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Background:Current knowledge of the nature and treatment of knee osteoarthritis (KOA) have shown that an effective prevention strategy and treatment to identify and avoid risk factors in the early stage of KOA are required. Therefore, we hope to be able to determine some modifiable risk factors for KOA through MR analysis from a genetically informed perspective to achieve early prevention to reduce the prevalence of KOA in the population. Methods:In our research, we used a series of quality control steps to identify eligible instrumental SNPs that were strongly related to exposure. We used numerous dependable analytical methods (Inverse-variance weighting, MR-PRESSO method, weighted median, MR–Egger regression, and MR. RAPS method) that consist of two MR extrapolation hypotheses to make our conclusions more robust and credible. The MR–Egger intercept test, Cochran’s Q test, and “leave-one-out” sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on KOA. Outlier variants identified by the MR-PRESSO outlier test were removed step-by-step to reduce heterogeneity and the effect of horizontal pleiotropy. Results:Through double sample MR analysis, we found that there was a causal relationship between obesity and KOA, and obesity was positively correlated with the incidence of KOA (IVW: beta (95% CI), 0.144 (0.089, 0.199); OR (95% CI) 1.155 (1.093, 1.221); p =3.09e-7). The genetic predisposition to smoking was associated with a decreased risk of KOA (IVW: beta (95% CI), 0.178 (0.045, 0.311); OR (95% CI), 1.195 (1.046, 1.365); p =0.008). Based on the IVW model, there was a causal relationship between alcohol consumption and KOA (IVW: beta (95% CI), 0.347 (0.003, 0.692); OR (95% CI) 1.416 (1.003, 1.998); p =0.047). Conclusion: Our two-sample MR analysis confirmed that some controllable risk factors (smoking, drinking and obesity) can lead to KOA from a genetic point of view, which provides an important clue for the prevention and treatment of KOA.

Background Systemic lupus erythematosus (SLE) is a polygenic autoimmune connective tissue disease in which heritable components play an essential role in the pathogenesis. However, the correlation between genetic variants and pathological changes in SLE is still unclear, and it is difficult to provide insights for the early diagnosis and treatment of SLE. Methods We conducted a transcriptome-wide association study (TWAS) of SLE by integrating a genome−wide association study (GWAS) summary dataset of SLE (538 diagnosed patients and 213,145 controls derived from the FinnGen consortium). To verify the results of the TWAS analysis, the significant genes were further compared with the mRNA expression profiles of SLE to screen for common genes. Finally, significant genes were analyzed using functional enrichment and annotation analysis in Metascape to examine SLE-related gene sets. Results The TWAS identified 30 genes with PTWAS−adjusted values − 6 (0.05/37665 = 1.33×10− 6), including HCP5 (PTWAS =8.74×10− 15) and APOM (PTWAS = 4.57×10− 12). Four common genes were identified through the comparison of the TWAS results with the differentially expressed genes (DEGs) of SLE, including APOM (PTWAS = 4.57×10− 12, PDEG = 3.31×10− 02) and C2 (PTWAS = 8.04×10− 11, PDEG = 1.54×10− 02). Moreover, 36 terms were detected for the enrichment results of the TWAS, including antigen processing and presentation (logP value = -4.1938). By integrating the pathway and process enrichment analysis results of DEGs, 17 terms were identified, including allograft rejection (logP value = -7.5738). Conclusion The study identified a group of SLE-related genes and pathways, and the findings provide novel insights for the early diagnosis and intervention of SLE.

