Association between uveitis onset and economic development in mainland China.

BACKGROUND: Economic prosperity has fostered numerous changes that may translate into better or worse outcomes across all domains of health. This study aims to explore the associations of economic development with uveitis onset in mainland China. METHODS: We used Poisson regression with generalized estimated equations to quantify the associations of per capita gross domestic product (GDP) with uveitis onset in 31 provinces of mainland China from 2006 to 2017. We further estimated the effects mediated by economic growth on the temperature-uveitis and PM2.5-uveitis associations established in our previous studies. RESULTS: A total of 12,721 uveitis patients from 31 provinces of mainland China were studied. Overall, every 10,000 Chinese yuan ($ 1491.278, 2006-2017) increase in per capita GDP, with no weighted value or weighted by population, corresponded to 1.85% (95% confidence interval, 1.19-2.52%) and 1.43% (95% confidence interval, 0.37-2.51%) lnRR decrease in the uveitis onsets. Stratified analysis showed this negative association between per capita GDP and uveitis onset, only existed in male patients (P < .001), individuals aged 20-50 years (P < 0 .05), non-infectious uveitis, uveitis with systemic disease, and Bechet's disease (all P < 0 .05). Moreover, the increased per capita GDP, if above the national level, could reinforce both temperature-uveitis and PM2.5-uveitis association (both P < 0.001). CONCLUSIONS: The findings suggest that economic development is negatively associated with uveitis onset. However, it may facilitate the uveitis onset mediated by both increased temperature and PM2.5 exposure if the per capita GDP is above national level.

Succinic acid exacerbates experimental autoimmune uveitis by stimulating neutrophil extracellular traps formation via SUCNR1 receptor.

AIMS: To investigate the effect of succinic acid on the development of experimental autoimmune uveitis (EAU) and the underlying mechanism. METHODS: Succinic acid was administrated intraperitoneally to evaluate its effects on immune response and EAU in mice. Intraocular inflammation was evaluated by histopathological scoring. Frequencies of Th1/Th17 cells were measured by flow cytometry. Concentrations of IFN-γ/IL-17A, neutrophil elastase (NE) and myeloperoxidase (MPO) were determined by enzyme-linked immunosorbent test. Infiltration of neutrophils and generation of neutrophil extracellular traps (NETs) within the eye were assessed by immumofluorescence. NETs formation in extracellular matrix was visualised by laser scanning confocal microscopy. Succinate receptor (SUCNR1) antagonist was used to investigate its effect on the generation of NETs. RESULTS: Intraperitoneal injection of succinic acid exacerbated EAU severity as evidenced by severe histological changes in association with elevated frequencies of splenic Th1/Th17 cells, and upregulated levels of IFN-γ/IL-17A and NETs in plasma. In vitro experiments showed that succinic acid could promote the generation of NETs by neutrophils as shown by increased expression of NE and MPO.NETs could increase the frequencies of Th1/Th17 cells in CD4+ T cells and their expression of IFN-γ/IL-17A. In the experiment of receptor antagonism, the upregulatory effect of succinic acid on NETs could be significantly blocked by SUCNR1 antagonist. CONCLUSIONS: Succinic acid could worsen EAU induced by IRBP in mice. This effect was possibly mediated by its upregulation on NETs generation and frequencies of Th1/Th17 cells in affiliation with increased production of IFN-γ/IL-17A through succinic acid-SUCNR1 axis.

Association of CDK6 gene polymorphisms with Behcet's disease in a Han Chinese population.

Cyclin-dependent kinases 4/6 (CDK4/6) and D1-type cyclins (CCND1) can regulate the pro-inflammatory functions of various cytokines during the inflammatory response. This study investigated the association between CDK4/6-CCND1 variants and susceptibility in patients with Behcet's disease (BD). This case-control study enrolled 542 patients with BD and 754 healthy controls. Fourteen tagged single nucleotide polymorphisms (tag SNPs) of the CDK4/6-CCND1 gene were genotyped using the Sequenom MassARRAY system and iPLEX® Pro assay. The results indicated that the frequency of the CDK6 rs2282983 TT genotype was higher in the BD group than the control group (Pc = 0.040, OR = 1.408, 95% CI = 1.124-1.765), and CDK6 rs2282983 CT and rs42034 AG were negatively associated with BD (Pc = 3.647 × 10-4, OR = 0.598, 95% CI = 0.471-0.758; Pc = 0.039, OR = 0.626, 95% CI = 0.459-0.852, respectively). Furthermore, statistical analysis showed that CDK6 rs2282983 TT and CT genotypes were significantly associated with skin lesions in patients with BD (Pc = 0.042, OR = 1.436, 95% CI = 1.130-1.824; Pc = 0.001, OR = 0.594, 95% CI = 0.461-0.764, respectively). This study suggests that the CDK6 loci rs2282983 and rs42034 might confer genetic susceptibility to BD in a Han Chinese population, which could provide new insights into the pathogenesis of BD.

