BackgroundPrevious studies have demonstrated an inverse association between parathyroid hormone (PTH) and the risk of osteoarthritis (OA). However, it remains unknown whether such association reflects causality. We aimed to apply a Mendelian randomization (MR) approach to investigate the causal association between PTH and OA.Materials and MethodsWe performed a two-sample MR analysis using summary statistics from 13 cohorts (PTH, N = 29,155) and a recent genome-wide association study meta-analysis (OA, N = 455,221) by the UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). MR analyses were carried out mainly using the inverse-variance-weighted method. Sensitivity analyses were performed to test the robustness of the associations using the weighted median method, the MR–Egger method, and “leave-one-out” analysis. Analyses were performed again to test whether the associations remained statistically significant after excluding any outlier variants that were detected using the MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) test.ResultsFive single-nucleotide polymorphisms (SNPs) were selected as instrumental variables at the genome-wide significance threshold (p < 5 × 10–8). The causal effect between PTH and OA was genetically predicted using the inverse-variance-weighted method (odds ratio = 0.67, 95% confidence interval: 0.50–0.90; p = 0.008). This result was borne out using the weighted median method (odds ratio = 0.73, 95% confidence interval: 0.60–0.90; p = 0.004). The causality remained robust after discarding the outlier variants as well as SNPs associated with confounding factors.ConclusionMR analysis supported a potential causative relationship between decreased serum circulating PTH and a higher risk of hip and knee OA.
Background Educational attainment is moderately heritable and inversely associated with the risk of rheumatoid arthritis. However, the causality from educational attainment on rheumatoid arthritis remained unknown. Here, we aimed to determine whether educational attainment is causally associated with rheumatoid arthritis (RA) by using Mendelian randomization (MR) approach. Methods Summary statistics data for RA were obtained from an available, published meta-analysis of genome-wide association studies (GWAS) that included 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables for educational attainment were obtained from a GWAS meta-analysis that included over 1 million individuals (N = 1,131,881) of European ancestry. MR analyses were mainly performed using the inverse-variance weighted (IVW) method. Sensitivity analyses were further performed to test the robustness of the association using the weighted median method, MR-Egger, Cochran Q test, “leave-one-out” analysis and MR-PRESSO test. Results A total of 387 SNPs were employed as instrumental variables in our MR analysis. Genetically predicted higher educational attainment was associated with a significantly lower risk of RA using the IVW method (odds ratio [OR] = 0.42, 95% confidence interval [CI]: 0.34–0.52; p = 1.78 × 10− 14). The weighted median method and MR Egger regression analysis yielded consistent results. The effect estimate remained robust after the outlier variants and SNPs (associated with the confounding factors) were excluded. “Leave-one-out” analysis confirmed the stability of our results. Additionally, the results suggested the absence of the horizontal pleiotropy. Conclusions The MR analysis supported a potential inverse causative relationship between educational attainment and the risk of RA.
Background Educational attainment is moderately heritable and positively associated with the risk of rheumatoid arthritis. However, the causality from educational attainment on rheumatoid arthritis remained unknown. Here, we aimed to determine whether educational attainment is causally associated with rheumatoid arthritis (RA) by using a Mendelian randomization (MR) approach.Methods Summary statistics data for RA were obtained from an available, published meta-analysis of genome-wide association studies (GWAS) that included 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables for educational attainment were obtained from a GWAS meta-analysis that included over 1 million individuals (N = 1,131,881) of European ancestry. MR analyses were performed using the inverse-variance weighted (IVW), weighted median, and MR-Egger methods. Sensitivity analyses were performed to test the robustness of the association using the Cochran Q test, MR Egger intercept test, “leave-one-out” analysis and MR-PRESSO test.Results A total of 387 SNPs were employed as instrumental variables in our MR analysis. Genetically predicted higher educational attainment was associated with a significantly lower risk of RA using the IVW method (odds ratio [OR] = 0.42, 95% confidence interval [CI]: 0.34–0.52; p = 1.78×10−14). The weighted median and MR Egger methods yielded consistent results. The causality remained robust after discarding the outlier variants and SNPs associated with the confounding factors. "Leave-one-out" analysis confirmed the stability of our results. Additionally, the results demonstrated the absence of the horizontal pleiotropy.Conclusions The MR analysis supported a potential inverse causative relationship between educational attainment and the risk of RA.
The vast majority of epidemiological studies suggested a link between systemic lupus erythematosus (SLE) and major depressive disorder (MDD). However, the causality for SLE on the risk of MDD remained unknown due to confounding factors or reverse causality. Herein, we investigated the causality between SLE and MDD in those of European ancestry by a Mendelian randomization (MR) approach. Summary genetic data of cases with SLE/MDD were derived from independent largest public genome-wide association study. Forty-six single nucleotide polymorphisms associated with SLE were used as instrumental variables. The main causal inference was carried out using the MRE-IVW method. Additional, reverse-direction MR and multivariable MR analyses were further performed. Result indicated that SLE was causally associated with a lower risk of MDD (using the MRE-IVW method, odds ratio [OR] = 0.983, 95% confidence interval [CI] = 0.974–0.991, p = 1.18 × 10−4). Complementary analysis found no heterogeneity or horizontal pleiotropy. Multivariate MR analysis yielded consistent results (OR = 0.981; 95% CI = 0.969–0.993; p = 2.75 × 10−3). Reverse-direction MR analysis suggested non-causal relationship of MDD on the risk of SLE (using the IVW method, OR = 0.846, 95% CI = 0.345–2.072; p = 0.714). Thus, this is the first study providing evidence of potential causal links between SLE and MDD and further related research is needed.
Spine–pelvis–lower extremity sagittal alignment is regarded as a global sagittal balance. Currently, there are few studies evaluating the pelvic and femoral sagittal alignment during total knee arthroplasty (TKA). This retrospective study aims to elucidate how pelvic and femoral sagittal alignment affect clinical outcomes of primary TKA for osteoarthritis (OA) and determine the proper range of femoral sagittal alignment. Patient-reported outcome measures (PROMs), including the Knee Society Score (KSS), Western Ontario and McMaster Universities (WOMAC), and patient satisfaction scores, and clinician-reported outcomes (CROs), including range of motion (ROM) and pelvic and femoral sagittal parameters, of 67 cases were evaluated (89 knees) before and 1 year after TKA. The angle between the distal femur anterior cortex line and flange of the femoral component (FC) was defined as the α angle. Correlations between the α angle and PROM and CRO were investigated using multivariate and secondary regression analyses. Patients were further divided into four cohorts (A, B, C, and D) according to the α angle, and comparisons of their postoperative PROM and ROM scores were performed. Postoperative PROM and ROM scores improved significantly compared with the preoperative scores (p < 0.01). Only the α angle was significantly associated with postoperative knee extension among all PROM and CRO indexes (p = 0.001). Secondary regression demonstrated a convex upward function, and the scores were the highest at α angles of 0.57, 0.96, and −1.42 degrees for postoperative KSS, satisfaction, and range of knee extension, respectively (p < 0.01). However, the concave upward degree was the lowest at an α angle of 0.33 degrees for pelvic incidence (p < 0.001). Bonferroni's paired comparisons indicated that postoperative KSS and satisfaction of the cohort B (0 degrees ≤ α angle ≤ 3 degrees) were better than those of other cohorts (p < 0.0125). The results indicate that surgeons should pay more attention to the sagittal alignment of FC in patients with increased pelvic incidence, the distal femoral anterior cortex is recommended as an anatomic landmark, and 0 to 3 degrees might be “safe zones” of the sagittal flexion of FC in TKA. This study reflects the level of evidence III.
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