UNASSIGNED: The relationship between adiposity and sepsis has received increasing attention. This study aims to explore the causal relationship between life course adiposity and the sepsis incidence.
UNASSIGNED: Mendelian randomization (MR) method was employed in this study. Instrumental variants were obtained from genome-wide association studies for life course adiposity, including birth weight, childhood body mass index (BMI), childhood obesity, adult BMI, waist circumference, visceral adiposity, and body fat percentage. A meta-analysis of genome-wide association studies for sepsis including 10,154 cases and 454,764 controls was used in this study. MR analyses were performed using inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. Instrumental variables were identified as significant single nucleotide polymorphisms at the genome-wide significance level (P < 5×10-8). The sensitivity analysis was conducted to assess the reliability of the MR estimates.
UNASSIGNED: Analysis using the MR analysis of inverse variance weighted method revealed that genetic predisposition to increased childhood BMI (OR = 1.29, P = 0.003), childhood obesity (OR = 1.07, P = 0.034), adult BMI (OR = 1.38, P < 0.001), adult waist circumference (OR = 1.01, P = 0.028), and adult visceral adiposity (OR = 1.53, P < 0.001) predicted a higher risk of sepsis. Sensitivity analysis did not identify any bias in the MR results.
UNASSIGNED: The results demonstrated that adiposity in childhood and adults had causal effects on sepsis incidence. However, more well-designed studies are still needed to validate their association.

UNASSIGNED: The concept of the gut-retinal axis proposed by previous scholars primarily focused on the relationship between intestinal microbiota and retinal diseases, and few further expanded the relationship between intestinal diseases and retinal diseases. To further substantiate the concept of the gut-retinal axis, we analyzed inflammatory bowel disease (IBD) and diabetic retinopathy (DR) using Mendelian randomization (MR), and use mediation analysis to further explore the potential substances that influence this causal relationship.
UNASSIGNED: The genome-wide association study\'s (GWAS) summary statistics for genetic variations were utilized in a Mendelian randomization (MR) investigation. GWAS data on IBD (including ulcerative colitis (UC), Crohn\'s disease (CD), and IBD) for non-Finnish Europeans (NFE) were sourced from published articles. In contrast, data on DR (including DR and diabetic maculopathy (DMP)) were obtained from FinnGen R9. The causal relationship has been investigated using inverse variance weighted (IVW), MR-Egger, and weighted median and sensitivity analysis was applied to verify the stability of the results. In addition, we applied mediation analysis to investigate whether circulating inflammatory proteins and plasma lipids played a mediating role, and calculated its effect ratio.
UNASSIGNED: The causal relationship between IBD and DR was discovered by employing the inverse variance weighted (IVW) method and weighted median method. In forward MR, UC was significantly associated with lower risk of DR (IVW: OR=0.874; 95%CI= 0.835-0.916; P value= 1.28E-08) (Weighted median: OR=0.893; 95%CI= 0.837-0.954; P value= 7.40E-04). In reverse MR, it was shown that DR (IVW: OR=0.870; 95%CI= 0.828-0.914; P value= 2.79E-08)(Weighted median: OR=0.857; 95%CI= 0.801-0.916; P value= 6.40E-06) and DMP (IVW: OR=0.900; 95%CI= 0.865-0.937; P value= 3.34E-07)(Weighted median: OR=0.882; 95%CI= 0.841-0.924; P value= 1.82E-07) could reduce the risk of CD. What\'s more, DR is associated with a lower risk of IBD according to genetic prediction (IVW: OR=0.922; 95%CI= 0.873-0.972; P value= 0.002) (Weighted median: OR=0.924; 95%CI= 0.861-0.992; P value= 0.029). Fibroblast growth factor 21 (FGF21), phosphatidylcholine (PC), and triacylglycerol (TG) serve as mediators in these relationships.
UNASSIGNED: Our research offers novel insights and sources for investigating the gut-retina axis in the genetic relationship between IBD and DR. We discover four mediators and more about the association between the intestine and retinal disorders and provide more evidence for the gut-retinal axis theory.

