Search

BACKGROUND: We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies. METHODS: Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836). RESULTS: Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10-07) on AF risk. CONCLUSIONS: Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention. [ABSTRACT FROM AUTHOR]

BACKGROUND: Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease. METHODS: The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses. P -gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D. RESULTS: The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile Q5 versus Q1, 1.196 [95% CI, 1.109–1.289] and 1.226 [95% CI, 1.160–1.296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (P -gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26–0.64) and CHD (0.48 [95% CI, 0.29–0.67]) with an absolute effect significantly larger compared with the effect of glycine (−0.06 [95% CI, −0.1 to −0.03] and −0.08 [95% CI, −0.11 to −0.05], respectively) or tBCAAs (0.22 [95% CI, 0.09–0.34] and 0.12 [95% CI, 0.01–0.24], respectively). CONCLUSIONS: The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hypertension, a complex condition, is primarily defined based on blood pressure readings without involving its pathophysiological mechanisms. We aimed to identify biomarkers through a proteomic approach, thereby enhancing the future definition of hypertension with insights into its molecular mechanisms. METHODS: The discovery analysis included 1560 participants, aged 55 to 74 years at baseline, from the KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 cohort study, with 3332 observations over a median of 13.4 years of follow-up. Generalized estimating equations were used to estimate the associations of 233 plasma proteins with hypertension and systolic blood pressure (SBP). For validation, proteins significantly associated with hypertension or SBP in the discovery analysis were validated in the KORA Age1/Age2 cohort study (1024 participants, 1810 observations). A 2-sample Mendelian randomization analysis was conducted to infer causalities of validated proteins with SBP. RESULTS: Discovery analysis identified 49 proteins associated with hypertension and 99 associated with SBP. Validation in the KORA Age1/Age2 study replicated 7 proteins associated with hypertension and 23 associated with SBP. Three proteins, NT-proBNP (N-terminal pro-B-type natriuretic peptide), KIM1 (kidney injury molecule 1), and OPG (osteoprotegerin), consistently showed positive associations with both outcomes. Five proteins demonstrated potential causal associations with SBP in Mendelian randomization analysis, including NT-proBNP and OPG. CONCLUSIONS: We identified and validated 7 hypertension-associated and 23 SBP-associated proteins across 2 cohort studies. KIM1, NT-proBNP, and OPG demonstrated robust associations, and OPG was identified for the first time as associated with blood pressure. For NT-proBNP (protective) and OPG, causal associations with SBP were suggested. [ABSTRACT FROM AUTHOR]

BACKGROUND: Genetic and experimental studies support a causal involvement of IL-6 (interleukin-6) signaling in atheroprogression. Although trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects. METHODS: Leveraging data from 522 681 individuals, we constructed a genetic instrument of 26 variants in the gene encoding the IL-6R (IL-6 receptor) that proxied for pharmacological IL-6R inhibition. Using Mendelian randomization, we assessed its effects on 3281 plasma proteins quantified with an aptamer-based assay in the INTERVAL cohort (n=3301). Using mediation Mendelian randomization, we explored proteomic mediators of the effects of genetically proxied IL-6 signaling on coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease. For significant mediators, we tested associations of their circulating levels with incident cardiovascular events in a population-based study (n=1704) and explored the histological, transcriptomic, and cellular phenotypes correlated with their expression levels in samples from human atherosclerotic lesions. RESULTS: We found significant effects of genetically proxied IL-6 signaling on 70 circulating proteins involved in cytokine production/regulation and immune cell recruitment/differentiation, which correlated with the proteomic effects of pharmacological IL-6R inhibition in a clinical trial. Among the 70 significant proteins, genetically proxied circulating levels of CXCL10 (C-X-C motif chemokine ligand 10) were associated with risk of coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease, with up to 67% of the effects of genetically downregulated IL-6 signaling on these end points mediated by decreases in CXCL10. Higher midlife circulating CXCL10 levels were associated with a larger number of cardiovascular events over 20 years, whereas higher CXCL10 expression in human atherosclerotic lesions correlated with a larger lipid core and a transcriptomic profile reflecting immune cell infiltration, adaptive immune system activation, and cytokine signaling. CONCLUSIONS: Integrating multiomics data, we found a proteomic signature of IL-6 signaling activation and mediators of its effects on cardiovascular disease. Our analyses suggest the interferon-γ–inducible chemokine CXCL10 to be a potentially causal mediator for atherosclerosis in 3 vascular compartments and, as such, could serve as a promising drug target for atheroprotection. [ABSTRACT FROM AUTHOR]

BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter (LAD) in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code--based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code--based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors. [ABSTRACT FROM AUTHOR]

Purpose: It has been hypothesized that the corticospinal tract (CST) is involved in the neural origins underlying muscular deficits after an ankle sprain. Microstructural differences in the CST have been reported in patients with and without a history of ankle sprain, but the causal links between the CST and the injuries have not been verified. This study aimed to explore whether genetically predisposed ankle sprains would impair the integrity and organization of CST neurites, manifesting as reduced fractional anisotropy (FA) and increased orientation dispersion index (ODI). Methods: Single-nucleotide polymorphisms (SNP) associated with ankle sprains were identified from genome-wide association studies (GWAS) in FinnGen based on hospital discharge records (7223 cases and 245,598 controls). Outcome statistics for CST microstructures were collected from the GWAS from diffusion-weighted-imaging outcomes in the UK Biobank (33,224 participants). Random-effect, inverse-variance weighted Mendelian randomization was used as the primary method. Results: Eighteen SNP were selected as forming possible causal links between ankle sprains and CST structure; F value ranged from 755 to 1026. Ankle sprains were associated with a reduction in the FA of the right CST (β = −0.033, P = 0.0439), whereas no significant effects were observed on the left side (β = −0.029, 0.004; P = 0.0748). Ankle sprains significantly increased the ODI of the left CST (β = 0.053, P = 0.0036) and the right CST (β = 0.038, P = 0.0259). No significant pleiotropy or heterogeneity was observed in the analyses. Conclusions: A genetic predisposition to ankle sprains can lead to maladaptive neuroplasticity of the CST, manifesting as abnormally organized neurites. