Causal relationship between the immune cells and ankylosing spondylitis: univariable, bidirectional, and multivariable Mendelian randomization.

Ankylosing spondylitis (AS) is an autoimmune disease that affects millions of individuals. Immune cells have been recognized as having a crucial role in the pathogenesis of AS. However, their relationship has not been fully explored. We chose to employ Mendelian randomization (MR) to investigate the potential correlation between immune cells and AS. We sourced the data on immune cells from the latest genome-wide association studies (GWASs). We obtained data on AS from the FinnGen consortium. Our comprehensive univariable MR analysis covered 731 immune cells to explore its potential causal relationship with AS. The primary analysis method was inverse-variance weighted (IVW). Additionally, we used Cochran's Q test and the MR-Egger intercept test to assess the presence of pleiotropy and heterogeneity. We examined whether our results could be influenced by individual single-nucleotide polymorphisms (SNPs) using the leave-one-out test. We conducted a bidirectional MR to investigate the reverse relationship. We also applied multivariable MR to decrease the potential influence between the immune cells. Overall, our univariable MR analysis revealed eight immune cells associated with AS. Among these, four immune cells contributed to an increased risk of AS, while four immune cells were identified as protective factors for AS. However, the Bonferroni test confirmed only one risk factor and one protective factor with a significance level of p < 6.84E-05. CD8 on effector memory CD8+ T cell could increase the risk of AS (p: 1.2302E-05, OR: 2.9871, 95%CI: 1.8289-4.8786). HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 1.2301E-06, OR: 0.5446, 95%CI: 0.4260-0.6962). We also identified a bidirectional relationship between CD4 on CD39+ activated CD4 regulatory T cells and AS utilizing the bidirectional MR. To address potential confounding among immune cells, we employed multivariable MR analysis, which revealed that only one immune cell had an independent effect on AS. HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 2.113E-06, OR: 0.0.5423, 95%CI: 0.4210-0.6983). Our findings were consistently stable and reliable. Our findings indicated a potential link between immune cells and AS, which could provide a new idea for future research. Nevertheless, the specific underlying mechanisms require further exploration.

Qin C ，Yu Q ，Deng Z ，Zhang Y ，Chen M ，Wang X ，Hu T ，Lei B ，Yan Z ，Cheng S ... -  《Frontiers in Immunology》

Causal relationship between the blood immune cells and intervertebral disc degeneration: univariable, bidirectional and multivariable Mendelian randomization.

Intervertebral disc degeneration (IVDD) is a prominent contributor to chronic low back pain, impacting millions of individuals annually. Current research on disc degeneration is placing a growing emphasis on the role of the immune system in this process. Nevertheless, the precise relationship between immunity and disc degeneration remains to be fully elucidated. We obtained GWAS data for immune cells from the latest summary-level GWAS, including 6,620 individuals from Sardinian and 746,667 individuals from five global populations. Summary results for IVDD were sourced from the FinnGen consortium, comprising 20,001 cases and 164,682 controls. We conducted a comprehensive univariable Mendelian randomization (MR) analysis to explore the potential causal relationship between immune cells and IVDD. Primary estimation was carried out using Inverse-Variance Weighting (IVW). To ensure robustness, we employed additional MR methods such as MR-Egger, Weighted Median, Weighted Mode, and Simple Mode. Various tests were employed to assess pleiotropy and heterogeneity, including the Cochran Q test, leave-one-out test, MR-Egger intercept analysis and MR-PRESSO test. To account for potential confounding factors among the immune cells, we conducted a multivariable MR analysis. Finally, we investigated the possibility of a reverse association between immune cells and IVDD through bidirectional MR. In total, our study identified 15 immune cells significantly associated with IVDD through univariable MR. Among these, 9 immune cell types were indicated as potential contributors to IVDD, while 6 were found to have protective effects. Importantly, we observed no evidence of heterogeneity or pleiotropy, signifying the robustness of our results. To mitigate confounding among immune cells, we utilized multivariable MR, leading to the discovery that only 9 immune cell types exerted independent effects on IVDD. These encompassed 7 as risk factors and 2 as protective factors. Additionally, our analysis revealed a bidirectional causal relationship between CD39+ CD4+ T cell %CD4+ T cell and IVDD. Our findings suggest a connection between immune cells and the risk of IVDD, shedding light on potential therapeutic avenues for modulating immune cell function in individuals with IVDD. However, the specific underlying mechanisms warrant further investigation in future experiments.