UNASSIGNED: Some epidemiological studies have shown that pregnant women who develop preeclampsia (PE) have elevated levels of testosterone in their maternal plasma compared to women with normal blood pressure during pregnancy, revealing a potential association between hyperandrogenism in women and PE. To explore the causal relationship between hyperandrogenism and PE, this study selected total testosterone (TT), bioavailable testosterone (BIOT), and sex hormone binding globulin (SHBG) as exposure factors and PE and chronic hypertension with superimposed PE as disease outcomes. Two-sample Mendelian randomization (MR) analyses were used to genetically dissect the causal relationships between the three exposure factors (TT, BIOT, and SHBG) and the outcomes of PE and chronic hypertension with superimposed PE.
UNASSIGNED: Two independent genome-wide association study (GWAS) databases were used for the two-sample MR analysis. In the GWAS data of female participants from the UK Biobank cohort, single nucleotide polymorphisms (SNPs) associated with TT, BIOT, and SHBG were analyzed, involving 230454, 188507, and 188908 samples, respectively. GWAS data on PE and chronic hypertension with superimposed PE from the Finnish database were used to calculate SNP, involving 3556 PE cases and 114735 controls, as well as 38 cases of chronic hypertension with superimposed PE and 114735 controls. To meet the assumptions of instrumental relevance and independence in MR analysis, SNPs associated with exposure were identified at the genome-wide level (P<5.0×10-8), and those in linkage disequilibrium interference were excluded based on clustering thresholds of R 2<0.001 and an allele distance greater than 10000 kb. Known confounding factors, including previous PE, chronic kidney disease, chronic hypertension, diabetes, systemic lupus erythematosus, or antiphospholipid syndrome, were also identified and the relevant SNPs were removed. Finally, we extracted the outcome data based on the exposure-related SNPs in the outcome GWAS, integrating exposure and outcome data, and removing palindromic sequences. Five genetic causal analysis methods, including inverse variance-weighted method (IVW), MR-Egger regression, weighted median method, simple mode method, and weighted mode method, were used to infer causal relationships. In the IVW, it was assumed that the selected SNPs satisfied the three assumptions and provided the most ideal estimate of the effect. IVW was consequently used as the primary analysis method in this study. Considering the potential heterogeneity among the instrumental variables, random-effects IVW was used for MR analysis. The results were interpreted using odds ratios (OR) and the corresponding 95% confidence interval (CI) to explain the impact of exposure factors on PE and chronic hypertension with superimposed PE. If the CI did not include 1 and had a P value less than 0.05, the difference was considered statistically significant. Sensitivity analysis was conducted to assess heterogeneity and pleiotropy. Heterogeneity was examined using Cochran\'s Q test, and pleiotropy was assessed using MR-Egger intercept analysis. Additionally, leave-one-out analysis was conducted to examine whether individual SNPs were driving the causal associations. To further validate the findings, MR analyses were performed using the same methods and outcome variables, but with different exposure factors, including waist-to-hip ratio adjusted for BMI (WHRadjBMI) and 25-hydroxyvitamin D levels, with MR results for WHRadjBMI and PE serving as the positive controls and MR results for 25-hydroxyvitamin D levels and PE as the negative controls.
UNASSIGNED: According to the criteria for selecting genetic instrumental variables, 186, 127, and 262 SNPs were identified as genetic instrumental variables significantly associated with testosterone indicators TT, BIOT, and SHBG. MR analysis did not find a causal relationship between the TT, BIOT, and SHBG levels and the risk of developing PE and chronic hypertension with superimposed PE. The IVW method predicted that genetically predicted TT (OR [95% CI]=1.018 [0.897-1.156], P=0.78), BIOT (OR [95% CI]=1.11 [0.874-1.408], P=0.392), and SHBG (OR [95% CI]=0.855 [0.659-1.109], P=0.239) were not associated with PE. Similarly, genetically predicted TT (OR [95% CI]=1.222 [0.548-2.722], P=0.624), BIOT (OR [95% CI]=1.066 [0.242-4.695], P=0.933), and SHBG (OR [95% CI]=0.529 [0.119-2.343], P=0.402) were not significantly associated with chronic hypertension with superimposed PE. Additionally, MR analysis using the MR-Egger method, weighted median method, simple mode method, and weighted mode method yielded consistent results, indicating no significant causal relationship between elevated testosterone levels and PE or chronic hypertension with superimposed PE. Heterogeneity was observed for SHBG in the analysis with PE (Cochran\'s Q test, P=0.01), and pleiotropy was detected for BIOT in the analysis with PE (MR-Egger intercept analysis, P=0.014), suggesting that the instrumental variables did not affect PE through BIOT. Other instrumental variables did not show significant heterogeneity or pleiotropy. Leave-one-out analysis confirmed that the results of the MR analysis were not driven by individual instrumental variables. Consistent with previous MR studies, the results of the control MR analyses using WHRadjBMI and 25-hydroxyvitamin D levels supported the accuracy of the MR analysis approach and the methods used in this study.
UNASSIGNED: The MR analysis results suggest that current genetic evidence does not support a causal relationship between TT, BIOT, and SHBG levels and the development of PE and chronic hypertension with superimposed PE. This study suggests that elevated testosterone may be a risk factor for PE but not a direct cause.