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia is a leading cause of maternal morbidity, and dyslipidemia has been associated with preeclampsia in observational studies. We use Mendelian randomization analyses to estimate the association between lipid levels, their pharmacological targets, and the risk of preeclampsia in 4 ancestry groups. Methods: We extracted uncorrelated (R2 <0.001) single-nucleotide polymorphisms strongly associated (P <5×10-8) with LDL-C (low-density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), and triglycerides from genome-wide association studies of European, admixed African, Latino, and East Asian ancestry participants. Genetic associations with risk of preeclampsia were extracted from studies of the same ancestry groups. Inverse-variance weighted analyses were performed separately for each ancestry group before they were meta-analyzed. Sensitivity analyses were conducted to evaluate bias due to genetic pleiotropy, demography, and indirect genetic effects. Results: The meta-analysis across 4 ancestry groups included 1.5 million subjects with lipid measurements, 7425 subjects with preeclampsia, and 239 290 without preeclampsia. Increasing HDL-C was associated with reduced risk of preeclampsia (odds ratio, 0.84 [95% CI, 0.74–0.94]; P =0.004; per SD increase in HDL-C), which was consistent across sensitivity analyses. We also observed cholesteryl ester transfer protein inhibition—a drug target that increases HDL-C—may have a protective effect. We observed no consistent effect of LDL-C or triglycerides on the risk of preeclampsia. Conclusions: We observed a protective effect of elevated HDL-C on risk of preeclampsia. Our findings align with the lack of effect in trials of LDL-C modifying drugs but suggest that HDL-C may be a new target for screening and intervention. [ABSTRACT FROM AUTHOR]

Background and Purpose: The aim of this study was to investigate the association between daytime napping frequency and the incidence of essential hypertension or stroke as well as to validate causality in this relationship via Mendelian randomization (MR). Methods: We conducted Cox regression analysis on 358 451 participants free of hypertension or stroke from UK Biobank. To validate the results of the observational analysis, we conducted a 2-sample MR for daytime napping frequency (123 single-nucleotide polymorphisms) with essential hypertension in FinnGen Biobank, stroke, and ischemic stroke in MEGASTROKE consortium and performed a corresponding 1-sample MR on the UK Biobank data. Results: Compared with never napping, usually napping was associated with a higher risk of essential hypertension (hazard ratio, 1.12 [95% CI, 1.08–1.17]), stroke (hazard ratio, 1.24 [95% CI, 1.10–1.39], and ischemic stroke (hazard ratio, 1.20 [95% CI, 1.05–1.36]) in our prospective observational analysis. Both the 1-sample and 2-sample MR results indicated that increased daytime napping frequency was likely to be a potential causal risk factor for essential hypertension in FinnGEN (odds ratio, 1.43 [95% CI, 1.06–1.92]) and UK Biobank (odds ratio, 1.40 [95% CI, 1.28–1.58]). The 2-sample MR results supported the potential causal effect of nap frequency on ischemic stroke in MEGASTROKE (odds ratio, 1.29 [95% CI, 1.04–1.62]). Conclusions: Prospective observational and MR analyses provided evidence that increased daytime nap frequency may represent a potential causal risk factor for essential hypertension. The potential causal association of increased nap frequency with ischemic stroke was supported by 2-sample MR and prospective observational results. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated a correlation between salt intake (SI) and various diseases. However, it remains uncertain whether the relationship between SI (including salt added to food and sodium levels in urine) and benign osteoarthritis is causal. To investigate this, we conducted a 2-sample Mendelian randomization (MR) analysis to estimate the causal impact of SI on osteoarthritis (OA). A genome-wide association study of salt added to food and sodium in urine was used as the exposure, while hip osteoarthritis, knee osteoarthritis, and rheumatoid arthritis were defined as the outcomes. Inverse variance weighting (IVW) was used to calculate causal estimates, and sensitivity analyses were performed using methods including weighted mode, weighted median, MR-Egger, and Bayesian weighted MR. All statistical analyses were conducted using R software. Our results, primarily based on the IVW method, support the existence of a causal relationship between salt added to food and knee osteoarthritis (KOA). Specifically, salt added to food was associated with a decreased risk of KOA (OR = 1.248, P = .024, 95% CI: 1.030-1.512). This study is the first MR investigation exploring the causal relationship between salt added to food and KOA, potentially providing new insights and a theoretical basis for the prevention and treatment of KOA in the future., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cysteine cathepsins are a family of lysosomal proteases that are often overexpressed in several human malignancies and haves been linked to cellular genomic alterations, disturbances in genomic stability, and the onset and spread of cancer. Recent studies have shown alterations in cysteine cathepsins in malignant ovarian tumors. However, it remains unclear whether there is a causal relationship between ovarian cancer, and its subtypes, and the cathepsin family. This study utilized two-sample Mendelian randomization (MR) analysis to examine this potential causal relationship. Genetic instruments derived from publicly available genetic summary data were used for the analyses. For MR analysis, the inverse-variance weighted method, weighted median method, and MR-Egger regression were employed. Multivariate MR analysis was performed concurrently. Univariate MR analysis indicated a strong correlation between decreased incidence of low-grade serous ovarian cancer and elevated levels of cathepsin L2 (odds ratio = 0.803, 95% confidence interval = 0.685-0.942, P = .007), whereas clear cell ovarian cancer showed a strong correlation with elevated levels of cathepsin H (odds ratio = 1.149, 95% confidence interval = 1.036-1.274, P = .008). Multivariate analysis, adjusted for 9 different cathepsins as covariates, confirmed the genetic relationships between cathepsin L2 and low-grade serous ovarian cancer and between cathepsin H and clear cell ovarian cancer. Our results suggest a causal relationship between cathepsins and ovarian malignancy and its subtypes. Cathepsin L2 has a protective effect on low-grade serous ovarian cancer, whereas cathepsin H is an adverse risk factor for clear cell ovarian cancer., Competing Interests: The authors have no funding and conflicts of interest. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request, (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Investigating the causal relationship between circulating immune cells, blood metabolites, and severe COVID-19 and revealing the role of blood metabolite-mediated circulating immune cells in disease onset and progression. Genetic variation data of 731 circulating immune cells, 1400 blood metabolites, and severe COVID-19 from genome-wide association study open-access database (https://gwas.mrcieu.ac.uk) were used as instrumental variables for bidirectional and two-step Mendelian randomization analysis. The study identified 11 circulating immune cells with unidirectional causality to severe COVID-19. Two-step Mendelian randomization analysis showed 10 blood metabolites were causally associated with severe COVID-19, and blood Myristate and Citrulline to phosphate ratio mediated the association of circulating effector memory double negative % DN and CD8dim natural killer T cell % T cells, respectively, with severe COVID-19 (Myristate mediated effect ratio was 10.20%, P = .011; Citrulline to phosphate ratio mediated effect ratio was -9.21%, P = .017). This study provides genetic evidence assessing the causal relationship between circulating immune cells, blood metabolites, and severe COVID-19, elucidates the role of blood metabolite-mediated circulating immune cells in severe COVID-19 development, and offers new insights into severe COVID-19 etiology and related preventive and targeted therapeutic strategies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

