AbstractBackgroundRheumatoid arthritis (RA) is a globally prevalent condition that has a significant impact on morbidity and mortality rates. As a result, there is growing interest in understanding its pathogenetic mechanisms, particularly genetic susceptibility. To explore the potential genes that may cause RA, we conducted a comprehensive Mendelian randomization analysis and co‐localization based on data from large sample size genome‐wide association studies.MethodsWe used two transcriptome datasets to identify expression quantitative trait loci as the exposure and employed genome‐wide association studies data from the FinnGen study as the outcome. We then performed co‐localization analysis to confirm that the expression quantitative trait loci and RA share causal genetic variants. Furthermore, we implemented a phenome‐wide scan to identify other clinical phenotypes associated with significant causal genes.ResultsAt a Bonferroni significance level of p < 2.70 × 10−6, the Mendelian randomization analysis revealed that 20 genes increased the risk of RA, while 16 genes showed a marginally protective effect. Co‐localization analyses indicated that AP4B1, GGA2, KEAP1, PTPN22, REG4, and TRAV38‐2DV8 were associated with the risk of RA. The phenome‐wide scan demonstrated shared genetic determinants between RA and other immune‐mediated disorders, including autoimmune thyroid disease, diabetes mellitus, cardiovascular disorders, inflammatory bowel disease, and malignant tumors.ConclusionsOur study identified six risk genes (AP4B1, GGA2, KEAP1, PTPN22, REG4, and TRAV38‐2DV8) that may have a causal role in RA. These findings provide novel therapeutic targets for the treatment of RA. Further exploration is required to elucidate the underlying biological mechanisms.

OBJECTIVE:Recent studies indicate that N-acetyltransferase 10 (NAT10)-mediated ac4C modification plays unique roles in tumour metastasis and immune infiltration. This study aimed to uncover the role of NAT10-mediated ac4C in fibroblast-like synoviocytes (FLSs) functions and synovial immune cell infiltration in rheumatoid arthritis (RA).METHODS:FLSs were obtained from active established patients with RA. Protein expression was determined by western blotting or immunohistochemistry or multiplexed immunohistochemistry. Cell migration was measured using a Boyden chamber. ac4C-RIP-seq combined with RNA-seq was performed to identify potential targets of NAT10. RNA immunoprecipitation was used to validate the interaction between protein and mRNA. NAT10 haploinsufficiency, inhibitor remodelin or intra-articular Adv-NAT10 was used to suppress arthritis in mice with delayed-type hypersensitivity arthritis (DYHA) and collagen II-induced arthritis (CIA) and rats with CIA.RESULTS:We found elevated levels of NAT10 and ac4C in FLSs and synovium from patients with RA. NAT10 knockdown or specific inhibitor treatment reduced the migration and invasion of RA FLSs. Increased NAT10 level in the synovium was positively correlated with synovial infiltration of multiple types of immune cells. NAT10 inhibition in vivo attenuated the severity of arthritis in mice with CIA and DTHA, and rats with CIA. Mechanistically, we explored that NAT10 regulated RA FLS functions by promoting stability and translation efficiency of N4-acetylated PTX3 mRNA. PTX3 also regulated RA FLS aggression and is associated with synovial immune cell infiltration.CONCLUSION:Our findings uncover the important roles of NAT10-mediated ac4C modification in promoting rheumatoid synovial aggression and inflammation, indicating that NAT10 may be a potential target for the treatment of RA, even other dysregulated FLSs-associated disorders.

Fibroblast-like synoviocytes (FLS) plays an important role in synovial inflammation and joint damage in rheumatoid arthritis (RA). As the most abundant mRNA modification, N6-methyladenosine (m6A) is involved in the development of various diseases; however, its role in RA remains to be defined. In this study, we reported the elevated expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in FLS and synovium from RA patients. Functionally, FTO knockdown or treatment with FB23-2, an inhibitor of the mRNA m6A demethylase FTO, inhibited the migration, invasion and inflammatory response of RA FLS, however, FTO-overexpressed RA FLS exhibited increased migration, invasion and inflammatory response. We further demonstrated that FTO promoted ADAMTS15 mRNA stability in an m6A-IGF2BP1 dependent manner. Notably, the severity of arthritis was significantly reduced in CIA mice with FB23-2 administration or CIA rats with intra-articular injection of FTO shRNA. Our results illustrate the contribution of FTO-mediated m6A modification to joint damage and inflammation in RA and suggest that FTO might be a potential therapeutic target in RA.

