Background Physical activity (PA) is considered to play an important role in the reduced gout risk. However, the epidemiology results are inconsistent and causality remains unclear. Objective To investigate the causal relationship of PA with serum urate concentrations and gout risk by a bidirectional Mendelian randomization (MR) approach. Method Two genome-wide association studies (GWASs) from UK Biobank were used to identify instrumental variables for self-reported moderate-to-vigorous PA (including 377,234 European individuals), accelerometer-measured 'average acceleration' PA (including 91,084 European individuals) and accelerometer-measured overall PA (including 91,105 European individuals). The summary data for serum urate (including 110,347 European individuals) and gout (including 2,115 cases and 67,259 controls) were derived from GWAS of Global Urate Genetics Consortium. Moreover, reverse direction Mendelian randomization study was conducted. The inverse-variance weighted, weighted median, Mendelian randomization Egger regression, simple mode and weighted mode and Mendelian Randomization Pleiotropy RESidual Sum and Outlier were methods we performed. Result Genetic predisposition to accelerometer-measured 'average acceleration' PA [beta = -0.038; 95% confidence interval (CI) = -0.060,-0.015; P = 0.001] and accelerometer-measured overall PA (beta = -0.339; 95% CI = -0.522,-0.156; P = 2.8E-4) were significantly associated with decreased serum urate concentrations. Besides, there was no evidence supporting the causal association between PA and gout risk. In the reverse direction analysis, genetic predisposition to both urate and gout were not associated with PA being investigated. Conclusions In MR study, we found that PA may reduce serum urate concentrations but not the risk of gout. Moreover, serum urate concentrations and gout were not associated with PA.

Objective: This two-sample Mendelian randomization (MR) study aimed to examine the potential causal association of telomere length (TL) with the risk of osteoarthritis (OA).Method: The summary-level data for OA was derived from the United Kingdom Biobank cohort, including 50,508 individuals of European descent. Eighteen single nucleotide polymorphisms associated with TL were identified as instrumental variables from the most up-to-date TL genome-wide association study (GWAS) involving over 78,592 individuals of European descent. Based on the GWASs data, MR was performed using established statistical analysis methods including the inverse variance weighted, weighted median, MR-Egger, and MR pleiotropy residual sum and outlier.Results: Genetically determined TL was not associated with the risk of total OA (IVW odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.83, 1.21). In subgroup analyses stratified by OA site, no evidence in favor of association between genetically determined TL and knee OA was found (IVW OR = 1.18, 95% CI = 0.89, 1.58). However, using WM method, we observed a limited protective effect of longer TL on the risk of hip OA (OR = 0.60, 95% CI = 0.36–0.99), whereas the results of the IVW (p = 0.931) and MR-PRESSO (p = 0.932) showed that TL had no effect on hip OA.Conclusions: This study does not support a causal association between TL and total OA. A potential protective association between longer TL and hip OA, though possible, remains less certain.

OBJECTIVES:SLE is a chronic autoimmune disease, which can affect the level of bone metabolism and increase the risk of osteoporosis and fracture. The purpose of this research is to study the effect of SLE on bone turnover markers without the influence of glucocorticoids.METHODS:A total of 865 female subjects were recruited from Zhejiang Provincial People's Hospital and the First Hospital of Jiaxing, including 391 SLE patients without the influence of glucocorticoids and 474 non-SLE people. We detected Bone turnover markers including amino-terminal propeptide of type 1 procollagen (P1NP), C-terminal turnover of β - I collagen (β-CTX), N-terminal midfragment of osteocalcin (NMID) and 25(OH)D, and analyzed the difference in Bone turnover markers between the SLE group and the control group, as well as the influence of age and season on bone metabolism in female SLE patients.RESULTS:In the SLE group, the average age was 43.93±13.95 years old. In the control group, the average age was 44.84±11.42 years old. There was no difference between the two groups (t = 1.03, P = 0.30). P1NP, NMID and 25(OH)D in the SLE group were significantly lower than those in the control group (Z = 8.44, p < 0.001; Z = 14.41, p < 0.001; Z = 2.19, p = 0.029), and β-CTX in the SLE group was significantly higher than that in the control group (Z = 2.61, p = 0.009). In addition, the levers of β-CTX, NMID, P1NP and 25(OH)D in older SLE female patients were statistically significantly higher than those in younger (ρ = 0.104, p = 0.041; ρ = 0.223, p < 0.001; ρ = 0.105, p = 0.038; ρ = 0.289, p < 0.001). Moreover, β-CTX reached a high value in summer and PINP reached a low value in winter.CONCLUSION:The bone formation markers of female SLE patients without glucocorticoid were lower than those of normal people and the bone resorption marker was higher than that of normal people. The 25 (OH) D of female SLE patients without glucocorticoid was lower than that of normal people. The risk of osteoporosis and fracture may be higher in elderly women with SLE. The bone resorption level of female SLE patients is high in summer and the bone formation level is low in winter.