In observational studies, there has been an association found between spleen volume and Crohn disease. We conducted a two-way, two-sample Mendelian randomization analysis to determine whether these associations have a causal relationship. Single nucleotide polymorphisms (P < 5 × 10-8) were used as instrumental variables for spleen volume and Crohn disease. Estimates of the genetic associations between spleen volume and Crohn disease were obtained from the Integrative Epidemiology Unit, European Bioinformatics Institute, UK Biobank, and FinnGen databases. Analysis was performed using MR-Egger regression, weighted median estimator, inverse variance weighted, simple model, and weighted model. Genetically predicted spleen volume was found to be associated with Crohn disease. In the IEU database, the odds ratios (ORs) for Crohn disease caused by spleen volume were 1.237 (95% CI, 1.056-1.417, P = .021), and the ORs for spleen volume caused by Crohn disease were 1.015 (95% CI, 0.985-1.044; P = .049). In the EBI database, the ORs for Crohn disease caused by spleen volume were 1.292 (95% CI, 1.120-1.463, P = .003), and the ORs for spleen volume caused by Crohn disease were 1.026 (95% CI, 1.005-1.046; P = .013). Results from the UKB and FinnGen databases showed no causal relationship between the two. The summary results showed that Crohn disease caused an increase in spleen volume, with ORs of 1.009 (95% CI, 1.000-1.018; P = .047). This study provides evidence for a mutual causal relationship between spleen volume and an increased risk of Crohn disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

IgA nephropathy is the most common primary glomerular disease worldwide, with inflammation and autoimmune response mechanisms permeating the entire disease development process. The advancement of genome-wide association studies has enabled deeper understanding of the disease mechanisms and genetic susceptibility. Therefore, this study aims to explore the causal relationship between 731 immune cell types and the disease through Mendelian randomization (MR) analysis. This 2-sample MR study investigated bidirectional causal relationships using summary statistics for immune cells characteristics from the Genome-Wide Association Study (GWAS) catalog and IgA nephropathy from the FinnGen dataset. The study primarily utilized the Inverse Variance Weighted method for its main outcome. Additionally, the robustness of the results is further enhanced by analyses of heterogeneity, pleiotropy, and multiple sensitivity tests. After adjusting for false discovery rate (FDR), the study results revealed a bidirectional causal relationship between CD8 on terminally differentiated CD8+ T cells (OR = 0.77, 95% CI = 0.67-0.88, P = .0001) and CD4 on CD28+ CD4+ T cells (OR = 0.75, 95% CI = 0.64-0.87, P = .0001) with the risk of IgA nephropathy. CD64 on CD14+ CD16+ monocytes (OR = 0.66, 95% CI = 0.51-0.85, P = .0013) is considered a protective factor, while the percentages of CD8+ and CD8dim T cells (1.38, 95% CI = 1.17-1.63, P = .0002) in leukocytes are viewed as risk factors. This study employed genetic variation as an instrumental variable to explore the genetic association between immune cells and IgA nephropathy, aiming to offer new insights into early prevention and personalized treatment of the disease., Competing Interests: All authors declare no business or financial relationships that could be perceived as a potential conflict of interest during the study., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To examine the possible causative association between Crohn disease (CD) and the T-cell surface glycoprotein CD5 and to ascertain whether sphingomyelin (SM) functions as a mediator. We conducted a two-step Mendelian randomization (MR) study to further explore the pathogenesis of Crohn and its related targets. MR study was performed on CD5 and CD using summary-level data from a genome-wide association study. Additionally, by employing a two-step MR study method, we determined that SM might mediate the causal effect of CD5 on CD. There was a favorable correlation between the surface glycoprotein CD5 on T cells and vulnerability to CD, and SM mediated the causal effect of CD5 on CD (the mediating effect accounts for 9.2%). Our study revealed that CD5 and CD are causally related, with SM mediating a small fraction of the impact (approximately 9.2%). The mediating function of SM in the link between CD5 and CD is anticipated to be realized through the regulation of immune cell transportation, apoptosis of intestinal barrier cells, and maintenance of the intestinal microenvironment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Childhood neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), attention-deficit hyperactivity disorder, and Tourette syndrome, are a predominant cause of health-related disabilities in children and adolescents. Nevertheless, disease biomarkers are still limited. The aim of this study was to evaluate the potential, causal relationship between mitochondrial DNA copy number (mtDNA-CN), metabolic disorders, and childhood NDDs using the two-sample Mendelian randomization (MR) method. Genetic associations with mtDNA-CN, disorders of lipoprotein metabolism, and disorders of iron metabolism were selected as exposures, and genome-wide association data from ASD, attention-deficit hyperactivity disorder, and Tourette syndrome were utilized as outcomes. Results of the study suggested that a high degree of disordered lipoprotein metabolism related increases in ASD risk result from a decrease in mtDNA-CN (disordered lipoprotein metabolism-mtDNA: inverse variance weighting β: -0.03, 95% confidence interval: -0.05 to -0.02, P = 2.08 × 10-5; mtDNA-CN-ASD: inverse variance weighting odds ratio: 0.83, 95% confidence interval: 0.69-0.99, P = .034). The research findings implied that mtDNA-CN can mediate disorders of lipoprotein metabolism, potentially influencing the development of ASD. The potential impact of the results of this study for the prevention and treatment of childhood NDDs warrants validation in robust randomized clinical trials., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Previous researches have revealed some links between thyroid function and sleep characteristics, however it remains unclear which one causes the other. The purpose of this study was to investigate the potential causal relationship between hyperthyroidism, hypothyroidism, and sleep characteristics., Methods: We utilized aggregated data from published genome-wide association studies (GWAS) to select genetic instruments for sleep variables. The 5 sleep-related traits (chronotype, short sleep duration, long sleep duration, daytime sleepiness, and insomnia) were associated with distinct genetic variants chosen as instrumental factors. Employing MR Egger's analysis of Mendelian randomization (MR), weighted median, weighted mode, and inverse variance weighted (IVW) methods to assess the 5 sleep traits in relation to hyperthyroidism and hypothyroidism, we subsequently conducted inverse MR analysis to examine the causal relationship between thyroid function and the 5 sleep characteristics., Results: The IVW technique did not reveal a causal association between chronotype, short sleep duration, long sleep duration, daytime sleepiness, or insomnia and the risk of abnormal thyroid function in the study investigating the influence of sleep characteristics on this risk. The outcomes of the IVW approach were consistent with the remaining 3 methods. The IVW, weighted median, MR