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.

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.

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.

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.