Association between temperature changes and uveitis onset in mainland China.

BACKGROUND: Some uveitis subtypes show seasonal patterns. Whether these patterns are caused by seasonally varying temperatures or by other climatic factors remains unknown. This ecological research aimed to quantify the association between climate variability and uveitis onset. METHODS: We combined data from the largest database of uveitis cases with surface climate data to construct panel data. We used choropleth maps to visually assess spatial uveitis variations. RESULTS: Among 12 721 reports of uveitis originating from 31 provinces of mainland China from 2006 to 2017, we found that a 1°C increase in monthly temperature was associated with a rise in approximately 2 uveitis reports per 1000 individuals (95% CI 0.00059 to 0.0029). This association was present across all provinces, ranging in effect size from 0.0011 to 0.072 (95% CI 0.00037 to 0.10). A clear 0-3 months of cumulative lagging effect was noted across all types of uveitis, with the strongest effect for non-infectious uveitis (0.0067, 95% CI 0.0041 to 0.013). Stratified by age and sex, we found that men and people aged 20-50 years were more affected by temperature variations. Our model predicts that China might experience an increase in uveitis cases due to future global warming. CONCLUSION: Our study is the largest-ever investigation of the association between uveitis and climate and, for the first time, provides evidence that rising temperature can affect large-scale uveitis onset. These results may help promote and implement policies to mitigate future temperature increases and the burden of disease caused by global warming.

Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study.

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD). METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1. RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1. CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Association between Fine Particulate Air Pollution and the Onset of Uveitis in Mainland China.

PURPOSE: Although it has long been recognized that air pollution can affect the immune system and human ocular symptoms, it is uncertain whether air pollutants may also contribute to the development of uveitis. This study aimed to quantify the association of particulate matters less than 2.5 µm (PM2.5) with uveitis onset. METHODS: We combined monthly averages of PM2.5 concentrations, with data from the largest database of uveitis cases to assess the association between PM2.5 and uveitis onset. We further estimated the uveitis burden that was attributed to PM2.5 exposure and used choropleth maps to precisely characterize geographical variations. RESULTS: We found that a 10 µg/m3 increase in PM2.5 concentration was associated with a one-case per 10 individuals increase in uveitis onset across the dataset. Our results further suggest that PM2.5 concentrations above the level of the minimum exposure are responsible for 13% of novel uveitis cases in our cohort. Conclusion: These findings provide evidence supporting the association between fine particulate air pollution and uveitis onset.

Trends in Corneal Transplantation and Characteristics of Donors in the Chongqing Eye Bank, China: A Retrospective Study, 1999-2018.