Egger, and weighted mode methods in the reverse magnetic resonance imaging investigation did not yield evidence of a causative association between the risk of time type, long sleep duration, and insomnia and abnormal thyroid function. In contrast, the weighted median and weighted mode methods showed a possible causal relationship between hypothyroidism and short sleep duration and daytime sleepiness. Sensitivity analyses showed that the results were robust and no pleiotropy or heterogeneity was detected., Conclusion: More precisely, our analysis did not uncover any indication of a reciprocal causal link between thyroid function and genetically predicted sleep characteristics., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Previous research has demonstrated a close connection between the development of bone neoplasms and variations in the abundance of specific gut microbiota. It remains unclear, however, how the gut microbiota and bone neoplasms are causally related. Hence, in our study, we aim to clarify this relationship between gut microbiota and 2 neoplasms, malignant neoplasm of bone and articular cartilage (MNBAC) and benign neoplasm of bone and articular cartilage (BNBAC), by employing a two-sample Mendelian randomization (MR) approach. In this study, single nucleotide polymorphisms (SNPs) from genome-wide association studies-pooled data related to bone neoplasms and gut microbiota abundance were evaluated. The inverse variance weighted was employed as the major method for assessing the aforementioned causal relationship. Furthermore, the horizontal multiplicity was evaluated utilizing the Mendelian randomization pleiotropy residual sum and outlier and the MR-Egger intercept test. Finally, inverse MR analysis was performed to assess reverse causality. Inverse variance weighted results indicate a potential genetic relationship between 4 gut microbiota and MNBAC, and 3 gut microbiota and BNBAC. On the one hand, Eubacterium eligens group (OR = 0.16, 95% CI = 0.04-0.67, P = .01), Odoribacter (OR = 0.23, 95% CI = 0.06-0.84, P = .03), Slackia (OR = 0.35, 95% CI = 0.13-0.93, P = .04), and Tyzzerella3 (OR = 0.44, 95% CI = 0.24-0.82, P = .01) exhibited a protective effect against MNBAC. On the other hand, of the 3 gut microbes identified as potentially causally related to BNBAC, Oscillibacter (OR = 0.79, 95% CI = 0.63-0.98, P = .03) and Ruminococcus torques group (OR = 0.62, 95% CI = 0.39-0.98, P = .04) were regarded as protective strains of B, while Eubacterium ruminantium group (OR = 1.24, 95% CI = 1.04-1.47, P = .02) was considered to be a risk factor for increasing the incidence of BNBAC. Additionally, the bone neoplasms were not found to have a reverse causal relationship with the above 7 gut microbiota taxa. Four gut microbiota showed causal effects on MNBAC, and 3 gut microbiota demonstrated causality in BNBAC, providing insights into the design of future interventions to reduce the burden of neoplasms., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Employing a two-sample Mendelian randomization (MR) analysis, we aimed to investigate the potential causal effect of Parkinson disease (PD) on osteoporosis. We conducted an in-depth MR analysis by leveraging extensive genome-wide association study datasets from the International Parkinson Disease Genomics Consortium and the Genetic Factors for Osteoporosis Consortium. We meticulously selected instrumental variables based on strict criteria, including significance thresholds, linkage disequilibrium, and the exclusion of confounding single-nucleotide polymorphisms. Our investigation utilized diverse MR methods, including inverse variance weighted, MR Egger regression, weighted median, and MR-PRESSO, to robustly evaluate the causal relationship. Our comprehensive analysis revealed noteworthy associations between PD and distinct measures of bone mineral density (BMD) (forearm BMD, femoral neck BMD, lumbar spine BMD). Specifically, the inverse variance weighted method underscored potential significant relationships between PD and forearm BMD (P = .037; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00-1.09), femoral neck BMD (P = .034; OR, 1.02; 95% CI, 1.00-1.05), and lumbar spine BMD (P = .043; OR, 1.03; 95% CI, 1.00-1.06). The consistency of results across various methods and sensitivity analyses indicated both robustness and minimal pleiotropy concerns. Through a two-sample MR approach, this study establishes a plausible causal relationship between PD and decreased BMD. The outcomes underscore the urgency of targeted interventions to mitigate bone loss and manage osteoporosis in individuals with PD., Competing Interests: The authors have no conflicts of interests to disclose, (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Gout is an inflammatory arthritis resulting from urate crystal deposition, now recognized as part of metabolic syndrome. Hyperuricemia, a hallmark of gout, is associated with various health complications, including liver cancer. Observational studies indicate a link between gout and increased cancer incidence. However, the causal relationship between gout and hepatocellular carcinoma remains uncertain. This study utilizes Mendelian randomization (MR) to explore this connection, minimizing confounding factors commonly present in observational studies. Genome-wide association study data for gout and liver cancer were sourced from the UK Biobank. We selected single nucleotide polymorphisms that are strongly associated with gout and liver cancer as instrumental variables for the analysis. We conducted 2-sample MR analysis using multiple MR methods (MR-Egger, weighted median, inverse variance weighting, and weighted mode) to evaluate causality. Co-localization and transcriptomic analyses were employed to identify target genes and assess their expression in hepatocellular carcinoma tissues. The 2-sample MR analysis indicated a significant causal relationship between gout and heightened liver cancer risk (P&#95;IVW = .014). Co-localization analysis identified phosphatidylethanolamine N-methyltransferase (PEMT) as a crucial gene associated with gout (pH4 = 0.990). Transcriptomic data showed that PEMT expression was significantly higher in normal liver tissues compared to malignant samples (P < .001), and higher PEMT levels correlated with improved survival outcomes (P = .045). Immunohistochemical analysis revealed lower PEMT expression in hepatocellular carcinoma from patients with concurrent gout compared to those without (P < .05). The results indicate that gout increases the risk of hepatocellular carcinoma, with PEMT potentially playing a key role. Although this study focused on European populations, indicating a need for further research in diverse groups, the results emphasize the potential for liver cancer screening in newly diagnosed gout patients. Understanding the relationship between these conditions may inform future clinical practices and cancer prevention strategies., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

