Protective Causal Effects of CCL19, CCL23, and IL17A on Achilles Tendinitis: Insights from Bidirectional Mendelian Randomization and Metabolite-Mediated Pathway Analysis

IntroductionThe increasing prevalence of myopia worldwide poses significant public health concerns. Accumulating evidence suggests a potential link between ocular diseases and the gut microbiota (GM); however, whether the GM directly contributes to myopia development remains to be established.MethodsThis study investigated the potential causal link between the GM and myopia through bidirectional Mendelian randomization (MR) analysis, further validated by experiments conducted on a form-deprivation myopia (FDM) guinea pig model. Bidirectional two-sample MR analysis was performed using genome-wide association study summary statistics comprising data on 196 GM taxa from the MiBioGen consortium and myopiaassociated data from the FinnGen database. Instrumental variables were carefully selected according to predetermined standards. Subsequently, MR estimates were calculated using the inverse variance weighted, MR-Egger regression, and weighted median approaches, along with supplementary sensitivity evaluations. Concurrently, FDM was experimentally induced in guinea pigs, and fecal samples were subjected to comprehensive full-length 16S rRNA gene sequencing analysis.ResultsMR analysis identified five bacterial taxa linked to the risk of myopia. Specifically, higher Bifidobacterium abundance was associated with lower myopia risk (odds ratio = 0.834, 95% confidence interval = 0.705–0.986, p < 0.05). Animal experiments validated the MR findings, demonstrating a significant enrichment of Bifidobacteria in control animals.DiscussionConclusively, supplementation with Bifidobacteria is a potential strategy for reducing the risk of myopia. Future research should focus on developing and testing Bifidobacterium-based interventions to validate their effectiveness in controlling myopia.

Previous studies reported that many inflammatory factors have associations with osteoporosis. This study use Mendelian randomization (MR) analysis to explore the causal genetic relationship between 41 inflammatory factors and osteoporosis. A bidirectional two-sample MR analysis was performed by employing five Mendelian randomization analysis methods including MR Egger regression, weighted median, inverse-variance weighted and weight mode methods. Summary statistics from the genome-wide association study (GWAS) of 41 inflammatory cytokines and osteoporosis were included in this study. This study examined the MR analysis results for heterogeneity and horizontal pleiotropy. Using the inverse variance weighted (IVW) method, this analysis indicated that elevated monocyte chemotactic protein-1 (MCP-1) levels were potentially linked to a 22% increased likelihood of osteoporosis (Odds Ratio (OR) = 1.22, 95% CI: 1.04-1.43, p = 0.014). Additionally, through the IVW approach, we observed that higher tumor necrosis factor-related apoptosis inducing ligand (TRAIL) levels were possibly associated with a 15% greater risk of osteoporosis (OR = 1.12, 95% CI: 1.03-1.29, p = 0.012). Other 39 inflammatory cytokines don't have casual genetic association with osteoporosis. When this study use MR to estimate the influence of osteoporosis on inflammatory factors, none of the p-values with IVW method were lower than 0.05. This is the first bidirectional MR analysis to explore the causal genetic relationship between inflammatory cytokines and osteoporosis. This study found that MCP-1 and TRAIL are probably the upstream factors correlated with osteoporosis, and no inflammatory cytokine was involved in osteoporosis development downstream.