Background: Accumulating evidence from observational studies suggested that circulating adiponectin levels are associated with the risk of rheumatoid arthritis (RA), but the causality remains unknown. We aimed to assess the causal relationship of adiponectin with RA risk.Methods: Based on summary statistics from large-scale genome-wide association studies (GWAS), we quantified the genetic correlation between adiponectin and RA. Then bidirectional Mendelian randomization (MR) analysis was performed to assess the causal relationship. Twenty single-nucleotide polymorphisms (SNPs) associated with adiponectin were selected as instrumental variables from a recent GWAS (n = 67,739). We applied theses SNPs to a large-scale GWAS for RA (14,361 cases and 43,923 controls) with replication using RA data from the FinnGen consortium (6,236 cases and 147,221 controls) and the UK Biobank (5,201 cases and 457,732 controls). The inverse-variance weighted (IVW) and multiple pleiotropy-robust methods were used for two-sample MR analyses.Results: Our analyses showed no significant genetic correlation between circulating adiponectin levels and RA [rG = 0.127, 95% confidence interval (CI): –0.012 to 0.266, P = 0.074]. In MR analyses, genetically predicted adiponectin levels were not significantly associated with the RA risk (odds ratio: 0.98, 95% CI: 0.88–1.09, P = 0.669). In the reverse direction analysis, there is little evidence supporting an association of genetic susceptibility to RA with adiponectin (β: 0.007, 95% CI: –0.003 to 0.018, P = 0.177). Replication analyses and sensitivity analyses using different models yielded consistent results.Conclusions: Our findings provided no evidence to support the causal effect of adiponectin levels on RA risk and of RA on circulating adiponectin levels.

BACKGROUND There is very little information about the association between physical activity (PA) and the risk of rheumatoid arthritis (RA). The purpose of this study is to understand the effect of PA on subsequent risk of developing RA. METHODS A literature search was performed in PubMed and Web of Science up to 19 September 2020. Observational studies examining associations between PA and the RA development were identified. Categorical and dose-response meta-analyses were both performed. Then two-sample Mendelian randomization (MR) analysis was conducted to interrogate the causal relationship by utilizing genetic instruments identified from a genome-wide association study of self-reported and accelerometer-based PA traits. RESULTS Four eligible studies were included in the meta-analyses, involving 4213 RA cases among 255 365 participants. The summary relative risk (RR) of RA risk was 0.79 [95% confidence interval (CI): 0.72, 0.87] for the highest vs the lowest PA, and 0.85 (95% CI: 0.79, 0.92) for PA vs inactivity/occasional PA. However, we found no convincing evidence supporting a causal role of genetically predicted accelerometer-measured PA [odds ratio (OR): 0.97; 95% CI: 0.88, 1.08 per 1-SD unit increment], genetically predicted moderate-to-vigorous PA (OR: 1.08; 95% CI: 0.49, 2.39 per 1-SD unit increment) or genetically predicted vigorous PA ≥3 days/week (OR: 2.63; 95% CI: 0.05, 130.96) with RA risk. CONCLUSIONS The meta-analyses of the observational studies indicated that higher PA levels correlate with reduced risk of RA. In contrast to meta-analyses, the MR analyses reported here suggested PA may not help to prevent RA.

