A Cross-Tissue Transcriptome-Wide Association Study Identifies Novel Susceptibility Genes for Juvenile Idiopathic Arthritis in Asia and Europe

BackgroundJuvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children, and its pathogenesis is still unclear. Genome-wide association studies (GWASs) of JIA have identified hundreds of risk factors, but few of them implicated specific biological mechanisms.MethodsA cross-tissue transcriptome-wide association study (TWAS) was performed with the functional summary-based imputation software (FUSION) tool based on GWAS summary datasets (898 JIA patients and 346,102 controls from BioBank Japan (BBJ)/FinnGen). The gene expression reference weights of skeletal muscle and the whole blood were obtained from the Genotype-Tissue Expression (GTExv8) project. JIA-related genes identified by TWAS findings genes were further compared with the differentially expressed genes (DEGs) identified by the mRNA expression profile of JIA from the Gene Expression Omnibus (GEO) database (accession number: GSE1402). Last, candidate genes were analyzed using functional enrichment and annotation analysis by Metascape to examine JIA-related gene sets.ResultsThe TWAS identified 535 significant genes with P < 0.05 and contains 350 for Asian and 195 for European (including 10 genes both expressed in Asian and European), such as CDC16 (P = 1.72E-03) and PSMD5-AS1 (P = 3.65E-02). Eight overlapping genes were identified based on TWAS results and DEGs of JIA patients, such as SIRPB1 (PTWAS = 4.21E-03, PDEG = 1.50E-04) and FRAT2 (PTWAS = 2.82E-02, PDEG = 1.43E-02). Pathway enrichment analysis of TWAS identified 183 pathways such as cytokine signaling in the immune system and cell adhesion molecules. By integrating the results of DEGs pathway and process enrichment analyses, 19 terms were identified such as positive regulation of T-cell activation.ConclusionBy conducting two populations TWAS, we identified a group of JIA-associated genes and pathways, which may provide novel clues to uncover the pathogenesis of JIA

No genetic causal association between iron status and osteoporosis: A two-sample Mendelian randomization

ObjectiveTo explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR).MethodsPublicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR–Egger methods. The pleiotropy of MR results was determined using MR–Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results.ResultsBased on IVW, MR–Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR–Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR.ConclusionOur results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded

Primary Pollutants and Air Quality Analysis for Urban Air in China: Evidence from Shanghai

In recent years, China’s urban air pollution has caused widespread concern in the academic world. As one of China’s economic and financial centers and one of the most densely populated cities, Shanghai ranks among the top in China in terms of per capita energy consumption per unit area. Based on the Shanghai Energy Statistical Yearbook and Shanghai Air Pollution Statistics, we have systematically analyzed Shanghai’s atmospheric pollutants from three aspects: Primary pollutants, pollutants changing trends, and fine particulate matter. The comprehensive pollution index analysis method, the grey correlation analysis method, and the Euclid approach degree method are used to evaluate and analyze the air quality in Shanghai. The results have shown that Shanghai’s primary pollutants are PM2.5 and O3, and the most serious air pollution happens during the first half of the year, particularly in the winter. This is because it is the peak period of industrial energy use, and residential heating will also lead to an increase in energy consumption. Furthermore, by studying the particulate pollutants of PM2.5 and PM10, we clearly disclosed the linear correlation between PM2.5 and PM10 concentrations in Shanghai which varies seasonally

Comparison of clinical outcomes among total knee arthroplasties using posterior-stabilized, cruciate-retaining, bi-cruciate substituting, bi-cruciate retaining designs: a systematic review and network meta-analysis

