phenotype frequencies of DQB1*05 were markedly higher in PV patients than in controls [P 0.001, OR: 2.640, 95%CI: 1.570-4.441; P = 0.030, OR 3.688, 95%CI: 1.138-11.946]. In addition, DQB1*03 was significantly increased at the allele level [P 0.001, OR: 2.080, 95%CI: 1.507-2.869], and DQB1*02 was significantly decreased in PV at the allele and phenotype levels [P = 0.002, OR: 0.450, 95%CI: 0.289-0.702; P = 0.001, OR: 0.293, 95%CI: 0.146-0.587]. When based on each subtype of HLA-DQB1, DQB1*05:03 and DQB1*03:02 may play susceptibility roles in PV, and DQB1*03:03, DQB1*05:01 and DQB1*06:01 are negatively associated with PV.In summary, our study suggests that alleles from the groups DQB1*05 and DQB1*03, concretely DQB1*05:03 and DQB1*03:02, respectively, may be the susceptibility factors for PV at allele and phenotype levels, whereas DQB1*05:01, DQB1*02, DQB1*06:01, and DQB1*03:03 are negatively associated with PV.

Currently published data regarding the relationship between plasma/serum leptin levels and systemic lupus erythematosus (SLE) are contradictory. To derive a more precise evaluation of this relationship, a meta-analysis was performed.Published literature from PubMed, Embase and Cochrane Library were obtained. The study quality was assessed by the Newcastle-Ottawa scale. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by fixed-effects or random-effect model analysis. Heterogeneity among studies was estimated using the Cochran Q and I(2) statistics.A total of 11 studies including 868 SLE patients and 591 controls were finally included in the meta-analysis. No significant differences in plasma/serum leptin levels was found between SLE patients and healthy controls when all studies were pooled into the meta-analysis (pooled SMD = 0.269, 95% CI = -0.188 to 0.726). However, subgroup analyses showed that SLE patients from an Asian population, age ≥40 years and BMI25 had higher plasma/serum leptin levels when compared with controls.There is no significant difference in plasma/serum leptin levels between the entire group of SLE patients and controls. However, plasma/serum leptin levels are significantly higher in the subgroup of SLE patients from an Asian population ≥40 years of age and with a BMI25.

Long noncoding RNA (lncRNA), with size larger than 200 nucleotides, is a new class of noncoding RNA. Emerging evidence has revealed that lncRNAs play a key role in the regulation of immunological functions and autoimmunity. Herein, we review the recent findings of lncRNA regulation in immune functions and in the development of autoimmunity and autoimmune disease. In addition, we focus on the involvement of lncRNA regulation in innate and adaptive immune responses, immune cell development, and differential expression of lncRNAs in autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes mellitus (T1DM), multiple sclerosis (MS), autoimmune thyroid disease (AITD), psoriasis, polymyositis/dermatomyositis (PM/DM) and Crohn's disease (CD).

Background and Aims Studies investigating the association between the peptidylarginine deiminase 4 (PADI4) gene polymorphisms and rheumatoid arthritis (RA) reported conflicting results. The aim of this meta-analysis was to assess the association between PADI4 gene polymorphisms and RA. Methods A systematic literature search was conducted to identify relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the association. Results A total of 34 studies from 28 articles involving 19859 patients with RA and 25771 healthy controls were included. Significant association of PADI4–94G/A polymorphism and RA was observed (OR = 0.891, 95% CI = 0.833–0.954, p = 0.001) in the overall study population and in the Asian populations (OR = 0.824, 95% CI = 0.759–0.894, p = 0.000) respectively. For the –92C/G polymorphism, a significant association was observed (OR = 1.481, 95% CI = 1.166–1.882, p = 0.001) in Africans. For the –90C/T polymorphism, a significant association was observed (OR = 0.576, 95% CI = 0.381–0.872, p = 0.009) in the Latin American population. The pooled estimates for the other polymorphisms were not statistically significantly associated with RA (PADI4–104C/T, –89A/G, –96T/C). Conclusions This meta-analysis demonstrates that PADI4–94G/A polymorphism is associated with susceptibility to RA in the overall population and in the Asian population. The PADI4 –92C/G polymorphism confers susceptibility to RA in Africans and the PADI4–90C/T polymorphism was associated with RA in the Latin American population.