INTRODUCTION:Fibroblast-like synoviocytes (FLSs) play critical roles in synovial inflammation and aggression in rheumatoid arthritis (RA). Here, we explored the role of eukaryotic translation initiation factor 6 (eIF6) in regulating the biological behaviors of FLSs from patients with RA. METHODS:FLSs were isolated from the synovial tissues of RA patients. Gene expression was assessed via RT-qPCR, and protein expression was evaluated via Western blotting or immunohistochemistry. Proliferation and nascent peptide synthesis were evaluated via EdU incorporation and HPG labeling, respectively. Cell migration and invasion were observed via Transwell assays. Polysome profiling was conducted to analyze the distribution of ribosomes and combined mRNAs. The in vivo effect of eIF6 inhibition was evaluated in a collagen-induced arthritis (CIA) rat model. RESULTS:We found that eIF6 expression was elevated in FLSs and synovial tissues from RA patients compared to those from healthy controls and osteoarthritis patients. Knockdown of eIF6 inhibited the migration, invasion, inflammation, and proliferation of FLSs from patients with RA. Mechanistically, eIF6 knockdown downregulated ribosome biogenesis in FLSs from with RA, leading to a decrease in the proportion of polysome-associated specificity protein 1 (SP1) mRNA and a subsequent reduction in the translation initiation efficiency of SP1 mRNA. Thus, eIF6 controls SP1 expression through translation-mediated mechanisms. Interestingly, intra-articular eIF6 siRNA treatment attenuated symptoms and histological manifestations in CIA rats. CONCLUSIONS:Our findings suggest that an increase in synovial eIF6 might contribute to rheumatoid synovial inflammation and aggression and that targeting eIF6 may have therapeutic potential in RA patients.

Fibroblast-like synoviocytes (FLS) plays an important role in synovial inflammation and joint damage in rheumatoid arthritis (RA). As the most abundant mRNA modification, N6-methyladenosine (m6A) 6 A) is involved in the development of various diseases; however, its role in RA remains to be defined. In this study, we reported the elevated expression of the m6A 6 A demethylase fat mass and obesity-associated protein (FTO) FTO ) in FLS and synovium from RA patients. Functionally, FTO knockdown or treatment with FB23-2, an inhibitor of the mRNA m6A 6 A demethylase FTO, , inhibited the migration, invasion and inflammatory response of RA FLS, however, FTO-- overexpressed RA FLS exhibited increased migration, invasion and inflammatory response. We further demonstrated that FTO promoted ADAMTS15 mRNA stability in an m 6 A- IGF2BP1 dependent manner. Notably, the severity of arthritis was significantly reduced in CIA mice with FB23-2 administration or CIA rats with intraarticular injection of FTO shRNA. Our results illustrate the contribution of FTO-mediated m6A 6 A modification to joint damage and inflammation in RA and suggest that FTO might be a potential therapeutic target in RA.