Aim: This study aimed to analyze corneal transplantation trends and voluntary donor characteristics at the Chongqing Eye Bank in China. Methods: We retrospectively reviewed and analyzed data from January 1, 1999, to December 31, 2018, covering 5,397 preregistered voluntary donors, 1,955 actual donors, 3,910 donated tissues, and 2,374 corneal transplantations. Results: The 5,397 preregistered donors included 13 ethnic groups, with an overall mean age of 39.6 years (SD 21.5) and 3,010 were women (55.8%). The most prevalent education level was college and above (2,546, 47.2%), and the most common ethnic group was Han (5,335, 98.85%). Of the 1,955 actual donors, the male-to-female ratio was 3.3, and the mean age was 57.1 (SD 23.0 years). Based on population size in 2018, Jiangbei county was the most active in donation willingness, with ~60 × 10-6 per capita, and the Yuzhong county was the most active in cornea donations, with ~451 × 0-6 per capita. Of the 3,910 donated corneas, 2,540 (65.0%) were clinically used. Of those not used, 978 (71.4%) were rejected for poor corneal quality. The 2,374 (93.5%) corneal transplantation procedures were done at the Department of Ophthalmology of the First Affiliated Hospital of Chongqing Medical University and the rest (n = 166, 6.5%) were performed in other centers. Of those 2,374 corneal transplantations, there were 1,671 penetrating keratoplasty (70.39%), 700 anterior lamellar keratoplasty (29.49%), and three corneal endothelial transplantations in our center (0.13%). The number of annual corneal transplantations increased by nearly 10 times, from 35 cases in 1999 to 327 cases in 2018. Among them, cases of penetrating keratoplasty and anterior lamellar keratoplasty increased from 27, and eight cases in 1999 to 230 and 94 cases in 2018, respectively. Infectious keratitis (37.0%) was the leading indication for keratoplasty, followed by corneal scar (19.8%). Over the study period, corneal scars dropped from the first (41.1% in 1999-2003) to the second indication (20.5% in 2014-2018), while infectious keratitis advanced to take the lead, ranging from 12.2% in 1999-2003 to 26.3% in 2014-2018. Conclusion: Our study reports corneal donation and transplantation trends in Chongqing over 20 years, showing that infectious keratitis is a leading indication for keratoplasty and that penetrating keratoplasty and anterior lamellar keratoplasty show upward trends. The analysis further suggests that a potential preregistered cornea donor is a female Han, with a higher education level.

SNP-mediated binding of TBX1 to the enhancer element of IL-10 reduces the risk of Behçet's disease.

Aims: The genetic association between Behçet's disease susceptibility and IL-10 has been confirmed in multiple cohorts, but the underlying mechanism of this association remains unclear. Materials & methods: We combined public resources and laboratory experiments (electrophoretic mobility shift assays, chromatin immunoprecipitation, luciferase reporter gene and CRISPR/Cas9 genome editing) to analyze transcription factor binding and enhancer activity controlling IL-10 expression. Results & conclusion: The T allele of noncoding rs3024490 within super-enhancer elements is able to specifically bind TBX1 and, in turn, promotes the enhancer activity and increased expression of IL-10. However, a relative deficiency in TBX1 in Behçet's disease patients leads to the low expression of IL-10 and increased risk of developing Behçet's disease.

Lay abstract Behçet's disease is a prominant cause of blindness. Previous reports show that genetic factors are linked with this disease, although the exact genetic mechanism is unclear. Many of these genetic factors are involved in the control of the immune response, including a large family of proteins known as cytokines. Some of the cytokines are proinflammatory while others can dampen the inflammatory response. An example of the latter is the IL-10 cytokine. We found that individuals carrying a specific site in the noncoding region of the IL-10 gene had a higher risk of Behçet's disease than other noncarriers. This study was designed to further investigate the biological mechanisms explaining the role of the specific site in the development of Behçet's disease. The results show that this specific site affects the binding of an important transcription factor, TBX1, which reduces IL-10 production. The dysregulated control of IL-10 explains why individuals with this genetic trait are more susceptible to developing Behçet's disease.

Meta-Analysis of miRNA Variants Associated with Susceptibility to Autoimmune Disease.

PURPOSE: Various studies have shown an association between miRNA polymorphisms and susceptibility to autoimmune disease (AD); however, the results are inconclusive. To evaluate whether miRNA polymorphisms account for a significant risk of AD, a total of 87 articles, including 39431 patients and 56708 controls, were identified to estimate their association with 12 AD subtypes. METHODS: Several electronic databases were searched to analyze population-based studies on the relationship between miRNA variants and AD risk. Fixed effects or random effect models were used in the meta-analysis for the risk assessment. RESULTS: In our meta-analysis, miR-146a rs2910164/rs57095329 conferred a marginally elevated risk for AD (allele model, OR = 1.08, 95% CI: 1.01-1.15, P = 0.019; allele model, OR = 1.09, 95 CI: 1.05-1.15, P < 0.001, respectively). Furthermore, miR-196a2 rs11614913 was also associated with AD risk (allele model, OR = 0.92, 95% CI: 0.88-0.97, P = 0.001) as well as miR-499 rs3746444 (allele model, OR = 1.16, 95% CI: 1.03-1.29, P = 0.011). In addition, associations were observed between miR-149 rs2292832/miR-27a rs895819 and AD susceptibility in the overall population (allele model, OR = 1.15, 95% CI: 1.06-1.24, P < 0.001; allele model, OR = 1.11, 95% CI:1.01-1.22, P = 0.043, respectively). CONCLUSIONS: Evidence from our systematic review suggests that miR-146a, miR-196a2, miR-499, miR-149, and miR-27a polymorphisms are associated with susceptibility to AD.