Background Intracranial Aneurysms (IA) are life-threatening cerebrovascular diseases, and their pathogenesis remains not fully understood. This study aims to systematically evaluate the causal relationship between cerebrospinal fluid (CSF) metabolites and IA through bidirectional two-sample Mendelian randomization (MR) analysis to identify potential biomarkers and therapeutic targets. Methods Using genome-wide association study data from public databases, the primary analysis was conducted with inverse variance weighting, supplemented by MR-Egger regression, weighted median, weighted mode, and simple mode. Sensitivity analyses were performed using heterogeneity tests, horizontal pleiotropy tests, and leave-one-out analyses to ensure the stability of the results. Results Forward MR analysis revealed that 1-arachidonoyl-gpc (20:4n6), 2’-deoxyuridine, 3-hydroxystachydrine, 5-hydroxyhexanoate, isobutyrylcarnitine (C4), phenylacetylglutamine, and X-10457 were protective factors for IA. In contrast, 2-hydroxybutyrate/2-hydroxyisobutyrate, arabonate/xylonate, argininosuccinate, citrate, cysteinylglycine disulfide, and isovalerate were identified as risk factors for IA. Reverse MR analysis showed a significant causal relationship between IA and changes in the concentrations of 14 CSF metabolites. Sensitivity analyses indicated the robustness of these findings. Conclusions This study, through bidirectional MR analysis, uncovered the causal relationship between CSF metabolites and IA, highlighting the significant roles of various amino acids and lipid metabolites in the pathophysiology of IA. These metabolites not only provide new insights into the mechanisms underlying IA but also present potential biomarkers and therapeutic targets, offering theoretical support for early intervention and prevention strategies for the disease.

Observational studies indicate an association between type 1 diabetes (T1D) and suicidal or self-harm behaviors. However, the causal relationship between the 2 remains uncertain. A 2-sample bidirectional Mendelian randomization (MR) analysis to investigate the association between T1D and suicide or self-harm behavior. All data were publicly available genome-wide association study summary statistics, and all individuals were of European descent. The inverse variance weighted (IVW) method, MR-Egger regression, and weighted median were employed to investigate the association between T1D and suicide or self-harm behavior. Sensitivity analyses were conducted using Cochran's Q test, MR-Egger regression, the MR pleiotropy residual sum method, leave-one-out analysis, and the MR residual sum and outlier test to assess the robustness of the findings. The IVW method indicated an association between T1D and suicidal or self-harm behavior (odds ratio (OR) = 1.011, 95% CI = 1.004-1.018, P = .002). However, there was no observed genetic influence on the relationship between suicidal or self-harm behavior and T1D. This study, based on bidirectional 2-sample MR analysis of genetic data, validated that T1D is a risk factor for suicidal or self-harm behaviors. These findings are based on data from European-descent individuals, and their generalizability to other populations is unknown.

Previous observational researchers have found an inverse bidirectional link between Alzheimer's disease (AD) and prostate cancer (PCa); yet, the causative nature of this link remains unclear. To investigate the causal interactions between AD and PCa, a bidirectional Mendelian randomization (MR) analysis was conducted. This study comprised two Genome-Wide Association Study (GWAS) summary statistics for AD (17,008 cases and 37,154 controls) and PCa (79,148 cases and 61,106 controls) in individuals of European ancestry. The inverse-variance weighted (IVW) method was employed as the primary approach, while MR-Egger, weighted median, weighted mode, and simple mode served as supplementary methods for estimating the causal effect. To assess pleiotropy, the MR-PRESSO global test and MR-Egger regression were used. Cochran's Q test was adopted to check heterogeneity, MR Steiger test and the leave-one-out analysis was performed to confirm the robustness and reliability of the results. The causal association genetically inferred of AD on PCa was found using IVW (OR = 0.974, 95% CI = 0.958-0.991, p = 0.003) in forward MR analysis and the causal association genetically inferred of PCa on AD was not found using IVW (OR = 1.000, 95% CI: 0.954-1.049, P = 0.988) in reverse MR analysis. The sensitivity analysis showed that no pleiotropy and heterogeneity was observed. The leave-one-out analysis showed that the findings were not inordinately affected by any instrumental variables. The results of this study demonstrated an absence of bidirectional causality between AD and PCa among the European population, suggested that a genetically predicted possibility of decreased PCa risk in AD patients, and no significant genetically predicted causal effect of PCa on AD.