Objectives: Although the potential serious threat of anthropogenic heat on human health was receiving considerable attention worldwide, its long-term health effect on blood pressure (BP) remained unknown. We aimed to evaluate the associations of long-term anthropogenic heat exposure with different components of BP and hypertension. Methods: In this cross-sectional study (Liaoning province, China) conducted in 2009, we included a total of 24,845 Chinese adults (18-74 years). We estimated the anthropogenic heat exposure in 2008 using multisource remote sensing images and ancillary data. We measured systolic blood pressure (SBP), diastolic blood pressure (IMP), mean arterial pressure (MAP) and pulse pressure (PP), and defined hypertension. We used generalized linear mixed model to examine the associations. Results: In the adjusted model, the estimates indicated that the difference in SBP, MAP and PP for those in highest quartiles of total anthropogenic heat exposure was greater compared with the lowest quartile (highest quartile: beta = 1.11 [95% CI: 0.28-1.94], 0.60 [95% CI: 0.04-1.17], 0.76 [95% CI: 0.17-1.35]). Compared with the lowest quartile, the odds of hypertension were higher among those in higher quartiles (second quartile: OR = 1.17 [95% CI: 1.05-1.30]; third quartile:1.10 [95% CI: 1.1.01-1.21]; highest quartile: 1.17 [95 % CI: 1.06-1.28]). These associations were stronger in female participants. Conclusion: Our study showed that long-term exposure to anthropogenic heat was associated with elevated BP and higher odds of hypertension. These findings suggest that mitigation strategies to reduce anthropogcnic heat should be considered.

BACKGROUND:Previous studies have separately linked either perfluoroalkyl acid (PFAA) or heavy metal exposure with kidney dysfunction. However, the relationships of co-exposure to PFAAs and heavy metals with kidney function are still unclear.OBJECTIVES:To explore the associations between exposure to PFAAs and heavy metals mixtures and kidney function in adults.METHODS:We conducted a cross-sectional community-based population study in Guangzhou, China, enrolling 1312 adults from November 2018 to August 2019. We quantified 13 PFAAs in serum and 14 heavy metals in plasma. We chose estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) as outcomes of interest. Distributed lag non-linear models (DLNMs) were used to check nonlinearity of individual pollutant with kidney function. Joint associations of pollutant mixtures on kidney function were assessed by Bayesian Kernel Machine Regression (BKMR) models. We further explored modification effects of gender.RESULTS:Most individual PFAA and heavy metal were associated with declined kidney function in single-pollutant models. We also observed significant dose-response relationships of pollutant mixtures with reduced eGFR levels and increased odds of CKD in BKMR models. Perfluoroheptanesulfonic acid (PFHpS), arsenic (As) and strontium (Sr) were the predominant contributors among pollutant mixtures. A change in log PFHpS, As and Sr concentrations from the 25th to the 75th percentile were associated with a decrease in eGFR of -5.42 (95% confidence interval (CI): -6.86, -3.98), -2.14 (95% CI: -3.70, -0.58) and -1.87 (95% CI: -3.03, -0.72) mL/min/1.73 m2, respectively, when other pollutants were at their median values. In addition, the observed associations were more obvious in females.CONCLUSIONS:We provided new evidence that co-exposure to PFAAs and heavy metals mixtures was associated with reduced kidney function in adults and PFHpS, As and Sr appeared to be the major contributors. Further studies are warranted to confirm our findings and elucidate the underlying mechanisms.

Background: Identifying hazardous trace elements (HTEs) is a critical function of public health. We aimed to identify HTEs using a panel of sensitive health indicators in a random sample of Chinese. Methods: Between August 13, 2020 and October 1, 2021, we recruited 2883 participants aged 18-75 years from 12 Chinese provinces using simple random sampling method and tested their plasma for 27 hazardous trace elements (HTEs). We also examined 36 biomarkers of impairments of the hepatic, renal, cardiovascular and immune systems, as well as lung function. We used two-level generalized linear regression models to assess associations between HTEs exposure and health outcomes adjusting for confounders. We used standardized Z-score to examine association of the sum of standard coefficients of a select HTEs and comprehensive set of health indicators. Findings: We found the most frequent and strongest human health indicator associations with plasma Ti, Sr, Ba, Ce and Y, especially for cardiovascular function. However, exposure to these five HTEs is not currently monitored in China and other countries. Interpretation: A more comprehensive and definitive study of Ti, Sr, Ba, Y and Ce exposure is merited to further investigate potential adverse human health effects and to inform possible interventions.Funding: We would like to thank the National Key R&D Program of China (Grant No. 2019YFC1803402), the National Natural Science Foundation of China (Grant No. 82173471, 41931298).Declaration of Interest: We declare no competing interests.Ethical Approval: The CERMP study protocol was approved by the Research Ethics Committee of Sun Yat-sen University. We obtained written informed consent from all participants before data and biospecimen collection.