High Ambient Temperature Aggravates Experimental Autoimmune Uveitis Symptoms.

Whether ambient temperature influences immune responses leading to uveitis is unknown. We thus tested whether ambient temperature affects the symptoms of experimental autoimmune uveitis (EAU) in mice and investigated possible mechanisms. C57BL/6 mice were kept at a normal (22°C) or high temperature (30°C) housing conditions for 2 weeks and were then immunized with human interphotoreceptor retinoid-binding protein (IRBP651-670) peptide to induce EAU. Histological changes were monitored to evaluate the severity of uveitis. Frequency of Th1 cells and Th17 cells was measured by flow cytometry (FCM). The expression of IFN-γ and IL-17A mRNA was measured by real-time qPCR. The generation of neutrophil extracellular traps (NETs) was quantified by enzyme-linked immunosorbent assay (ELISA). Differential metabolites in the plasma of the mice kept in the aforementioned two ambient temperatures were measured via ultra-high-performance liquid chromatography triple quadrupole mass spectrometry quadrupole time of flight mass spectrometry (UHPLC-QQQ/MS). The differential metabolites identified were used to evaluate their effects on differentiation of Th1 and Th17 cells and generation of NETs in vitro. The results showed that EAU mice kept at high temperature experienced a more severe histopathological manifestation of uveitis than mice kept at a normal temperature. A significantly increased frequency of Th1 and Th17 cells in association with an upregulated expression of IFN-γ and IL-17A mRNA was observed in the splenic lymphocytes and retinas of EAU mice in high temperature. The expression of NETs as evidenced by myeloperoxidase (MPO) and neutrophil elastase (NE), was significantly elevated in serum and supernatants of neutrophils from EAU mice kept at high temperature compared to the normal temperature group. The metabolites in the plasma from EAU mice, fumaric acid and succinic acid, were markedly increased in the high temperature group and could induce the generation of NETs via the NADPH oxidase-dependent pathway, but did not influence the frequency of Th1 and Th17 cells. Our findings suggest that an increased ambient temperature is a risk factor for the development of uveitis. This is associated with the induction of Th1 and Th17 cells as well as the generation of NETs which could be mediated by the NADPH oxidase-dependent pathway.

Sharing of Genetic Association Signals by Age-Related Macular Degeneration and Alzheimer's Disease at Multiple Levels.

Age-related macular degeneration and Alzheimer's disease are closely related complex diseases that may share overlapping pathogenesis in gene networks. This study was conducted to investigate the genetic factors shared by both diseases. We analyzed genome-wide association studies' summary statistics from both diseases using a new platform known as functional mapping and annotation (FUMA) and a co-localization analysis. We obtained disease-related gene expression profile data from the Gene Expression Omnibus and analyzed these data using weighted gene co-expression network analysis. FUMA analysis and Bayesian co-localization analysis showed that ten genes on chromosome 7, one pathway (complement and coagulation cascade), and forty-two biological processes were common for both diseases. Among these ten genes, two protein-coding genes, two pseudogenes, and two RNA genes were, for the first time, identified to be associated with both diseases. Weighted gene co-expression network analysis identified 19 age-related macular degeneration hub genes and 19 Alzheimer's disease hub genes and revealed that these two diseases shared nine pathways and 63 biological processes. Using FUMA, co-localization analysis, and weighted gene co-expression network analysis, 10 genes on chromosome 7, 10 pathways, and 105 biological processes were found to be associated with the two degenerative diseases. This suggests that these10 genes and the hub genes of these modules associated with the shared pathways are potential diagnostic markers for both diseases.

Functional Genetic Polymorphisms in the IL1RL1-IL18R1 Region Confer Risk for Ocular Behçet's Disease in a Chinese Han Population.