UNASSIGNED: In recent years, the prevalence of obesity has continued to increase as a global health concern. Numerous epidemiological studies have confirmed the long-term effects of exposure to ambient air pollutant particulate matter 2.5 (PM2.5) on obesity, but their relationship remains ambiguous.
UNASSIGNED: Utilizing large-scale publicly available genome-wide association studies (GWAS), we conducted univariate and multivariate Mendelian randomization (MR) analyses to assess the causal effect of PM2.5 exposure on obesity and its related indicators. The primary outcome given for both univariate MR (UVMR) and multivariate MR (MVMR) is the estimation utilizing the inverse variance weighted (IVW) method. The weighted median, MR-Egger, and maximum likelihood techniques were employed for UVMR, while the MVMR-Lasso method was applied for MVMR in the supplementary analyses. In addition, we conducted a series of thorough sensitivity studies to determine the accuracy of our MR findings.
UNASSIGNED: The UVMR analysis demonstrated a significant association between PM2.5 exposure and an increased risk of obesity, as indicated by the IVW model (odds ratio [OR]: 6.427; 95% confidence interval [CI]: 1.881-21.968; P FDR = 0.005). Additionally, PM2.5 concentrations were positively associated with fat distribution metrics, including visceral adipose tissue (VAT) (OR: 1.861; 95% CI: 1.244-2.776; P FDR = 0.004), particularly pancreatic fat (OR: 3.499; 95% CI: 2.092-5.855; PFDR =1.28E-05), and abdominal subcutaneous adipose tissue (ASAT) volume (OR: 1.773; 95% CI: 1.106-2.841; P FDR = 0.019). Furthermore, PM2.5 exposure correlated positively with markers of glucose and lipid metabolism, specifically triglycerides (TG) (OR: 19.959; 95% CI: 1.269-3.022; P FDR = 0.004) and glycated hemoglobin (HbA1c) (OR: 2.462; 95% CI: 1.34-4.649; P FDR = 0.007). Finally, a significant negative association was observed between PM2.5 concentrations and levels of the novel obesity-related biomarker fibroblast growth factor 21 (FGF-21) (OR: 0.148; 95% CI: 0.025-0.89; P FDR = 0.037). After adjusting for confounding factors, including external smoke exposure, physical activity, educational attainment (EA), participation in sports clubs or gym leisure activities, and Townsend deprivation index at recruitment (TDI), the MVMR analysis revealed that PM2.5 levels maintained significant associations with pancreatic fat, HbA1c, and FGF-21.
UNASSIGNED: Our MR study demonstrates conclusively that higher PM2.5 concentrations are associated with an increased risk of obesity-related indicators such as pancreatic fat content, HbA1c, and FGF-21. The potential mechanisms require additional investigation.

UNASSIGNED: Heavy metals, ubiquitous in the environment, pose a global public health concern. The correlation between these and diabetic kidney disease (DKD) remains unclear. Our objective was to explore the correlation between heavy metal exposures and the incidence of DKD.
UNASSIGNED: We analyzed data from the NHANES (2005-2020), using machine learning, and cross-sectional survey. Our study also involved a bidirectional two-sample Mendelian randomization (MR) analysis.
UNASSIGNED: Machine learning reveals correlation coefficients of -0.5059 and - 0.6510 for urinary Ba and urinary Tl with DKD, respectively. Multifactorial logistic regression implicates urinary Ba, urinary Pb, blood Cd, and blood Pb as potential associates of DKD. When adjusted for all covariates, the odds ratios and 95% confidence intervals are 0.87 (0.78, 0.98) (p = 0.023), 0.70 (0.53, 0.92) (p = 0.012), 0.53 (0.34, 0.82) (p = 0.005), and 0.76 (0.64, 0.90) (p = 0.002) in order. Furthermore, multiplicative interactions between urinary Ba and urinary Sb, urinary Cd and urinary Co, urinary Cd and urinary Pb, and blood Cd and blood Hg might be present. Among the diabetic population, the OR of urinary Tl with DKD is a mere 0.10, with a 95%CI of (0.01, 0.74), urinary Co 0.73 (0.54, 0.98) in Model 3, and urinary Pb 0.72 (0.55, 0.95) in Model 2. Restricted Cubic Splines (RCS) indicate a linear linkage between blood Cd in the general population and urinary Co, urinary Pb, and urinary Tl with DKD among diabetics. An observable trend effect is present between urinary Pb and urinary Tl with DKD. MR analysis reveals odds ratios and 95% confidence intervals of 1.16 (1.03, 1.32) (p = 0.018) and 1.17 (1.00, 1.36) (p = 0.044) for blood Cd and blood Mn, respectively.
UNASSIGNED: In the general population, urinary Ba demonstrates a nonlinear inverse association with DKD, whereas in the diabetic population, urinary Tl displays a linear inverse relationship with DKD.