Object: To determine some modifiable risk factors for KOA through MR analysis from a genetically informed perspective to achieve early prevention to reduce the prevalence of KOA in the population.Methods: First, we used a series of quality control steps to identify eligible instrumental SNPs that were strongly related to exposure. Second, we used numerous dependable analytical methods (Inverse-variance weighting, MR-PRESSO method, weighted median, MR–Egger regression, and MR. RAPS method) to make our conclusions more robust and credible. The MR–Egger intercept test, Cochran’s Q test and “leave-one-out” sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on KOA. Outlier variants identified by the MR-PRESSO outlier test were removed step-by-step to reduce heterogeneity and the effect of horizontal pleiotropy.Results: Through double sample MR analysis, we found a causal association between obesity and KOA, and obesity was positively correlated with the incidence of KOA (IVW: beta (95% CI), 0.144 (0.089, 0.199); OR (95% CI) 1.155 (1.093, 1.221); p =3.09e-7). The genetic predisposition to smoking was associated with a decreased risk of KOA (IVW: beta (95% CI), 0.178 (0.045, 0.311); OR (95% CI), 1.195 (1.046, 1.365); p =0.008). In addition, there was a causal association between alcohol consumption and KOA (IVW: beta (95% CI), 0.347 (0.003, 0.692); OR (95% CI) 1.416 (1.003, 1.998); p =0.047).Conclusion: Our study confirmed some controllable risk factors (smoking, drinking and obesity) had causal associations with KOA from a genetic point of view, which provides an important clue for the prevention and treatment of KOA.

In recent years, polygenic risk score (PRS) analysis has become one of the most practical ways to leverage genome wide association studies (GWAS) findings for disease prediction. This approach is useful for addressing the challenge to translate the vast knowledge of complex disease genetics into clinically usable information. As machine learning is being widely applied to life science and PRS analysis comes into wide use for disease prediction, we systematacially evaluated the performance of random forest and PRS in predicting the status of complex diseases. Simulation studies were conducted by the GWAsimulator software, considering various genetic effects, genetic models and sample sizes. Two target complex disease related diseases and two environmental exposure factors were also simulated to obtain the additional genetic information of target complex disease, which were generally ignored in previous PRS studies. We found that PRS-based disease prediction using random forest had moderate accuracies (~ 70%) under various scenarios simulated by this study. The genetic effects of simulated disease loci showed the most significant impact on the performance of PRS-based disease prediction. This novel approach can leverage pleiotropy and gene-environment interactions. Furthermore, it is an attempt combining publicly available summary statistics and individual-level genotype data. We hope that this study provides useful information for further approaches development and disease prediction.

Objective To identify novel candidate genes, the expression of which are associated with child body mineral density (BMD) and body lean mass (LM). Methods The tissue specific transcriptome-wide association (TWAS) was conducted utilizing a large scale GWAS dataset of BMD and LM, totally involving 10,414 participants. The measurement of BMD and LM phenotypes was made by TB-DXA scans. TWAS was conducted by FUSION software. The reference panels of muscle skeleton (MS), peripheral blood (NBL) and whole blood (YBL) were used for TWAS analysis. Functional enrichment and protein-protein interaction analyses of the genes identified by TWAS were performed by the online tool of Metascape (http://metascape.org). Results For BMD, we detected 120, 86 and 174 genes with TWAS P value P = -3.13), autophagy (LogP = -2.65), cellular response to glucocorticoid stimulus (LogP = -2.95). GO enrichment analysis of LM associated genes detected 287 GO terms, such as Diseases of carbohydrate metabolism (LogP = -2.43), regulation of lipid localization (LogP = -2.80) and lipid storage (LogP = -3.55). Conclusion This study identified several candidate genes for child BMD and LM, providing novel clues for revealing the genetic mechanism underlying the development of child BMD and LM.