Single nucleotide polymorphisms (SNPs) in the IL1RL1-IL18R1 region are associated with various immune-mediated diseases. This study was carried out to investigate the causal variant for ocular Behçet's disease (BD) and elucidate its target genes in the IL1RL1-IL18R1 region. Nine candidate functional SNPs were prioritized with bioinformatics analysis, followed by a two-stage association study in 694 ocular BD patients and 1,458 unaffected controls. Functional studies were performed in the peripheral blood mononuclear cells (PBMCs) of 45 healthy men and 16 active male BD patients. Genotyping was performed using the MassARRAY System. The mRNA expressions of IL1RL1, IL18R1, IL18RAP, and SLC9A4 were assayed by real-time PCR and secretion of cytokines was examined by ELISA. Significantly lower frequencies of the rs12987977 GG genotype/G allele (P c = 8.93 × 10-7, OR = 0.39; P c = 2.60 × 10-3, OR = 0.77, respectively), rs12999364 TT genotype/T allele (P c = 3.15 × 10-4, OR = 0.51; P c = 1.13 × 10-2, OR = 0.80, respectively), and rs4851569 AA genotype/A allele (P c = 3.29 × 10-4, OR = 0.52; P c = 9.72 × 10-3, OR = 0.80, respectively) were observed in BD patients compared with the controls. Functional experiments revealed a downregulation of IL1RL1, IL18R1, and SLC9A4 and a decreased secretion of IFN-γ in the anti-CD3/CD28 antibody-treated PBMCs as well as a decreased production of TNF-α in the lipopolysaccharide (LPS)-stimulated PBMCs in carriers of the protective homozygous rs12987977/GG genotype compared with the TT genotype. Our findings show that functional SNPs-rs12987977, rs12999364, and rs4851569-in the IL1RL1-IL18R1 region confer susceptibility to ocular BD in a Chinese Han population. And IL1RL1, IL18R1, and SLC9A4 may be the target genes of rs12987977.

Weak association of a TNFRSF1A polymorphism with Behcet's disease in Chinese Han.

The purpose of this study was to investigate whether single nucleotide polymorphisms (SNPs) of the tumor necrosis factor receptor superfamily (TNFRSF) and their ligand (TNFSF) gene are associated with susceptibility to Behcet's Disease (BD) in Chinese Han. A two-phase case-control study was performed in 1055 BD patients and 1829 healthy controls. A total of 27 SNPs was tested using MassARRAY iPLEX® technology. Data were analyzed using a Chi-square (χ2) test and Fisher's exact calibration test. The Bonferroni correction was applied for multiple testing. A statistically significant higher frequency of the A allele and a lower frequency of the G allele of rs1800692 was found in BD (Pc = 0.013, OR = 1.233, 95% CI = 1.103-1.379: Pc = 0.013, OR = 0.811, 95% CI = 0.725-0.907, respectively). Our findings indicate that TNFRSF1A might confer genetic susceptibility to BD in a Chinese Han population.

Cypermethrin-induced cortical neurons apoptosis via the Nrf2/ARE signaling pathway.

Pesticide residue is a common problem worldwide. Cypermethrin is a type II pyrethroid pesticide that has been widely used in recent years. It has become a widespread residual pesticide in the environment and agricultural products. The neurotoxicity of cypermethrin remains a matter of concern. However, few studies have evaluated its toxicity on cerebral cortical neurons. As the center of the nervous system, the cerebral cortex is involved in a series of biological processes, such as learning, memory, emotions, and movement. The Nrf2/ARE signaling pathway has been considered to play a protective role in several central nervous system (CNS) diseases. We investigated whether this pathway plays a protective role in cypermethrin-induced apoptosis of the cortical neurons. We established a cypermethrin-induced apoptosis model in the cortical neurons using different cypermethrin doses and different incubation periods. The changes in Nrf2 protein and mRNA expression and its downstream genes HO-1 and NQO1 were detected by quantitative real-time PCR and Western blotting to study the role of the Nrf2/ARE pathway in cypermethrin-induced apoptosis of the cortical neurons. The results showed that the Nrf2/ARE signaling pathway has a protective effect in cypermethrin-induced apoptosis of the cortical neurons. However, this protective effect of the Nrf2/ARE pathway is very limited and is dependent on the exposure dose and exposure period of cypermethrin.

Identification of Ribosomal Protein S4, Y-Linked 1 as a cyclosporin A plus corticosteroid resistance gene.