UNASSIGNED: Type 1 diabetes mellitus (T1DM) is frequently associated with various infections, including mycoses; however, the direct link between T1DM and fungal infections remains under-researched. This study utilizes a Mendelian randomization (MR) approach to investigate the potential causal relationship between T1DM and mycoses.
UNASSIGNED: Genetic variants associated with T1DM were sourced from the European Bioinformatics Institute database, while those related to fungal infections such as candidiasis, pneumocystosis, and aspergillosis were obtained from the Finngen database, focusing on European populations. The primary analysis was conducted using the inverse variance weighted (IVW) method, with additional insight from Mendelian randomization Egger regression (MR-Egger). Extensive sensitivity analyses assessed the robustness, diversity, and potential horizontal pleiotropy of our findings. Multivariable Mendelian randomization (MVMR) was employed to adjust for confounders, using both MVMR-IVW and MVMR-Egger to evaluate heterogeneity and pleiotropy.
UNASSIGNED: Genetically, the odds of developing candidiasis increased by 5% in individuals with T1DM, as determined by the IVW method (OR = 1.05; 95% CI 1.02-1.07, p = 0.0001), with a Bonferroni-adjusted p-value of 0.008. Sensitivity analyses indicated no significant issues with heterogeneity or pleiotropy. Adjustments for confounders such as body mass index, glycated hemoglobin levels, and white blood cell counts further supported these findings (OR = 1.08; 95% CI:1.03-1.13, p = 0.0006). Additional adjustments for immune cell counts, including CD4 and CD8 T cells and natural killer cells, also demonstrated significant results (OR = 1.04; 95% CI: 1.02-1.06, p = 0.0002). No causal associations were found between T1DM and other fungal infections like aspergillosis or pneumocystosis.
UNASSIGNED: This MR study suggests a genetic predisposition for increased susceptibility to candidiasis in individuals with T1DM. However, no causal links were established between T1DM and other mycoses, including aspergillosis and pneumocystosis.

BACKGROUND: Observational studies have found a link between two autoimmune diseases, namely, primary sclerosing cholangitis (PSC) and systemic lupus erythematosus (SLE). However, the relationship remains unclear.
METHODS: Bidirectional Mendelian randomization (MR) analysis and statistical methods, including inverse variance weighting, weighted median, and MR-Egger tests, were performed using data from genome-wide association studies to detect a causal relationship between PSC and SLE. Sensitivity analyses were subsequently performed to assess the robustness of the results. Univariate MR methods were also investigated.
RESULTS: Results of MR analysis suggested that PSC was associated with an increased risk for SLE (odds ratio: 1.33, 95% confidence interval: 1.10-1.61, P=0.0039) However, SLE had no significant causal relationship with PSC.
CONCLUSIONS: Results of MR analysis revealed that patients with PSC were at an increased risk for SLE, which provides new insights into the relationship between these two autoimmune diseases.