Qin C ，Chen M ，Yu Q ，Wang X ，Hu T ，Lei B ，Yan Z ，Cheng S ... -  《Frontiers in Immunology》

Assessing the association of leukocyte telomere length with ankylosing spondylitis and rheumatoid arthritis: A bidirectional Mendelian randomization study.

Telomere length shortening can cause senescence and apoptosis in various immune cells, resulting in immune destabilization and ageing of the organism. In this study, we aimed to systematically assess the causal relationship of leukocyte telomere length (LTL) with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) using a Mendelian randomization study. LTL (n=472174) was obtained from the UK Biobank genome-wide association study pooled data. AS (n=229640), RA (n=212472) were obtained from FinnGen database. MR-Egger, inverse variance weighting, and weighted median methods were used to estimate the effects of causes. Cochran's Q test, MR Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots were used to look at sensitivity, heterogeneity, and multiple effects. Forward MR analysis considered LTL as the exposure and AS, RA as the outcome. Reverse MR analysis considered AS, RA as the exposure and LTL as the outcome. In the forward MR analysis, inverse variance-weighted and weighted median analysis results indicated that longer LTL might be associated with increased risk of AS (IVW: OR = 1.55, 95% CI: 1.14-2.11, p = 0.006). MR Egger regression analysis showed no pleiotropy between instrumental variables (IVs) (Egger intercept= 0.008, p = 0.294). The leave-one-out analysis showed that each single nucleotide polymorphism (SNP) of AS was robust to each outcome. No significant causal effects were found between AS, RA and LTL in the reverse MR analysis. Longer LTL may be related with an increased risk of developing AS, and these findings provide a foundation for future clinical research on the causal association between LTL and AS.

Wei D ，Jiang Y ，Cheng J ，Wang H ，Sha K ，Zhao J ... -  《Frontiers in Immunology》

Bayesian-based analysis of the causality between 731 immune cells and erectile dysfunction: a two-sample, bidirectional, and multivariable Mendelian randomization study.

Chen J ，Liu Y ，Zhan P ，Gao T ，Zuo J ，Li X ，Zhang F ，Wang H ，Fu S ... -  《Sexual Medicine》

Relationship between immune cells and diabetic nephropathy: a Mendelian randomization study.

Although previous studies have suggested potential correlations between immunocytes and diabetic nephropathy (DN), the causal correlations between them remain unclarified. In this study, we employed Mendelian randomization (MR) to analyze the potential causative correlations between immune 731 cells and DN. We used the Genome-Wide Association Studies (GWAS) database to aggregate signatures of immune cells and DN from European and East Asian populations. Single-nucleotide polymorphisms (SNPs) were used as instrumental variables. MR analysis was conducted using Mendelian randomization-Egger (MR-Egger) regression and the random-effects inverse-variance weighted (IVW) method. A total of 3,571 SNPs were included as instrumental variables. The MR-Egger regression model indicated no genetic pleiotropy (P = 0.6284). The results of the IVW method indicated a statistically significant causal relationship between immune cell HLA-DR on CD14-CD16- (P = 0.029), CD45RA-CD28-CD8 + T cell% T cells (P = 0.0278), CD11c on myeloid dendritic cells (P = 0.0352), HLA-DR on CD14+ monocytes (P < 0.001), CD27 on CD24 + CD27 + B cells (P = 0.0334), CD27 on IgD + CD24 + B cells (P = 0.0137), CD4 on CD39 + CD4 + T cells (P = 0.0347), CD28 on CD39 + CD4 + T cells (P = 0.0414), CD39 on CD39 + CD4 + T cells (P = 0.0426), and DN. Additionally, there was no heterogeneity in SNPs related HLA-DR on CD14-CD16-cells and DN(I2 = 32%, Cochran's Q = 2.9476, P = 0.2291). Moreover, leave-one-out analysis showed a causal correlation between HLA-DR on CD14-CD16- cells and DN. Higher expression of immune cell HLA-DR on CD14-CD16- cells may indicate a lower risk of DN.

Li X ，Zhang L ，Yan C ，Zeng H ，Chen G ，Qiu J ... -  《-》