This study aims to rigorously explore the potential causal relationships among gut microbiota (GM), immune cells, and melanoma skin cancer among participants from Europe, where this disease exhibits significant prevalence and profound societal impact. Using the genome-wide association analysis database, a double-sample Mendelian randomization (MR) analysis was drawn upon to investigate GM, immune cells, and melanoma skin cancer. The inverse variance weighted approach was applied to estimate the causal connections among these variables. A two-step MR analysis was employed to quantitatively gauge the impact of immune cells mediated GM on melanoma skin cancer. To address potential sources of bias, such as pleiotropy and heterogeneity, multiple analytical techniques were integrated. The MR analysis pinpointed 6 GM taxa related to either an augmented or declined risk of late-stage melanoma skin cancer. In the same vein, 32 immune cell phenotypes were noticed as correlates with modified risk of melanoma skin cancer. Our study also implies that the probable association between GM and melanoma could be facilitated by 5 immune cell phenotypes. The findings of our study underline certain GM taxa and immune cells as potential influencers on the onset and development of melanoma skin cancer. Importantly, our results spotlight 5 immune cell phenotypes as potential agents mediating this association., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Previous evidence suggests that dietary intake can affect liver diseases; However, the causal relationship between dietary intake and liver diseases remains unclear. To investigate this, we conducted a bidirectional Mendelian randomization (MR) analysis to comprehensively assess the potential causal relationship between dietary intake and liver diseases. Two-sample bidirectional MR was performed based on genome-wide association studies summary data from the UK Biobank and FinnGen database. The primary analysis method for evaluating causal relationships was inverse-variance weighted. Supplementary analyses included MR-Egger and weighted median methods. Subsequently, sensitivity analyses were performed using Cochran Q test, MR-Egger intercept test, MR-PRESSO, RadialMR, and leave-one-out analysis to assess heterogeneity and horizontal pleiotropy. MR evidence indicated that genetically predicted poultry intake (adjusted odds ratio [OR] = 0.04, 95% confidence interval [CI] = 0.00-0.43, P = .007) and salad/raw vegetable intake (adjusted OR = 0.18, 95% CI = 0.04-0.83, P = .028) were directly associated with a reduced risk of cirrhosis. Conversely, there is no causal association between dietary intake and nonalcoholic fatty liver disease, alcoholic liver disease, or hepatocellular carcinoma. This study provides evidence supporting the impact of dietary intake on liver disease. Increased intake of poultry and salad/raw vegetables is associated with a reduced risk of cirrhosis. These findings can inform preventive and therapeutic strategies for cirrhosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Deep vein thrombosis (DVT) is a serious condition characterized by blood clots in deep veins, posing a significant public health burden. Muscle strength has been implicated as a potential risk factor for DVT due to its influence on venous return. This study aims to investigate the causal association between muscle strength and DVT using a Mendelian randomization (MR) approach, leveraging genetic variants as instrumental variables (IVs). We conducted a 2-sample MR analysis using genome-wide association study (GWAS) data for hand-grip strength and DVT. IVs were selected based on their significant associations with muscle strength and DVT, as well as their linkage disequilibrium patterns. We employed statistical methods including inverse-variance weighting (IVW), MR-Egger, and weighted median to address pleiotropy bias. Sensitivity analyses were conducted to evaluate the robustness of the results. A total of 21 and 14 independent IVs were identified for hand grip strength (EWGSOP) and hand grip strength (FNIH), respectively. IVW analysis revealed a consistent causal and negative association between both definitions of hand grip strength and DVT (EWGSOP: OR = 0.702, 95% CI: 0.511-0.964, P = .029; FNIH: OR = 0.715, 95% CI: 0.570-0.898, P = .004). No directional pleiotropy was detected in MR-Egger and MR-PRESSO analyses for either definition (EWGSOP: MR-Egger Intercept P = .516; MR-PRESSO global test P = .162; FNIH: MR-Egger Intercept P = .569; MR-PRESSO global test P = .371).Sensitivity analyses demonstrated the stability of the causal effect estimates, with little influence from individual IVs. The MR analysis provided evidence of a causal association between muscle strength and DVT risk, suggesting that increasing muscle strength may have a protective effect. These findings have implications for preventive strategies and the promotion of resistance exercises and muscle-strengthening activities. Further research and validation of these results could inform clinical guidelines and interventions for DVT prevention., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

This study aims to investigate the potential causal relationship between cerebrospinal fluid (CSF) metabolites and Guillain-Barré syndrome (GBS) using a bidirectional two-sample Mendelian randomization (MR) approach. Publicly available summary data from genome-wide association studies (GWAS) were utilized for comprehensive analysis. The CSF metabolite GWAS summary data were extracted from a GWAS conducted by Panyard et al encompassing 338 CSF metabolites in European participants (n = 291). GWAS summary statistics for GBS were obtained from the FinnGen consortium (n = 215,931) comprising European populations. The primary method for MR analysis was the inverse variance weighted method. Various sensitivity analyses were conducted to assess the heterogeneity and pleiotropy of the findings. In the forward MR analysis, we identified a causal relationship between 15 CSF metabolites, including ribitol levels (odds ratio = 3.833, 95% confidence interval: 1.949-7.540, P = 9.87E-05), and the risk of developing GBS. In the reverse MR analysis, we found a causal relationship between GBS and 21 CSF metabolites, including gamma-glutamylphenylalanine levels (odds ratio = 0.934, 95% confidence interval: 0.904-0.966, P = 7.10E-05). No evidence of heterogeneity or horizontal pleiotropy was found in the MR analysis. Our findings suggest that the identified CSF metabolites and metabolic pathways can serve as valuable biomarkers for clinical screening and prevention of GBS. They may also be considered as candidate molecules for future research into the underlying mechanisms and for selecting drug targets., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

This study aims to employ the Mendelian randomization (MR) approach to investigate the relationship between leukocyte telomere length (TL) and 2 prevalent forms of cardiomyopathies. Using R software (4.3.1) for MR study, independent genetic variants associated with leukocyte TL were extracted from the Integrative Epidemiology Unit database, while cardiomyopathies data were pooled from FinnGen and European Bioinformatics Institute databases. Analytical methodologies included inverse-variance weighting, MR-Egger regression, and weighted median methods. Further analyses involved MR-Egger intercept and MR-PRESSO for handling horizontal pleiotropy and Cochran Q test for study heterogeneity. Our forward Mendelian randomization study indicates a positive correlation between longer leukocyte TL and the risk of 2 forms of cardiomyopathies: the longer the leukocyte telomere, the higher is the risk of cardiomyopathies. Specifically, for hypertrophic obstructive cardiomyopathy the OR is 2.23 (95% CI: 1.19-4.14, P = .01), for hypertrophic cardiomyopathy the OR is 1.80 (95% CI: 1.14-2.85, P = .01), and for dilated cardiomyopathy the OR is 1.32 (95% CI: 1.01-1.71, P = .04). In contrast, our reverse Mendelian randomization showed that cardiomyopathies were not directly associated with TL, and the inverse-variance-weighted test was not statistically significant for any of the 3 (P > .05). The reliability tests for the forward Mendelian randomization, including both MR-Egger intercept and MR-PRESSO tests, show no evidence of horizontal pleiotropy, and Cochran Q test indicates no heterogeneity. The "leave-one-out" sensitivity analysis revealed no outlier genes. The reliability tests for the reverse Mendelian randomization, including both MR-Egger intercept and MR-PRESSO tests, also indicate no genetic pleiotropy. Despite the heterogeneity shown in our study between hypertrophic cardiomyopathy and leukocyte TL, the sensitivity analysis did not identify any anomalies. Our Mendelian randomization study suggests that longer leukocyte TL is associated with an increased risk of hypertrophic obstructive cardiomyopathy, hypertrophic cardiomyopathy, and dilated cardiomyopathy. However, the onset of these 2 kinds of disease does not directly lead to changes in leukocyte TL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