BACKGROUND: Previous observational studies have shown a bidirectional association between immune-mediated inflammatory disorders (IMID) and periodontal disease. However, evidence regarding the causal role of IMID and periodontal disease is still lacking. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) study to uncover the potential genetic causal effects between IMID and periodontal disease.
METHODS: Bidirectional two-sample MR analysis was employed. Data for ten IMIDs were sourced from genome-wide association studies (GWAS) conducted by the FinnGen Consortium (range from 1023 to 36321 cases) and UK Biobank (UKB) (range from 150 to 17574 cases). Furthermore, GWAS data for periodontal disease were obtained from the FinnGen Consortium (87497 cases), UKB (458 cases), and Gene Lifestyle Interactions in Dental Endpoints (GLIDE) consortium (17,353 periodontitis cases). Subsequently, the causal relationships were analyzed by random effects inverse variance weighting, weighted median, and MR-Egger. Sensitivity analyses were performed using the Cochrane Q test, funnel plot, and Mr-Egger intercept test to ensure robustness. Eventually, replication analysis and meta-analysis across different databases were carried out.
RESULTS: Systemic lupus erythematosus (SLE) [IVW: OR = 1.079 (95% CI: 1.032-1.128) and P < 0.001], Sjogren syndrome [IVW: OR = 1.082 (95% CI: 1.012-1.157) and P = 0.022] and hypothyroidism [IVW: OR = 1.52 (95% CI: 1.13-2.04) and P = 0.005] may increase the risk of periodontal disease. In addition, periodontal disease may reduce the risk of SLE [IVW: OR = 0.8079 (95% CI: 0.6764-0.9650) and P = 0.019] and hyperthyroidism [IVW: OR = 5.59*10-9 (95% CI: 1.43*10-15-2.18*10-2) and P = 0.014]. Meta-analysis indicated a causal correlation between SLE and an increased risk of periodontal disease: [OR = 1.08 (95% CI: 1.03-1.13), P = 0.0009]. No significant evidence suggests bilateral causal relationships between other IMIDs and periodontal disease. No significant estimation of heterogeneity or pleiotropy is detected.
CONCLUSIONS: Our study has confirmed a genetic causal relationship between IMIDs and periodontal disease, thereby unveiling novel potential mechanisms underlying IMIDs and periodontal disease. This discovery is promising in fostering interdisciplinary collaboration between clinicians and stomatologists to facilitate appropriate and precise screening, prevention, and early treatment of IMIDs and periodontal disease.

Idiopathic Sudden Sensorineural Hearing Loss (ISSHL) is a sudden onset, unexplained sensorineural hearing loss. Depression is a common mental disorder and a leading cause of disability. Here, We used a two-sample Mendelian randomization approach using pooled statistics from genome-wide association studies of ISSHL (1491 cases, 196,592 controls) and depression (23,424 cases, 192,220 controls) in European populations. This study investigated the bidirectional relationship between single nucleotide polymorphisms associated with depression and ISSHL using inverse variance weighting.Additional sensitivity analyses, such as Mendelian randomization-Egger (MR-Egger), weighted median estimates, and leave-one-out analysis, were performed to assess the reliability of the findings. Significant causal association between genetic susceptibility to ISSHL and depression in a random-effects IVW approach (OR = 1.037, 95% CI = 1.004-1.072, P = 0.030). In contrast, genetic depression was not risk factors for ISSHL (OR = 1.134, 95% CI = 0.871-1.475, P = 0.350). After validation by different MR methods and the sensitivity analysis, all of the above results are consistent. The evidence we have gathered suggests a causal relationship between ISSHL and depression. The presence of the former induces or further exacerbates the latter, whereas a similar situation does not exist when the latter is an influencing factor.

Self-reported shorter/longer sleep duration, insomnia, and evening preference are associated with hyperglycaemia in observational analyses, with similar observations in small studies using accelerometer-derived sleep traits. Mendelian randomization (MR) studies support an effect of self-reported insomnia, but not others, on glycated haemoglobin (HbA1c). To explore potential effects, we used MR methods to assess effects of accelerometer-derived sleep traits (duration, mid-point least active 5-h, mid-point most active 10-h, sleep fragmentation, and efficiency) on HbA1c/glucose in European adults from the UK Biobank (UKB) (n = 73,797) and the MAGIC consortium (n = 146,806). Cross-trait linkage disequilibrium score regression was applied to determine genetic correlations across accelerometer-derived, self-reported sleep traits, and HbA1c/glucose. We found no causal effect of any accelerometer-derived sleep trait on HbA1c or glucose. Similar MR results for self-reported sleep traits in the UKB sub-sample with accelerometer-derived measures suggested our results were not explained by selection bias. Phenotypic and genetic correlation analyses suggested complex relationships between self-reported and accelerometer-derived traits indicating that they may reflect different types of exposure. These findings suggested accelerometer-derived sleep traits do not affect HbA1c. Accelerometer-derived measures of sleep duration and quality might not simply be \'objective\' measures of self-reported sleep duration and insomnia, but rather captured different sleep characteristics.