Chlorinated polyfluorinated ether sulfonates (Cl-PFESAs) are one kind of replacement chemistry for perfluorooctanesulfonate (PFOS). Recent studies have shown that Cl-PFESAs could interfere with thyroid function in animal models. However, epidemiological evidence on the link between Cl-PFESAs and thyroid function remains scarce. In this study, we focused on two representative legacy perfluoroalkyl substances (PFAS), including PFOS and perfluorooctanoic acid (PFOA), and two PFOS alternatives (6:2 and 8:2 Cl-PFESAs) in the general adult population from a cross-sectional study, the "Isomers of C8 Health Project in China". Three serum thyroid hormones (THs), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), were measured. We fitted generalized linear regression, restricted cubic spline regression, and Bayesian kernel machine regression models to assess associations of individual Cl-PFESAs, legacy PFAS, and PFAS mixtures with THs, respectively. We found individual PFAS and their mixtures were nonlinearly associated with THs. The estimated changes of the TSH level (μIU/mL) at the 95th percentile of 6:2 Cl-PFESA and PFOS against the 5th percentile were -0.74 (95% CI: -0.94, -0.54) and -1.18 (95% CI: -1.37, -0.98), respectively. The present study provided epidemiological evidence for the association of 6:2 Cl-PFESA with thyroid hormone levels in the general adult population.

Background: Epidemiological studies on the associations of legacy per- and polyfluoroalkyl substances (PFASs) and glucose homeostasis remain discordant. Understanding of PFAS alternatives is limited, and few studies have reported joint associations of PFASs and PFAS alternatives. Objectives: To investigate associations of novel PFAS alternatives (chlorinated perfluoroalkyl ether sulfonic acids, Cl-PFESAs and perfluorobutanoic acid, PFBA) and two legacy PFASs (Perfluorooctanoic acid, PFOA and perfluorooctane sulfonate, PFOS) with glucose-homeostasis markers and explore joint associations of 13 legacy and alternative PFASs with the selected outcomes. Methods: We used cross-sectional data of 1,038 adults from the Isomers of C8 Health Project in China. Associations of PFASs and PFAS alternatives with glucose-homeostasis were explored in single-pollutant models using generalized linear models with natural cubic splines for PFASs. Bayesian Kernel Machine Regression (BKMR) models were applied to assess joint associations of exposures and outcomes. Sex-specific analyses were also conducted to evaluate effect modification. Results: After adjusting for confounders, both legacy (PFOA, PFOS) and alternative (Cl-PFESAs and PFBA) PFASs were positively associated with glucose-homeostasis markers in single-pollutant models. For example, in the total study population, estimated changes with 95% confidence intervals (CI) of fasting glucose at the 95th percentile of 6:2Cl-PFESA and PFOS against the thresholds were 0.90 (95% CI: 0.59, 1.21) and 0.44 (95% CI: 0.26, 0.62). Positive joint associations were found in BKMR models with 6:2Cl-PFESA contributing most. Sex-specific associations existed in both single- and multi-pollutant models. Conclusions: Legacy and alternative PFASs were positively associated with glucose-homeostasis markers. 6:2Cl-PFESA was the primary contributor. Sex-specific associations were also identified. These results indicate that joint associations and effect modification should be considered in risk assessment. However, further studies are recommended to strengthen our findings and to elucidate the mechanisms of action of legacy and alternative PFASs.