Abstract. Background:. Despite the advent of innovative knee prosthesis design, a consistent first-option knee implant design in total knee arthroplasty (TKA) remained unsettled. This study aimed to compare the clinical effects among posterior-stabilized (PS), cruciate-retaining (CR), bi-cruciate substituting (BCS), and bi-cruciate retaining designs for primary TKA. Methods:. Electronic databases were systematically searched to identify eligible randomized controlled trials (RCTs) and cohort studies from inception up to July 30, 2021. The primary outcomes were the range of knee motion (ROM), and the secondary outcomes were the patient-reported outcome measures (PROMs) and complication and revision rates. Confidence in evidence was assessed using Confidence in Network Meta-Analysis. The Bayesian network meta-analysis was performed for synthesis. Results:. A total of 15 RCTs and 18 cohort studies involving 3520 knees were included. The heterogeneity and inconsistency were acceptable. There was a significant difference in ROM at the early follow-up when PS was compared with CR (mean difference [MD] = 3.17, 95% confidence interval [CI] 0.07, 7.18) and BCS was compared with CR (MD = 9.69, 95% CI 2.18, 17.51). But at the long-term follow-up, there was no significant difference in ROM in any one knee implant compared with the others. No significant increase was found in the PROMs and complication and revision rates at the final follow-up time. Conclusions:. At early follow-up after TKA, PS and BCS knee implants significantly outperform the CR knee implant in ROM. But in the long run, the available evidence suggests different knee prostheses could make no difference in clinical outcomes after TKA with extended follow-up

The efficacy and safety of combined administration of intravenous and topical tranexamic acid in primary total knee arthroplasty: a meta-analysis of randomized controlled trials

Abstract Background The combined administration of intravenous (IV) and topical tranexamic acid (TXA) in primary total knee (TKA) knee remains controversial. The purpose of this meta-analysis was to assess the efficacy and safety of combined administration of IV and topical TXA in primary TKA. Methods PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, Google Search Engine and China National Knowledge Infrastructure databases were searched for randomized controlled trials (RCTs) were comparing the combined administration of IV and topical TXA following primary TKA. The primary outcomes were total blood loss, maximum hemoglobin drop, and deep venous thrombosis (DVT) and/or pulmonary embolism (PE). The second outcomes were drainage volume and transfusion requirements. Data were analyzed using RevMan 5.3. Results A total of 6 RCTs involving 701 patients were included in the meta-analysis. The combined group provided lower total blood loss (MD − 156.34 mL, 95% CI, − 241.51 to − 71.18; P = 0.0003), drainage volume (MD − 43.54 mL, 95% CI, − 67.59 to − 19.48; P = 0.0004), maximum hemoglobin drop (MD − 0.56 g/dl, 95% CI, − 0.93 to − 0.19; P = 0.003) than IV TXA alone. No significant difference were found in terms of transfusion requirements (RR 0.48, 95% CI, 0.16 to 1.44; P = 0.19), DVT (RR 1.01, 95% CI, 0.14 to 7.12; P = 0.99) and PE (RR 0.33, 95% CI, 0.01 to 7.91; P = 0.49) between the two group. Subgroup analyses shows that the combined group was less total blood loss in non-tourniquet (P = 0.0008), topical TXA dose > 1.5 g (P  1.5 g and number of IV TXA ≥ 2 doses of TXA. There was no increase the rates of DVT and PE

The role of the sirtuin family in cartilage and osteoarthritis: molecular mechanisms and therapeutic targets

Abstract Osteoarthritis (OA) is mainly characterized by the progressive destruction of articular cartilage. Mounting studies have revealed that disruption of extracellular matrix (ECM) homeostasis, aberrant chondrocyte metabolism, an increase in the number of senescent chondrocytes and abnormal activation of cell death such as chondrocyte apoptosis and autophagy, are the crucial steps in OA development. Additionally, mitochondrial dysfunction also participates in the abovementioned processes and is the key element of OA pathogenesis. Sirtuin (SIRT) is a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that can actively participate and primarily regulate chondrocyte function in OA pathophysiological processes. Some members of the SIRT family located in mitochondria can regulate mitochondrial function and mediate mitochondrial homeostasis via deacetylation to protect chondrocytes. In addition, SIRT can maintain ECM homeostasis, regulate chondrocyte metabolism, inhibit chondrocyte apoptosis and autophagy, and prevent chondrocyte senescence in cartilage by exerting its deacetylation activity. However, the molecular mechanism of the SIRT family against the onset and development of OA remains poorly elucidated. In this review, we will discuss the potential protective role of SIRT in the progression of OA and summarize several sirtuin-activating molecules as well as their potential therapeutic applications for OA