An increasing body of evidence suggests that diabetes mellitus (DM) plays a role in sensorineural hearing loss (SNHL). However, the specific causal relationship between DM and SNHL remains partially uncertain. This study aimed to investigate the causal relationship between DM and the risk of SNHL using a Mendelian randomization (MR) study. Single nucleotide polymorphisms closely related to DM were selected as instrumental variables using open genome-wide association study datasets. Three methods based on inverse variance weighted were utilized to investigate the causal relationship between DM and SNHL. Subsequently, multivariable MR (MVMR) was executed to adjust for confounding genetic associations. In addition, a range of sensitivity analyses were performed to assess the stability and reliability of the MR results. The inverse variance weighted analysis indicated a potential genetic causality between DM and SNHL (odds ratio [OR]: 2.179; 95% confidence interval [CI]: 1.123-4.231; P = .021). The sensitivity analyses showed that the included single nucleotide polymorphisms had no heterogeneity, horizontal pleiotropy, and outliers (P > .05). Moreover, the leave-one-out method further verified the robustness of the MR analysis results. Finally, the results of the MVMR study predicted that there was a genetic causal relationship between type 1 DM and SNHL (OR: 1.032; 95%CI: 1.018-1.047; P = 5.45 × 10-6), while there was no causality between type 2 DM and SNHL (OR: 1.000; 95%CI: 0.958-1.036; P = .853). Our study suggested that DM and type 1 DM may be genetically responsible for SNHL. Although our study did not detect a genetic causal relationship between type 2 DM and SNHL, this does not rule out a relationship between them at other mechanistic levels. Further studies are required to confirm the findings and look into the physiological and pathological mechanism underlying these relationships., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Genome-wide association studies (GWAS) identified over 100 susceptibility loci and candidate causal genes for diverticular disease (DD) at the transcriptional level. However, effective therapeutics or preventions based on underlying disease mechanisms remain to be elucidated. In this study, we explored potential causal genes for DD at the protein level. We used 2 GWAS summary statistics of DD; 1 was obtained from the United Kingdom Biobank (UKBB) with 31,917 cases and 419,135 controls, and the other from the FinnGen consortium with 30,649 cases and 301,931 controls. For the primary analysis, we employed proteome-wide Mendelian randomization (MR) studies using 738 cis-acting protein quantitative trait loci (pQTLs) for 735 plasma proteins from the 5 published studies. For external validation, we conducted 2-sample MR analyses using plasma pQTLs of the screened proteins from another study by deCODE genetics. Moreover, we performed a series of sensitivity analyses including reverse MR and Bayesian colocalization tests. The primary MR identified 4 plasma proteins that were associated with DD risk including CCN3/NOV (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97-0.99; P = 1.2 × 10-11 for UKBB. OR, 0.73; 95% CI, 0.66-0.81; P = 7.2 × 10-10 for FinnGen). The validation MR well replicated the primary result of CCN3/NOV (OR, 0.95; 95% CI, 0.93-0.96; P = 1.9 × 10-11 for UKBB. OR, 0.43; 95% CI, 0.33-0.56; P = 7.0 × 10-10 for FinnGen). Sensitivity analyses supported the causal association. We prioritized plasma CCN3/NOV protein as a protective factor for DD for follow-up functional studies to elucidate the disease mechanisms and therapeutics., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Numerous studies have demonstrated a correlation between alterations in gut microbiota (GM) and levels of body metabolites in ovarian cancer (OC). However, the specific causal relationships underlying these associations remain unclear. This study utilized summary statistics of GM from the MiBioGen consortium, along with an unprecedented dataset comprising 1091 blood metabolites and 309 metabolite ratios from the UK Biobank, in conjunction with OC data from the FinnGen Consortium R9 release. We conducted bidirectional Mendelian randomization (MR) analyses to investigate the causal relationships between GM and OC. Additionally, a two-step MR approach was employed to identify potential mediating metabolites. Our analysis revealed significant associations between 6 specific microbiota taxa and OC. Furthermore, we identified several plasma metabolites that act as mediators of the association between GM and OC. In the two-step MR analysis, we observed a negative correlation between 4-methoxyphenol sulfate and pregnenetriol disulfate levels with OC. The genus Lachnospiraceae UCG008 potentially increases the risk of OC by decreasing 4-methoxyphenol sulfate levels, while the genus Howardella may elevate the risk of OC by reducing pregnenetriol disulfate levels, with mediation proportions of 22.35% and 4.23%, respectively. Additionally, levels of dilinoleoyl-GPE (18:2/18:2) and N-acetylkynurenine (2) were positively correlated with OC. The inhibitory effect of the genus Ruminococcus 1 on OC may be mediated through 1,2-dilinoleoyl-GPE (18:2/18:2) and N-acetylkynurenine (2), with mediation proportions of 10.15% and 11.32%, respectively. Our findings highlight the complex relationship among GM, plasma metabolites, and OC. The identified associations and mediation effects offer valuable insights into potential therapeutic approaches targeting GM for the management of OC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Type 1 diabetes (T1D) is a form of diabetes caused by pancreatic β-cell destruction and absolute insulin deficiency. Lichen planus (LP) is an idiopathic inflammatory skin disease of unclear etiology. The role of SIRPG gene dysregulation in T1D and LP remains unclear. Mendelian randomization (MR) using matched samples was employed to study causal relationship between T1D and increased risk of LP. T1D-related single nucleotide polymorphism identification was conducted. Datasets GSE156035 for T1D and GSE52130 for LP were obtained from gene expression omnibus. Differentially expressed genes were identified, analyses included weighted gene co-expression network analysis, functional enrichment, gene set enrichment analysis, and protein-protein interaction network construction and analysis. Heatmaps of gene expression levels were generated. Comparative toxicogenomics database was used to identify diseases most relevant to core genes. Inverse variance weighted, MR-Egger, weighted median methods estimated genetic predisposition between T1D and LP, showing consistent positive correlations using both weighted median and inverse variance weighted methods. Horizontal pleiotropy analysis with MR-Egger intercept indicated no evidence of significant directional pleiotropy (P = .70645) for LP. There was no evidence of directional pleiotropy effects between T1D and LP. One hundred eighteen differentially expressed genes were identified. In biological processes, they were mainly enriched in apoptosis, inflammatory response, insulin receptor signaling pathway, glucose metabolism. In cellular components, enrichment was observed in mediator complex and replication fork. In molecular function, they were concentrated in leukotriene receptor activity and helicase activity. Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment in metabolic pathways, PI3K-Akt signaling pathway, cell cycle, p53 signaling pathway, AGE-RAGE signaling pathway in diabetic complications. Weighted gene co-expression network analysis with a soft threshold power of 4. SIRPG showing high expression in both T1D and LP samples. There is a positive causal relationship between T1D and LP. Comparative toxicogenomics database analysis revealed associations of core genes with metabolic syndrome, lipid metabolism disorders, cardiovascular diseases, immune system diseases, peripheral neuropathic pain, and inflammation. SIRPG is highly expressed in both T1D and LP, providing a new insight into the pathogenesis of T1D and LP., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The pathogenesis of frozen shoulder (FS) remains unclear, and current research primarily focuses on immune responses. Increasing evidence suggests that immune cells play a significant role in FS development. However, the causal relationship between the two remains poorly understood. Therefore, we aimed to investigate this using Mendelian randomization (MR) analysis. Single nucleotide polymorphisms closely associated with 731 immune phenotypes were obtained from publicly available GWAS datasets as instrumental variables. FS was used as the outcome with a sample size of 451,099 cases. Causal effects were analyzed using the inverse variance-weighted method. We conducted sensitivity tests, including the intercept of the MR-Egger and MR-PRESSO analyses. The presence of heterogeneity was evaluated using Cochran Q test. We identified potential causal relationships in terms of increased risk for FS with 5 immune phenotypes: CD25++ CD45RA+ CD4 not regulatory T cell %CD4+ T cells (odds ratio [OR] = 1.0273, 95% confidence interval [CI]: 1.0093-1.0457, P = .0028), CD25++ CD45RA+ CD4 not regulatory T cell %T cell (OR = 1.0240, 95% CI: 1.0057-1.0427, P = .0098), CD127 on CD28+ CD4+ T cells (OR = 1.0398, 95% CI: 1.0121-1.0682, P = .0046), CD4 on human leukocyte antigen DR+ CD4+ T cells (OR = 1.0795, 95% CI: 1.0316-1.2195, P = .0009), and human leukocyte antigen DR on CD14- CD16+ monocytes (OR = 1.0533, 95% CI: 1.0136-1.0945, P = .0081). Few significant heterogeneities or horizontal pleiotropies were observed. Through MR analysis, we identified distinct 5 types of immune cells that were positively correlated with the occurrence and development of FS, providing guidance for clinical intervention in FS., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Colorectal cancer (CRC) is a significant global public health concern. Several observational studies have examined the association between inflammatory cytokines and the risk of colorectal cancer, but the findings have been inconsistent. In this study, we employed a 2-sample Mendelian randomization (MR) analysis, primarily using the inverse variance weighted approach, to investigate the causal relationship between inflammatory cytokines and CRC. The forward MR analysis revealed a positive association between higher levels of interleukin (IL)-16 (OR: 1.37, P = .002), vascular endothelial growth factor (OR: 1.44, P = .001), and MIG (OR: 1.23, P = .040) with an increased risk of rectal cancer. Conversely, higher levels of macrophage colony-stimulating factor (OR: 0.80, P = .010) may potentially decrease the risk of colon cancer. In the reverse MR analysis, it was found that rectal cancer is linked to higher levels of IL-1b (OR: 0.93, P = .022), IL-1ra (OR: 0.90, P = .001), IL-5 (OR: 0.93, P = .022), IL-9 (OR: 0.93, P = .017), and TNF-a (OR: 0.91, P = .003). Additionally, colon cancer is associated with elevated levels of FGF-Basic (OR: 1.10, P = .028). Consistent results were also found in MR-Egger, weighted median, and weighted mode analysis. Our study presents novel evidence supporting the causal relationship between inflammatory cytokines and CRC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The causal relationships between amyotrophic lateral sclerosis (ALS), Parkinson disease and different intensities of physical activity (PA) are still inconclusive. To evaluate the causal impact of PA on ALS and Parkinson disease (PD), this study integrates evidence from Mendelian randomization (MR) using a meta-analysis approach., Methods: MR analyses on genetically predicted levels of PA (compose of self-reported moderate-to-vigorous physical activity [MVPA], self-reported vigorous physical activity [VPA], and strenuous sports or other exercises [SSOE]) regarding ALS and PD published up to July 27, 2024, were obtained from PubMed, Scopus, Web of Science, and Embase. De novo MR studies were analyzed utilizing publicly accessible datasets from genome-wide association studies and then meta-analyses were performed to pool the results., Results: Meta-analyses of results of 12 de novo MR studies analyses and 2 published MR studies indicated that genetic predicted levels of MVPA (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.08-1.38), VPA (OR: 1.32, 95% CI: 1.08-1.60), and SSOE (OR: 1.35, 95% CI: 1.07-1.70) were related to a raised risk of ALS, but not causally with PD., Conclusion: Our findings showed no causal relationships between MVPA, VPA, SSOE, and PD, while MVPA, VPA, and SSOE were associated with increased ALS risk, highlighting the need for targeted PA recommendations for disease management., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Many studies have shown that myocardial infarction (MI) is significantly associated with atrial fibrillation (AF), but the causal relationship between MI and AF has not been established. Therefore, we performed this Mendelian randomization (MR) study to investigate the relationship between MI and AF. We used a publicly available summary statistical dataset for MI based on genome-wide analysis studies (GWAS; ebi-a-GCST011364; 14,825 cases and 2680 controls) and a summary statistical dataset for AF based on an European GWAS (finn-b-I9&#95;AF&#95;REIMB; 10,516 cases and 116,926 controls). The 2-sample bidirectional MR analysis was performed using the inverse-variance weighted (IVW), MR-Egger, and weighted median methods. The causal effect of MI on AF was analyzed using 30 MI-specific single nucleotide polymorphisms (SNPs) that were characterized as instrumental variables (IVs) based on the GWAS data. The causal effect of MI on AF was confirmed by the IVW (odds ratio [OR] 1.42; 95% confidence interval [CI] 1.27-1.58; P < .001), MR-Egger (OR: 1.49; 95% CI: 1.15-1.93; P = .005), and weighted median (OR: 1.42; 95% CI: 1.24-1.63; P < .001) analyses. Furthermore, in the reverse MR analyses, the causal effect of AF on MI was analyzed using 20 AF-specific SNPs that were screened as IVs. The causal effect of AF on MI was significant based on the results from the IVW method (OR: 1.05; 95% CI: 1.00-1.09; P = .033). In conclusion, the bidirectional MR analyses demonstrated a clear bidirectional causal association between MI and AF., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The immune system and inflammatory processes play crucial roles in the development of esophageal cancer (EC). This study aimed to investigate the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC, with a particular focus on the mediating role of circulating inflammatory proteins. Utilizing public genetic data, we applied a 2-sample Mendelian Randomization (MR) method to examine the causal relationships between 731 immune cell phenotypes, 91 circulating inflammatory proteins, and EC. Comprehensive sensitivity analyses were conducted to assess the robustness, heterogeneity, and horizontal pleiotropy of the MR results. Additionally, a 2-step MR method