Objective: To evaluate the associations between childhood, parental, and grandparental asthma.Methods: We studied 59,484 children randomly selected from 94 kindergartens, elementary, and middle schools in seven Chinese cities from 2012 to 2013, using a cross-sectional survey-based study design. Information on their and their family members' (parents, paternal grandparents, and maternal grandparents) asthma status were reported by children's parents or guardians. Mixed effects logistic regressions were used to assess hereditary patterns of asthma and mediation analysis was performed to estimate the potential mediation effect of parents on the association between grandparental asthma and childhood asthma.Results: The magnitude of ORs for childhood asthma increased as the number of family members affected by asthma increased. Among children who had one family member with asthma, childhood asthma was associated with asthma in maternal grandmothers (OR: 2.08, 95% CI: 1.67–2.59), maternal grandfathers (OR: 2.08, 95% CI: 1.71–2.53), paternal grandmothers (OR: 2.40, 95% CI: 1.93–2.99), and paternal grandfathers (OR: 2.59, 95% CI: 2.14–3.13). Among children who had two family members with asthma, the highest asthma risk was found when both parents had asthma (OR: 15.92, 95% CI: 4.66–54.45). Parents had a small proportion of mediation effect (9–12%) on the association between grandparental asthma and childhood asthma.Conclusions: Grandparents with asthma were associated with childhood asthma and parents with asthma partially mediated the association.

Numerous epidemiological studies have investigated the lipid interference effects of legacy PFASs, however, no studies on PFAS alternatives and blood lipids have been published. In this study, we explored the association between Cl-PFESAs, a typical PFASs alternative in China, and blood lipid profiles in 1336 Guangzhou community residents using linear and non-linear regression models. The results showed a deleterious effect of Cl-PFESAs and blood lipids: adjusted estimates (β) for TC, TG, LDL-C and HDL-C per natural log unit increase of 6:2 Cl-PFESA were 0.029 (95% CI: 0.020, 0.038), 0.075 (95% CI: 0.049, 0.101), 0.035 (95% CI: 0.021, 0.049) and -0.071 (95% CI: -0.084, -0.058), respectively. The association between Cl-PFESAs and dyslipidemia was also positively significant (P < 0.05). Furthermore, a non-linear relationship was observed in Cl-PFESAs and serum lipid levels using a restricted cubic splines (RCS) model. In summary, our research suggested a negative impact of Cl-PFESAs on blood lipid patterns and a possible non-linear association.

Background Invasive fungal disease (IFD) was well studied in patients with AIDS and organ transplant recipients. A few researches illustrated that patients with connective tissue disease (CTD) were also predisposed to IFD. However, few researches were designed to focus on invasive mycosis (IM) in patients with CTD. Objectives To investigate the clinical features and associated factors of IM in patients with CTD from Southern China. Methods A retrospective study CTD was performed. Demographic and clinical data were recorded. Associated factors were analyzed by logistic regression analysis. Results A total of 32 patients with CTD were included. The incidence of IM was 0.5% in patients with CTD (32/6911) and the highest in patients with ANCA-associated vasculitis (AAV) (7/480, 1.5%). Molds were isolated in 20 sputum specimens (20/29, 69.0%). Aspergillus spp. (81.3%) were the leading strain. Positivity of serum G-test and GM-test was 47.8% (11/23) and 34.6% (9/26), respectively. GM-test was positive in BALF from seven patients. Lung was commonly involved (30/32, 93.8%). Pulmonary nodules (46.7%) and cavitary lesions (36.7%) were common. Ten patients died (31.3%), including three with AAV (42.9%) and seven with SLE (36.8%). Multivariate logistic regression analysis showed that lymphopenia [odds ratio (OR) =3.28, 95% confidential interval (CI) 1.29-8.38, P=0.01] and median-to-high dose of glucocorticoid (GC) [OR=3.40, 95% CI 1.04-11.13, P=0.04] was associated with IM in patients with CTD. Patients with lymphopenia experienced higher risk of co-infection (50.0% vs 0%, P=0.01) and mortality (45.5% vs 0%, P=0.01) compared with patients with normal lymphocyte count. Conclusion IM tended to develop in patients with AAV, resulting in high mortality. Sputum culture could be an effective and non-invasive method to diagnose IM. Lymphopenia, and median-to-high dose of GC are associated with IM in patients with CTD. Acknowledgement: no Disclosure of Interests None declared