The relationship between peripheral immune cells and immunoglobulin A nephropathy (IgAN) is widely known; however, causal evidence of this link is lacking. Here, we aimed to determine the causal effect of peripheral immune cells, specifically total white blood cells, lymphocytes, monocytes, basophils, eosinophils, and neutrophils, as well as lymphocyte subset traits, on the IgAN risk using a Mendelian randomization (MR) analysis. The inverse-variance weighted (IVW) method was used for the primary analysis. We applied three complementary methods, including the weighted median, MR-Egger regression, and MR-PRESSO, to detect and correct for the effect of horizontal pleiotropy. Additionally, we performed a multivariable MR (MVMR) analysis, adjusting for the effects of C-reactive protein (CRP) levels. The roles of specific lymphocyte subtypes and their significance have garnered interest. Bidirectional two-sample MR analysis was performed to test the potential causal relationships between immune traits, including median fluorescence intensities (MFIs) and the relative cell count (AC), and IgAN. The IVW-MR analysis suggested a potential causal relationship between lymphocyte counts and IgAN in Europe (OR per 1-SD increase: 1.43, 95% CI: 1.08-1.88, P = 0.0123). The risk effect of lymphocytes remained even after adjusting for CRP levels using the MVMR method (OR per 1-SD increase: 1.44, 95% CI: 1.05-1.96, P = 0.0210). The other sensitivity analyses showed a consistent trend. The largest GWAS published to date was used for peripheral blood immunophenotyping to explore the potential causal relationship between peripheral immune cell subsets and IgAN. Six AC-IgAN and 14 MFI-IgAN pairs that reached statistical significance (P < 0.05) were detected. Notably, CD3, expressed in eight subsets of T cells, consistently showed a positive correlation with IgAN. The bidirectional MR analysis did not reveal any evidence of reverse causality. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. Genetically determined high lymphocyte counts were associated with IgAN, supporting that high lymphocyte counts is causal risk factor for IgAN.

Previous studies have reported an association between gut microbiota and cirrhosis. However, the causality between intestinal flora and liver cirrhosis still remains unclear. In this study, bi-directional Mendelian randomization (MR) analysis was used to ascertain the potential causal effect between gut microbes and cirrhosis. Large-scale Genome Wide Association Study (GWAS) data of cirrhosis and gut microbes were obtained from FinnGen, Mibiogen consortium, and a GWAS meta-analysis of Alcoholic cirrhosis (ALC). Two-sample MR was performed to determine the causal relationship between gut microbiota and cirrhosis. Furthermore, a bi-directional MR analysis was employed to examine the direction of the causal relations. In MR analysis, we found that 21 gut microbiotas were potentially associated with cirrhosis. In reverse MR analysis, 11 gut microbiotas displayed potentially associations between genetic liability in the gut microbiome and cirrhosis. We found that the family Lachnospiraceae (OR: 1.59, 95% CI:1.10-2.29) might be harmful in cirrhotic conditions (ICD-10: K74). Furthermore, the genus Erysipelatoclostridium might be a protective factor for cirrhosis (OR:0.55, 95% CI:0.34-0.88) and PBC (OR:0.68, 95% CI:0.52-0.89). Combining the results from the MR analysis and reverse MR analysis, we firstly identified the Genus Butyricicoccus had a bi-directional causal effect on PBC (Forward: OR: 0.37, 95% CI:0.15-0.93; Reverse: OR: 1.03, 95% CI:1.00-1.05). We found a new potential causal effect between cirrhosis and intestinal flora and provided new insights into the role of gut microbiota in the pathological progression of liver cirrhosis.