Objectives: Previous studies have indicated that dietary monounsaturated fatty acids (MUFAs) are associated with decreased risk of osteoarthritis (OA) and rheumatoid arthritis (RA). However, the causality of the observed associations is largely undetermined. We sought to ascertain the potential causal roles of two of the most common MUFAs, oleic acid and palmitoleic acid, in RA and OA risk using a two-sample Mendelian randomization approach. Methods: For the outcomes, we used summary-level data for RA (14361 people with RA and 43 923 controls) and OA (10083 people with OA and 40425 controls) from two genome-wide association studies in European ancestry. For the exposures, five single-nucleotide polymorphisms associated with palmitoleic acid and one associated with oleic acid with genome-wide significance (P < 5 x 10(-8)) were selected as instrumental variables. The causal effects were estimated using the inverse-variance weighted method with several sensitivity analyses. Results: For genetically predicted levels, an increase of one SD in palmitoleic acid (odds ratio, 0.24; 95% confidence interval, 0.10-0.59; P = 0.002) and oleic acid (odds ratio, 0.78; 95% confidence interval, 0.67-0.90; P < 0.001) was significantly associated with lower risk of RA. However, genetic predisposition to either of the two individual MUFAs was not associated with OA risk. Sensitivity analyses yielded similar results. Conclusions: Our Mendelian randomization analyses suggest a causal relationship between higher genetically predicted MUFA levels and lower risks of RA. However, the causality between MUFAs and OA cannot be inferred from this study. Further research is required to unravel the role of MUFA supplementation in arthritis prevention. (C) 2021 Elsevier Inc. All rights reserved.

Background: Circulating adipokines levels have been reported to be associated with the risk of rheumatoid arthritis (RA). However, it is still unclear whether these associations are causal or biased by reverse causation or residual confounding. This study aimed to assess potential causal roles of five adipokines (namely, adiponectin, leptin, resistin, chemerin, and retinol-blinding protein 4 [RBP4]) in the occurrence of RA. Methods: We conducted a two-sample Mendelian randomization analysis to investigate these associations. We used summary-level data from genome-wide association studies (GWASs) for adipokines in individuals of European ancestry as the exposure, and a separate large-scale meta-analysis of a GWAS which included 14,361 RA cases and 43,923 controls of European ancestry as the outcome. Genetic variants were selected as instrumental variables if robustly genome-wide significant in their associations with adipokines. The causal effects were estimated using the inverse-variance weighted method in the primary analysis. Sensitivity analyses were performed to warrant that bias due to genetic pleiotropy was unlikely. Results: The circulating resistin was found to be the only adipokinetic factor having statistical significance, with higher levels causally associated with the risk of RA (odds ratio: 1.28; 95% confidence interval: [1.07, 1.53] per unit increase in the natural log-transformed resistin). In contrast, associations of adiponectin, leptin, chemerin, and RBP4 with risk of RA were not statistically significant. The MR assumptions did not seem to be violated. Sensitivity analyses yielded consistent findings. Conclusions: Genetically predicted circulating resistin levels were positively associated with RA risk. Our analysis suggested that resistin may play a notable causal role in RA pathogenesis. It would be beneficial for the development of clinical as well as public health strategies that target appropriate levels of resistin for future RA intervention.