Objective Degenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all the components of the cervical spine. DCS has brought a huge social and economic burdens to society. However, the genetic basis of DCS remains elusive now. Methods Firstly, by integrating the gene-expression prediction models of whole blood and skeletal muscle and genome-wide association study (GWAS) summary data of DCS (including 3739 DCS patients and 382326 controls), we conducted a transcriptome-wide association study (TWAS) to evaluate the associations of genetically predicted gene-expression with DCS risk using Functional Summary-based Imputation (FUSION) software. Secondly, to validate the genes identified by TWAS analysis, these genes were further compared with the differentially expressed genes (DEGs) detected by the RNA expression profiles of DCS acquired from the Gene Expression Omnibus database (GEO, accession number: GSE153761). Thirdly, we used Functional Mapping and Annotation of Genome-wide Association Study (FUMA) and Metascape tools to conduct gene functional enrichment and annotation analysis. Results TWAS identified 420 significant genes for DCS with a P value PTWAS = 0.0003), and 110 genes in the whole blood, such as SELL (PTWAS = 0.0028). After comparing with RNA expression profiling of DCS, we identified 12 common genes, such as APLNR (PTWAS = 0.0013, PDEG = 0.0254). We identified 148 GO terms enriched for DCS, such as mast cell degranulation (GO:0043303). We also identified 15 KEGG pathways enriched for DCS, such as sphingolipid signaling pathway (ko04071). By integrating the enrichment results of TWAS analysis and RNA expression profile, 9 common terms were identified such as Degradation of the extracellular matrix (R-HSA-1474228). Conclusion Our results identified putative susceptibility genes for DCS, providing new insights into the genetic mechanisms underlying DCS development.

Objective: Osteoarthritis (OA) is a common musculoskeletal disease and a significant source of pain, disability, and socioeconomic cost worldwide. Genetic factors play important roles in the development of OA. However, the genetic basis of OA remains elusive now. Methods: Utilizing recently released large-scale genome-wide association study (GWAS) summary statistics of OA and 529 human blood metabolites, we explored the potential associations between OA and human blood metabolites from three aspects. Firstly, linkage disequilibrium score regression (LDSC) was applied to detect genetic correlations between OA and each of the 529 blood metabolites. Secondly, Mendelian Randomization (MR) analysis was used to evaluate the causal relationship between OA and significant blood metabolites identified by LDSC. Finally, mRNA expression and DNA methylation profiles of OA were used to detect the differentially expressed gene (DEG) and differentially methylated gene (DMG) which related to the blood metabolites identified by LDSC.Results: LDSC analysis found 19 candidate human blood metabolites showing genetic correlation signals with OA, such as citrate (genetic correlation coefficient (rg) = -0.2285, P value = 0.0034), proline (rg = 0.1777, P value = 0.0272), leucine (rg = 0.0891, P value = 0.0431), valine (rg = 0.1565, P value = 0.0405), methylcysteine (rg = -0.2488, P value = 0.0391) and 1-palmitoylglycerophosphoinositol (rg =0.3514, P value = 0.0434). MR analysis identified a significant causal relationship between OA and 1,6-anhydroglucose (β = -1.755, SE = 0.7992, P = 0.0281). mRNA expression and DNA methylation analysis identified FMO3 was the DEG and the LIPC was the DMG, which were related to methylcysteine and 1-palmitoylglycerophosphoinositol.Conclusion: Our results provide novel clues for understanding the genetic mechanism of OA, focusing on the possible roles of abnormal human blood metabolites in the pathogenesis of OA.

Background: Spondyloarthritis (SpA) is a kind of complex bone disease influenced by genetic factors, environment, and lifestyles. In recent years, the impact of human plasma proteins on the development of SpA has been reported. However, the genetic relationships between human plasma proteins and SpA have not systematically studied.Methods: The genome-wide association study (GWAS) summary dataset of SpA was derived from a published study, involving a total of 452,264 White British individuals (3,966 SpA patients and 448,298 controls). The GWAS summary dataset for 3,622 human plasma proteins was derived from the published study. Consequently, linkage disequilibrium score regression (LD score regression) analysis was performed to evaluate the genetic correlations between each human plasma protein and SpA. The significant plasma proteins were further compared with the differentially expressed genes (DEGs) detected by the mRNA expression profiles of SpA.Results: For LD score regression analysis, 5 kinds of human plasma proteins were found to be associated with SpA, such as Testis-specific chromodomain protein Y 1(rg =0.2973, P value=0.0439), Interleukin-17D (rg =0.3890, P value=0.0381), Neurensin-1(rg =0.3667, P value=0.0333), Trypsin-2(rg =0.3653, P value=0.0380), Serpin A9(rg =0.3746, P value=0.0424). Among them, IL-17D is the common gene identified for SpA both at protein level and gene expression level (P protein value=0.0006, P mRNA value=0.0381).Conclusions: We identified several SpA associated human plasma proteins. Our novel findings may provide new ideas for the future study of the genetic mechanism of SpA.