This study aimed to investigate putative causal effects between constipation and stroke using bidirectional Mendelian randomization (MR) analysis. Based on the cross-sectional study, logistic regression models were developed to assess the association between constipation and stroke prevalence. Subsequently, genome-wide association studies statistics were employed to perform MR analysis between constipation and stroke, as well as its subtypes. The inverse variance weighting (IVW) method was the primary method, complemented by four additional methods, namely weighted median, weighted mode, simple mode, and MR-Egger regression. Cochran's Q test, MR-Egger intercept test, MR Pleiotropy RESidual Sum and Outlier, and MR Steiger test were performed to assess heterogeneity and pleiotropy effects. Constipation was associated with a greater risk of stroke even after adjusting for all covariates in logistic regression [odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.01-2.09, p = 0.042]. IVW MR analysis revealed that constipation affected large artery atherosclerosis (LAS; IVW OR = 1.5, 95% CI = 1.07-2.104, p = 0.019). No significant or suggestive association was observed with the risk of stroke or its various subtypes in MR analysis. Meanwhile, reverse MR analysis revealed no significant causal relationship between stroke or other stroke subtypes and constipation. The results of sensitivity analyses revealed no significant horizontal pleiotropy affecting causal estimates. While cross-sectional studies have established that constipation increases the risk of stroke, this two-sample bidirectional MR analysis revealed a positive correlation between constipation and LAS. However, no such correlation was observed between constipation and stroke, including its various subtypes.

Metabolic syndrome (MetS) is a group of co-occurring conditions that increase the risk of cardiovascular disease, which include the conditions of hypertension, overweight or obesity, hyperglycemia, and dyslipidemia. Psychological stress is gradually being taken seriously, stemming from the imbalance between environmental demands and individual perceptions. However, the potential causal relationship between psychological stress and MetS remains unclear. We conducted cross-sectional and bidirectional Mendelian randomization (MR) analyses to clarify the potential causal relationship of psychological stress with MetS and its components. Multivariable logistic regression models were used to adjust for potential confounders in the cross-sectional study of the Chinese population, including 4,933 individuals (70.1% men; mean age, 46.13 ± 8.25). Stratified analyses of sexual characteristics were also performed. Bidirectional MR analyses were further carried out to verify causality based on summary-level genome-wide association studies in the European population, using the main analysis of the inverse variance-weighted method. We found that higher psychological stress levels were cross-sectionally associated with an increased risk of hypertension in men (odds ratio (OR), 1.341; 95% confidence interval (CI), 1.023-1.758; p = 0.034); moreover, higher levels of hypertension were cross-sectionally associated with an increased risk of psychological stress in men and the total population (men: OR, 1.545 (95% CI, 1.113-2.145); p = 0.009; total population: OR, 1.327 (95% CI, 1.025-1.718); p = 0.032). Genetically predicted hypertension was causally associated with a higher risk of psychological stress in the inverse-variance weighted MR model (OR, 2.386 (95% CI, 1.209-4.710); p = 0.012). However, there was no association between psychological stress and MetS or the other three risk factors (overweight or obesity, hyperglycemia, and dyslipidemia) in cross-sectional and MR analyses. Although we did not observe an association between psychological stress and MetS, we found associations between psychological stress and hypertension both in cross-sectional and MR studies, which may have implications for targeting hypertension-related factors in interventions to improve mental and metabolic health. Further study is needed to confirm our findings.

Mendelian randomization analysis does not reveal a causal association between genetic liability to chronic pain and autism spectrum disorder.

There is currently evidence supporting an association between periodontitis and prostate disease, but further research is needed to establish a causal relationship due to potential confounding factors and uncertainty about the direction of causality. The present study employs a bidirectional Mendelian Randomization (MR) analysis to eliminate confounding factors at the genetic level and determine the causal relationship between periodontitis and prostate diseases. Summary data for periodontitis were obtained from the GLIDE consortium (N = 45,563), while data for prostate diseases, including benign prostatic hyperplasia (N = 163,095), prostatitis (N = 134,299), and prostate cancer (N = 146,465), were sourced from the FinnGen database. Various methods were employed in the Mendelian randomization (MR) analysis, including the inverse variance-weighted (IVW) method, MR-Egger regression, weighted median, and weighted mode. Sensitivity analyses, such as the MR-Egger intercept test and MR-PRESSO method, were performed to ensure the reliability and robustness of the results. Results from the bidirectional MR analysis using the IVW method as the primary approach, indicate that no causal relationship exists between periodontitis and prostate disease. Consequently, there is insufficient evidence to substantiate their association. Moreover, additional sensitivity analyses performed further reinforce the robustness of our findings. Our MR study did not identify a causal relationship between periodontitis and prostate disease. However, we do not rule out the possibility of an underlying etiological connection and shared mechanisms between the two conditions. Therefore, further large-scale studies using various approaches are needed to explore their association in greater depth and provide more comprehensive and accurate guidance for clinical practice.