OBJECTIVEThis two-sample Mendelian randomization study aimed to delve into the effects of genetically predicted adipokine levels on OA.METHODSSummary statistic data for OA originated from a meta-analysis of a genome-wide association study with an overall 50 508 subjects of European ancestry. Publicly available summary data from four genome-wide association studies were exploited to respectively identify instrumental variables of adiponectin, leptin, resistin, chemerin and retinol-blinding protein 4. Subsequently, Mendelian randomization analyses were conducted with inverse variance weighted (IVW), weighted median and Mendelian randomization-Egger regression. Furthermore, sensitivity analyses were then conducted to assess the robustness of our results.RESULTSThe positive causality between genetically predicted leptin level and risk of total OA was indicated by IVW [odds ratio (OR): 2.40, 95% CI: 1.13-5.09] and weighted median (OR: 2.94, 95% CI: 1.23-6.99). In subgroup analyses, evidence of potential harmful effects of higher level of adiponectin (OR: 1.28, 95% CI: 1.01-1.61 using IVW), leptin (OR: 3.44, 95% CI: 1.18-10.03 using IVW) and resistin (OR: 1.18, 95% CI: 1.03-1.36 using IVW) on risk of knee OA were acquired. However, the mentioned effects on risk of hip OA were not statistically significant. Slight evidence was identified supporting causality of chemerin and retinol-blinding protein 4 for OA. The findings of this study were verified by the results from sensitivity analysis.CONCLUSIONSAn association between genetically predicted leptin level and risk of total OA was identified. Furthermore, association of genetically predicted levels of adiponectin, leptin and resistin with risk of knee OA were reported.

目的 探讨益肾蠲痹法含药血清对骨代谢信号通路的影响.方法 正常SD大鼠随机分为对照组和益肾蠲痹组,分别经生理盐水和益肾蠲痹汤灌胃给药,获取含药血清;分离大鼠成骨细胞和破骨细胞,利用碱性磷酸酶和Van kossa染色鉴定成骨细胞,TRAP和甲苯胺蓝染色鉴定破骨细胞;将成骨和破骨细胞各分为4组:对照组、益肾蠲痹法含药血清低、中和高浓度组;通过免疫印迹检测成骨细胞骨保护蛋白(OPG)、核因子κB受体活化因子配体(RANKL)和破骨细胞核因子κB受体活化因子(RANK)的表达.结果 低、中、高浓度含药血清诱导成骨细胞OPG的表达分别为对照组的97％ (P =0.710)、122％ (P =0.005)和155％ (P ＜0.001),RANKL表达分别为对照组的81％ (P ＜0.001)、63％ (P ＜0.001)和53％ (P＜0.001),表明OPG和RANKL表达与含药血清浓度分别呈正、负相关;含药血清使破骨细胞RANK表达分别调节对照组的75％(P＜0.001)、50％(P＜0.001)和46％(P＜0.001),表明RANK表达与含药血清剂量呈负相关.结论 益肾蠲痹法含药血清通过调节OPG/RANKL/RANK信号轴可能在抗骨丢失过程中发挥作用.

Objective To study the correlations among disease activity and cytokines and blood lipids in patients with ankylosing spondylitis(AS). Methods A total of 115 AS patients were enrolled. CRP,ESR,TG,TC,HDL-C,LDL-C,apoAI,LP(a),IL-6,IL-10 and other targets were measured,and the correlations between the levels of cytokines,blood lipid and AS were analyzed. Results TC,HDL-C and apoAI in 115 patients with AS were negatively correlated with ESR. TC,HDL-C and apoAI were also negatively correlated with CRP. At the same time,IL-6 was negatively correlated with HDL-C and apoAI. However,when IL-6 was controlled,there was no significant correlation between ESR and HDL-C(P>0.05). In addition, when apoAI was controlled,there was no significant correlation between ESR and HDL-C(P>0.05),and when HDL-C was controlled,ESR was still negatively correlated with apoAI(r=0.-308,P=0.001). When controlled IL-6,ESR was positively correlated with LP(a)(r=0.349,P<0.001). Conclusion The inflammatory state of AS patients may affect the level of apoAI through the change of IL-6 level,and then lead to the change of HDL-C level. After excluding the influence of IL-6,the level of inflammation in AS patients is still significantly correlated with LP(a).