Background Spondyloarthritis(SpA) is a group of multi-factorial bone diseases influenced by genetic factors, environment and lifestyles. However, the genetic and pathogenic mechanism of SpA is still elusive. Methods Firstly, the tissue-specific transcriptome-wide association study (TWAS) of SpA was performed by utilizing the genome-wide association study (GWAS, including 3966 SpA patients and 452264 controls) summary data and gene expression weights of the whole blood and skeletal muscle. Secondly, the SpA-associated genes identified by TWAS were further compared with the differentially expressed genes(DEGs) detected by gene expression profile of SpA acquired from the Gene Expression Omnibus database (GEO, accession number:GSE58667). Finally, FUMA and Metascape tools were used to conduct gene functional enrichment and annotation analysis. Results TWAS detected 28 significant genes associated with SpA both in the whole blood and skeletal muscle, such as CTNNAL1 (PSM=0.0304, PWB=0.0096). Further comparing with gene expression profile of SpA, we identified 20 candidate genes which overlapped in TWAS, such as MCM4 (PTWAS=0.0132, PDEG=0.0275), KIAA1109 (PTWAS=0.0371,PDEG=0.0467). The enrichment analysis of the genes identified by TWAS detected 93 significant GO terms 33 and KEGG pathways, such as mitochondrion organization (GO:0007005, log10(P)= -4.29) and axon guidance(hsa04360, log10(P)= -4.26). Conclusion We identified multiple candidate genes genetically related to SpA. Our study may provide some novel clues for the further study of the genetic mechanism, diagnosis and treatment of SpA.

BackgroundHigh extensor strength decreased knee osteoarthritis symptomatic progression in female was well demonstrated. However, few studies detected a significant association between extensor strength and structural progression when joint space narrowing or cartilage loss were the indicators. The pathological change in meniscus could come earlier than that in cartilage and JSN, but no studies have specifically investigated the association between extensor strength and meniscus progression. MethodsParticipants in Osteoarthritis Initiative with both muscle strength and meniscus assessment, KL grade ≤ 1, and BMI < 30, were enrolled. In separate-sex analysis, participants were divided into the high strength group and the low strength group referring to the median baseline maximum extensor muscle strength/weight. Overall and classified meniscus progression in MRI Osteoarthritis Knee Score was compared between the two groups, at 12 months (622 knees) and 24 months (548 knees). ResultsIn females, less overall medial meniscus progression (11.1% [17/153] VS 23.2% [32/138], P=0.04), less medial meniscal medially extrusion (5.2 % [8/155] VS 12.5 % [18/144], P =0.04), and less medial meniscal anteriorly extrusion progression (0 % [0/108] VS 5.3% [6/113], P=0.03), was presented in the high strength group over 24 months. No significant difference was detected in other comparisons (in males, or in lateral meniscus, or in 12 months). Conclusion High baseline extensor strength in females was associated with a decreased risk of 24- month medial meniscus progression. High extensor strength does not only correlate with less symptomatic progression of KOA, but also with lower risk of structural progression.