BackgroundIgA vasculitis (IgAV) is an immune-associated vasculitis, yet its exact etiology remains unclear. Here, we explore the interaction between IgAV and inflammatory factors using bidirectional Mendelian randomization (MR).MethodsWe conducted a bidirectional summary-level MR analysis to delineate the causality of C-reactive protein (CRP), procalcitonin (PCT), and 41 circulating inflammatory regulators with IgAV. Data on genetic variants related to inflammation were obtained from three genome-wide association studies (GWASs) on CRP, PCT, and human cytokines, whereas data on IgAV was from large meta-analyses of GWAS among 216 569 FinnGen Biobank participants. The primary MR analysis was performed using the inverse-variance weighted (IVW) approach, and the sensitivity analyses were carried out using MR-Egger, weighted median, weighted mode, and MR-pleiotropy residual sum and outlier.ResultsThis study revealed the association of CRP higher levels with increased risk of IgAV through IVW method (Estimate odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.01-1.98, P = 0.04), MR-Egger (OR = 1.87, CI: 1.15-3.02, P = 0.01), weighted median (OR = 2.00, CI: 1.21-3.30, P = 0.01) and weighted mode (OR = 1.74, CI: 1.13-2.68, P = 0.02). Furthermore, elevated IL-8 was strongly implicated with a higher risk of IgAV (IVW OR = 1.42, CI: 1.05-1.92; P = 0.02). Conversely, genetically predicted IgAV was associated with decreased levels of TNF-β (IVW estimate β = -0.093, CI: -0.178 - -0.007; P = 0.033). Additionally, no such significant statistical differences for other inflammatory factors were found.ConclusionOur current study using bidirectional MR analysis provides compelling evidence for a causal effect of CRP, PCT, and circulating inflammatory regulators on IgAV. These findings contribute to a better understanding of the pathogenesis of IgAV and emphasize the potential of targeting inflammatory factors for therapeutic interventions.

Observational studies have underscored a robust association between frailty and chronic obstructive pulmonary disease (COPD), yet the causality remains equivocal. This study employed bidirectional two-sample Mendelian randomization (MR) analysis. Univariable MR investigated the causal relationship between frailty and COPD. Genetic correlation was assessed using linkage disequilibrium score (LDSC) regression. Multivariable MR and mediation analysis explored the influence of various confounders and their mediating effects. The primary analytic approach was inverse variance weighted (IVW). LDSC analysis revealed moderate genetic correlations between frailty and Global Biobank Meta-Analysis Initiative (GBMI) COPD (rg = 0.643, P = 6.66×10-62) as well as FinnGen COPD (rg = 0.457, P = 8.20×10-28). IVW analysis demonstrated that frailty was associated with increased risk of COPD in both the GBMI cohort (95% CI, 1.475 to 2.158; P = 2.40×10-9) and the FinnGen database (1.411 to 2.434; 9.02×10-6). Concurrently, COPD was identified as a susceptibility factor for frailty (P < 0.05). These consistent findings persisted after adjustment for potential confounders in MVMR. Additionally, mediation analysis revealed that walking pace mediated 19.11% and 15.40% of the impact of frailty on COPD risk, and 17.58% and 23.26% of the effect of COPD on frailty risk in the GBMI and FinnGen cohorts, respectively. This study has strengthened the current evidence affirming a reciprocal causal relationship between frailty and COPD, highlighting walking pace as a pivotal mediator.