Combination of corticosteroids (CS) with cyclosporin A (CsA) is widely used in the treatment of autoimmune diseases, autoinflammatory diseases and transplantation rejection. However, some patients fail to respond or develop resistance to the combination regimen. In Vogt-Koyanagi-Harada (VKH) disease model, we performed RNA sequencing (RNA-seq) based transcriptomics, isobaric tags for relative and absolute quantification (iTRAQ) based proteomics and assays in vitro to screen and validate potential resistant molecules. We found that a total of 1697 differentially expressed genes (DEGs) and 21 differentially expressed proteins (DEPs) in CD4+ T cells between CsA & CS-resistant and -sensitive VKH patients. Ribosomal Protein S4, Y-Linked 1 (RPS4Y1) was verified to regulate the resistance of CD4+ T cells from male VKH patients to CsA & CS. Importantly, we showed that chlorambucil (CLB) could reverse the resistance by RPS4Y1 suppression. Taken together, we identify RPS4Y1 as an important CsA & CS resistance gene in VKH disease. Researchers should consider validating the resistant effect of RPS4Y1 in other autoimmune diseases or organ transplantation.

Genetic aspects of idiopathic paediatric uveitis and juvenile idiopathic arthritis associated uveitis in Chinese Han.

BACKGROUND: Idiopathic paediatric uveitis (IPU) and juvenile idiopathic arthritis associated uveitis (JIA-U) are the two most common entities in paediatric uveitis. This study addressed the possible association of IPU and JIA-U with genes that had been shown earlier to be associated with juvenile idiopathic arthritis. METHODS: We carried out a case-control association study involving 286 IPU, 134 JIA-U patients and 743 healthy individuals. A total of 84 candidate single nucleotide polymorphisms (SNPs) in 60 genes were selected for this study. The MassARRAY platform and iPLEX Gold Genotyping Assay was used to genotype 83 candidate SNPs and the remaining SNP (rs27293) was analysed using the TaqMan SNP Genotyping Assay. RESULTS: No evidence was found for an association of the candidate polymorphisms tested with IPU. Six SNPs (PRM1/rs11074967, JAZF1/rs73300638, IRF5/rs2004640, MEFV/rs224217, PSMA3/rs2348071 and PTPN2/rs7234029) showed an association with JIA-U (p<1.0×10-2). CONCLUSION: Our findings showed associations of six SNPs (PRM1/rs11074967, JAZF1/rs73300638, IRF5/rs2004640, MEFV/rs224217, PSMA3/rs2348071 and PTPN2/rs7234029) with JIA-U. No association was detected between the 84 tested SNPs and IPU.

Association of toll-like receptor 10 polymorphisms with paediatric idiopathic uveitis in Han Chinese.

AIMS: We aimed to determine whether paediatric idiopathic uveitis (PIU) and juvenile idiopathic arthritis associated paediatric uveitis (JIA-PU) have an association with Toll-like receptor 10 (TLR10) gene polymorphisms in Han Chinese. METHODS: Ten tag single nucleotide polymorphisms (SNPs) of TLR10 were analysed in 992 PIU patients, 127 JIA-PU patients and 1600 controls using the Sequenom MassARRAY system and iPLEX Gold assay. Genotype and allele frequencies were analysed using the χ2 test. A stratified analysis was performed according to the clinical features of PIU. RESULTS: Increased frequencies of the rs2101521 A allele, rs10004195 A allele, rs11725309 CC genotype and rs6841698 AA genotype were found in PIU patients compared with controls (corrected p values (Pc)=1.81×10-4, Pc= 1.12×10-2, Pc=2.41×10-2 and Pc=3.29×10-3, respectively). There was no association between these 10 tag SNPs and JIA-PU. In the stratified analysis, the frequency of the rs6841698 A allele was higher in PIU patients with cataract (Pc=1.45×10-6). The frequencies of the rs2101521 A allele and rs6841698 AA genotype were increased in PIU patients with band keratopathy (BK) (Pc=2.32×10-2, Pc=3.30×10-3, respectively). CONCLUSION: TLR10 gene polymorphisms (rs2101521, rs10004195, rs11725309 and rs6841698) confer susceptibility to PIU in Han Chinese. In a stratified analysis, rs2101521 and rs6841698 are associated with PIU with BK, and rs6841698 correlates with PIU with cataract.

Aqueous cytokine levels in four common uveitis entities.