BackgroundHuman albumin (HA) administration is associated with an increased risk of acute renal failure and most other complications in patients undergoing total hip or knee arthroplasty (THA, TKA). Therefore, it is vital to reduce the use of HA and identify risk factors for its use. This study aims to determine the incidence and risk factors of HA administration in patients undergoing THA or TKA.MethodsWe identified patients undergoing THA or TKA in multiple institutions from 2014 to 2016 and collected patient demographics and perioperative variables. The criterion of HA administration was defined as a postoperative albumin level < 32 g/L or 32 to 35 g/L for at-risk patients. We compared 14 variables between patients who received HA administration and those who did not after stratification by the preoperative albumin (pre-ALB) level. Multivariate regressions identified the independent risk factors associated with HA administration.ResultsIn total, 958 (20.3 %) of 4713 patients undergoing THA and 410 (9.7 %) of 4248 patients undergoing TKA received HA administration. In addition to pre-ALB < 35 g/L, preoperative anemia (odds ratio [OR] 2.12, P = 0.001; OR 1.39, P < 0.001) and drain use (OR 3.33, P = 0.001; OR 4.25, P < 0.001) were also independent risk factors for HA administration after THA regardless pre-ALB < 35 g/L or not, and patients undergoing TKA diagnosed of rheumatoid arthritis or ankylosing spondylitis tended to receive HA administration regardless pre-ALB < 35 g/L or not (OR 3.67, P = 0.002; OR 2.06, P < 0.001).ConclusionThe incidence of HA administration was high in patients undergoing THA or TKA, and several variables were risk factors for HA administration. This finding may aid surgeons in preoperatively identifying patients requiring HA administration and optimizing perioperative managements.

Background: Whether the cement could be given up in total knee arthroplasty (TKA) was still in controversy. We perform this meta-analysis to compare the rate of revision and functional recovery between two kinds of fixation in TKA. Methods: Randomized controlled trials (RCTs), prospective/retrospective observational studies from PubMed (on 2019 Sep), EMBASE (on 2019 Sep), and the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science (on 2019 Sep) were searched. Continuous outcomes were presented as mean difference or standard mean difference with 95% CI and discontinuous outcomes were reported as relative risk (RR) with 95% CI. Random-effects or fixed-effects model was conducted to analyze the extracted data. The PRISMA guidelines and Cochrane Handbook were adopted to assess the quality of the results reported in included studies to ensure that the results of our meta-analysis were reliable and veritable. The continuous and dichotomous outcome were collected in a standard form, and the data were analysed by using Review Manager 5.3 software. Finally, the results were presented in the Forest plots. The rate of revision and reasons caused revision was the primary outcome of our study.Results: Twenty-six studies involving 2369 patients in cementless TKA and 2654 patients in cemented TKA were finally included in our meta-analysis. 26 studies were divided into three subgroups according to the length of follow-up. The studies in the first subgroup followed less than 5.5 years, the second followed less than 10.5 years, and the third followed more than 10.5 years. Cementless fixation significantly decreased the rate of aseptic loosing (p=0.0002) and revision (p=0.0002) in the first subgroup. Other reasons such as periprosthetic joint infection (PJI), instability and polyethylene wear were not significantly different between two groups. Significantly better functional recovery was got in cementless TKA in terms of Knee Society Score (p=0.004) and Oxford Knee Score (p=0.007). Significantly less patients in cementless group require manipulation under anesthesia (p=0.007). However, there was no significant difference regarding the rate of complication between two kinds of fixation in TKA.Conclusion: Not only the rate of aseptic loosing was decreased, rate of revision was also significantly decreased in cementless TKA within 5.5 years. In addition, the cementless TKA performed better in postoperative functional recovery according to Knee Society Function Score and Oxford Knee Score. However, the rate of complication was not significantly different in two kinds of fixation in TKA.

Background The purpose of this study is to evaluate whether incisional negative pressure therapy dressing (iNPWT) has an advantage over conventional wound dressing (CWD) on wound healing for patients with total joint arthroplasty (TJA) Methods We searched the electronic databases including PubMed, The Cochrane Library, EMBASE via Ovid SP, Medline via Ovid SP, to screening published randomized controlled trials and high-quality cohort studies reported that incisional negative pressure therapy dressing applied in hip and knee arthroplasty. We analyzed the overall complications, major and minor complications, dressing changes, infection rate, and the rate of reoperation. The relevant data was analyzed by RevMan5.3. Results Six studies met our criteria, and included 1405 incisions in 971 participants with total joint arthroplasty which were randomized either to incisional negative pressure therapy dressing group (n=578) or to conventional wound dressing group (n=827) .The risk for developing a minor complication between two groups was not significantly different (risk ratio [RR] 0.58, p =0.40) and for major complication was also not significantly different (RR 0.71, p =0.39). In terms of dressing changes, the iNPWT was fewer than the control group ( P