BACKGROUND: Opioid medications are widely used for pain management, but their impact on obstructive sleep apnea (OSA) remains controversial. Given the high prevalence of OSA and the increasing use of opioids, understanding the causal relationship between the condition and this type of medication is critical. OBJECTIVES: This study aims to investigate the causal relationship between opioid use and OSA using a bidirectional 2-sample Mendelian randomization (MR) analysis. Specifically, the study seeks to determine whether exposure to opioid use increases the risk of developing OSA and whether OSA influences the likelihood of opioid use. STUDY DESIGN: The study employed a bidirectional 2-sample MR analysis to explore the causal relationship between opioid use and OSA. Genetic variants from large-scale genome-wide association studies (GWAS) were used as instrumental variables to ensure robust causal inference. SETTING: The study utilized data from 2 large-scale GWAS datasets. Opioid use data were obtained from the UK Biobank, while OSA data were sourced from the FinnGen study. Both datasets predominantly included patients of European ancestry with similar demographic characteristics. METHODS: This study employed a 2-sample bidirectional Mendelian randomization (MR) approach to investigate the causal relationship between opioid use and obstructive sleep apnea (OSA). Genetic instruments for opioid use and OSA were selected from large-scale genome-wide association studies (GWAS) conducted in European populations, ensuring consistency in genetic backgrounds. The inverse variance-weighting (IVW) method was used as the primary analysis to estimate causal effects, supplemented by the weighted median, MR-Egger, simple mode, and weighted mode methods to ensure robustness. Sensitivity analyses, including MR-Egger regression, leave-one-out analysis, and MR-PRESSO, were conducted to assess pleiotropy, heterogeneity, and the influence of individual SNPs on the results. RESULTS: The IVW method demonstrated a significant causal effect of opioid use on the risk of developing OSA, with a causal effect size of 0.28 (OR = 1.32, 95% CI = 0.09 to 0.46, P-value = 0.004). This association was supported by the weighted median method, though the MR-Egger, simple mode, and weighted mode methods did not achieve statistical significance but showed a consistent direction of effect. Conversely, no significant causal relationship was observed between OSA and opioid use across all methods, suggesting that OSA did not significantly influence opioid use. LIMITATIONS: The primary limitations of this study include the use of binary phenotypes for opioid use and OSA, which precludes the assessment of dose-response relationships. Additionally, the genetic data were derived predominantly from European populations, limiting the generalizability of the findings to other ethnic groups. Potential pleiotropy and unmeasured confounders, although addressed through various sensitivity analyses, may still introduce bias into the results. CONCLUSION: This study provides strong evidence of a unidirectional causal relationship in which opioid use increases the risk of developing OSA. These findings underscore the importance of monitoring patients who use opioids for potential respiratory complications, particularly OSA. KEY WORDS: Mendelian randomization, opioid, Obstructive Sleep Apnea (OSA)

Despite previous observational studies linking obstructive sleep apnea (OSA) to venous thromboembolism (VTE), these findings remain controversial. This study aimed to explore the association between OSA and VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), at a genetic level using a bidirectional two-sample Mendelian randomization (MR) analysis. Utilizing summary-level data from large-scale genome-wide association studies in European individuals, we designed a bidirectional two-sample MR analysis to comprehensively assess the genetic association between OSA and VTE. The inverse variance weighted was used as the primary method for MR analysis. In addition, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for complementary analyses. Furthermore, a series of sensitivity analyses were performed to ensure the validity and robustness of the results. The initial and validation MR analyses indicated that genetically predicted OSA had no effects on the risk of VTE (including PE and DVT). Likewise, the reverse MR analysis did not find substantial support for a significant association between VTE (including PE and DVT) and OSA. Supplementary MR methods and sensitivity analyses provided additional confirmation of the reliability of the MR results. Our bidirectional two-sample MR analysis did not find genetic evidence supporting a significant association between OSA and VTE in either direction.