To investigate aqueous cytokine profiles in acute anterior uveitis (AAU), Fuchs' syndrome, Vogt-Koyanagi-Harada (VKH) disease and Behcet's disease (BD), we assayed the concentrations of 17 cytokines by multiplex immunoassay in aqueous humor (AqH) collected during cataract surgery from 24 AAU, 29 Fuchs' syndrome, 29 VKH disease, 30 BD and 30 senile cataract control patients. Aqueous cytokine levels were compared between the five groups and analysed by logistic regression. Cytokine levels were then compared between uveitis patients who underwent cataract surgery within 3 months and those who underwent this surgery more than 3 months after complete control of intraocular inflammation. The results showed that aqueous levels of interferon (IFN)-γ, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1ß and tumour necrosis factor (TNF)-α levels in AqH from patients with Fuchs' syndrome were significantly higher than those in the other four groups. Using multivariate analysis, MIP-1ß was found to be significantly associated with Fuchs' syndrome. There was no difference in aqueous cytokine levels between cases having cataract surgery within 3 months compared to those after 3 months of complete control of their intraocular inflammation. The current study shows that Chinese patients with Fuchs' syndrome appear to have a specific cytokine profile. MIP-1ß is an important chemokine in the intraocular environment of Fuchs' syndrome. Aqueous cytokine profiles support the performance of cataract surgery in uveitis within 3 months after intraocular inflammation control.

Different Methylation of CpG-SNPs in Behcet's Disease.

PURPOSE: We recently performed an Epigenome-Wide Association Studies (EWAS) study in Behcet's disease (BD) and identified various cytosine-phosphate-guanine (CpG) loci that were aberrantly methylated. In the current study, we wanted to investigate whether these sites contained genetic polymorphisms and whether the frequency of these polymorphisms was altered in BD. METHODS: A two-stage study was performed. The first stage involved 358 BD patients and 704 healthy controls to investigate genetic variants of 10 CpG-SNPs (rs10454134, rs176249, rs3808620, rs10176517, rs11247118, rs78016579, rs9461624, rs10492166, rs34929465, and rs6507921) using an iPLEX Gold genotyping assay and a Sequenom MassARRAY. In the second stage, an additional 172 independent BD patients and 330 healthy individuals are to confirm trends found in the first stage. RESULTS: A higher frequency of both the rs10454134 AG genotypes (p = 0.008, OR = 1.413, 95% CI = 1.094-1.826) and a lower GG genotype frequency (p = 0.003, OR = 0.630, 95% CI = 0.465-0.854) were found in BD patients compared to the controls in the first stage. However, after correcting for multiple comparisons, all associations identified in the first stage lost statistical significance. The frequencies of the other CpG-SNPs investigated were not different between BD patients and controls. The second stage was designed using an additional cohort to confirm the association with CpG-SNP, rs10454134. The data failed to confirm the association between this CpG-SNP and BD. CONCLUSIONS: This study did not show an association between BD and CpG-SNPs in gene sites that were earlier shown to be aberrantly methylated.

[Cypermethrin induces cell injury in primary cortical neurons of C57BL/6 mice by inhibiting Nrf2/ARE signaling pathway].

OBJECTIVE: To study the role of Nrf2/ARE signaling pathway in cypermethrin-induced oxidative stress and apoptosis of cerebral cortex neurons in C57BL/6 mice. METHODS: The cortical neurons of C57BL/6 mice were cultured and identified, and a cypermethrin-induced cell injury model was established by treating the cells with 0, 25, 50 and 100 µmol/L of cypermethrin for 48 h. CCK-8 assay was used to analyze the effects of cypermethrin on the cell viability, and the fluorescence probe DCFH-DA was used for detecting intracellular reactive oxygen species (ROS); flow cytometry was performed for determining the apoptosis rate of the cells. The mRNA and protein expression levels of Nrf2 and its downstream genes HO-1 and NQO1 were detected using qPCR and Western blotting. RESULTS: Exposure to cypermethrin at different doses inhibited the viability of the cultured cortical neurons. With the increase of cypermethrin dose, the viability of the neurons decreased progressively, the intracellular ROS and the cell apoptosis rate increased, and the neuronal injury worsened. At the dose of 50 and 100 µmol/L, cypermethrin significantly down-regulated the expressions of HO-1, NQO1 and Nrf2 at both the mRNA and protein levels in the cells (P < 0.01). CONCLUSIONS: Cypermethrin exposure shows a dose-dependent neurotoxicity by inhibiting Nrf2/ARE signaling pathway, down-regulating the expression of Nrf2 and its downstream genes HO-1, NQO1 mRNA and protein, and inducing oxidative damage and apoptosis in primary mouse cortical neurons, .