was employed to quantify the impact and proportion of immune cell phenotypes mediated by circulating inflammatory proteins on EC. Eleven immune cell phenotypes and 1 inflammatory cytokine were found to have causal relationships with EC, with results stable across all sensitivity analyses. Mediation analyses revealed that only 2 cell phenotypes had causal relationships with EC through interleukin-10: CD3 on human leukocyte antigen-DR (HLA-DR)+ T cells (mediation effect = -0.009; mediation proportion = 12.01%) and monocytic myeloid-derived suppressor cell absolute count (mediation effect = 0.018; mediation proportion = 18.97%). This study enhances the understanding of the causal relationships between immune cells, circulating inflammatory proteins, and EC. The findings highlight the potential mediating role of interleukin-10, providing new insights into the mechanisms by which immune cells may influence esophageal tumorigenesis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To examine the causal bidirectional relationships between epilepsy and microstructural changes in the white matter (WM). A genome-wide association study meta-analysis of the International League Against Epilepsy Consortium on Epilepsy and 360 WM imaging-derived phenotypes (IDPs) from the UK Biobank was used for the analysis. Genetic correlation analyses were conducted based on summary statistics of various "IDP-epilepsy" pairs for 2-sample Mendelian randomization (MR) analysis to explore the causal relationships. We used the inverse variance weighted (IVW) method as the primary MR analysis approach, and conducted sensitivity analyses for pleiotropy and heterogeneity. Forward MR analysis revealed that alterations in the 16 WM IDPs increased the risk of epilepsy (q value < 0.05). Changes in the 38 WM IDPs were associated with a decreased risk of epilepsy (q value < 0.05). In the reverse analysis, seizures from all epilepsy types changed 5 WM IDPs, whereas seizures from juvenile myoclonic epilepsy altered 11 WM IDPs (q value < 0.05). This study revealed causal associations between changes in the WM microstructure and epilepsy subtypes. These findings offer new directions for early prevention and treatment of epilepsy., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Background: Recent observational studies have suggested that osteoporosis may be a risk factor for sepsis. To mitigate confounding factors and establish the causal relationship between sepsis and osteoporosis, we conducted a two-sample Mendelian randomization analysis using publicly available summary statistics. Methods: Utilizing summary data from FinnGen Biobank, we employed a two-sample Mendelian randomization (MR) analysis to predict the causal relationship between osteoporosis and sepsis. The MR analysis primarily utilized the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, weighted mode, and simple mode analyses, with Bayesian weighted MR (BWMR) analysis employed for result validation. Sensitivity analyses included MR-PRESSO, "leave-one-out" analysis, MR-Egger regression, and Cochran Q test. Results: In the European population, an increase of one standard deviation in osteoporosis was associated with an 11% increased risk of sepsis, with an odds ratio (OR) of 1.11 (95% CI, 1.06-1.16; P = 3.75E-06). BWMR yielded an OR of 1.11 (95% CI, 1.06-1.67; P = 1.21E-05), suggesting osteoporosis as a risk factor for sepsis. Conversely, an increase of one standard deviation in sepsis was associated with a 26% increased risk of osteoporosis, with an OR of 1.26 (95% CI, 1.11-1.16; P = 0.45E-03). BWMR yielded an OR of 1.26 (95% CI, 1.09-1.45; P = 1.45E-03), supporting sepsis as a risk factor for osteoporosis. Conclusion: There is an association between osteoporosis and sepsis, with osteoporosis serving as a risk factor for the development of sepsis, while sepsis may also promote the progression of osteoporosis., Competing Interests: Conflicts of interest: The authors declare no conflicts of interest in this work., (Copyright © 2024 by the Shock Society.)

The relationship between iron status and female infertility has been observed in several studies, yet its causal nature remains ambiguous. We employed univariate Mendelian randomization (MR) analyses to explore the potential causal connection between these 2 factors. For our analysis, genetic instrumental variables pertaining to iron status were selected using data from the Iron Status Genetics Consortium, encompassing 48,972 individuals of European descent from 19 cohorts (11 discovery and 8 replication). For female infertility data, we referred to FinnGen Consortium Release 9, which includes 11,442 cases and 107,564 controls. Our MR approach utilized both a conservative strategy (involving single nucleotide polymorphisms pertinent to general iron status) and a liberal strategy (encompassing single nucleotide polymorphisms linked to any iron status indicator). The conservative approach relied on inverse variance-weighted methods, whereas the liberal strategy integrated inverse variance weighted with MR-Egger regression, the weighted median approach, and simple mode techniques. The conservative strategy did not reveal a significant link between iron status and female infertility risk. Conversely, the liberal strategy indicated a positive correlation specifically between serum iron levels and female infertility risk (odds ratio from MR: 1.225; 95% confidence interval: 1.064-1.410; P = .030), while no significant associations were found for other iron indicators (P > 0.05). Our MR investigation suggests a potential positive association between serum iron levels and the risk of female infertility, while other iron markers do not appear to significantly influence this risk. These findings highlight the need for further research into the possible connection between serum iron status and female infertility risk., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Polymyositis is a prominent subgroup of idiopathic inflammatory myopathy, considered to have an autoimmune etiology. However, research exploring the condition between immunocytes and polymyositis remains limited, indicating the need for further investigation to unravel these intricate associations. We employed bidirectional Mendelian randomization (MR) analysis to ascertain causality between 731 immunocytes and polymyositis. We also compared the positive immunocytes with dermatomyositis. Our primary analytical method was inverse variance weighted, supplemented by 4 other MR techniques. Additionally, Cochran Q test was performed to assess heterogeneity, MR-Egger to appraise pleiotropy, and MR-PRESSO to identify and eliminate potential outliers. Furthermore, the leave-one-out test evaluated the impact of each instrumental variable (IV) on the causal effect. The inverse variance weighted results revealed that 10 immunocytes exert a protective effect against polymyositis (P < .05, OR < 1), while 16 immunocytes are connected with an elevated risk of the disease (P < .05, OR > 1). In reverse MR, polymyositis was found to decrease the levels of 2 immune cells (P < .05, OR < 1) and elevate the expression of 5 immune cell phenotypes (P < .05, OR > 1). A complex correlation was found between polymyositis and the immunocyte phenotypes CD8, CD33dim, HLA-DR, CD11b, and CD45. Additionally, it was discovered that 15 types of immune cells share a causal relationship between polymyositis and dermatomyositis. All analyses demonstrated no heterogeneity or horizontal pleiotropy (P > .05). Our study provides compelling evidence regarding the intricate causal relationships between immunocytes and polymyositis. Polymyositis and dermatomyositis share common immunocytes' regulatory mechanisms. CD8, CD33dim, HLA-DR, CD11b, and CD45 may represent potential immune cell markers for polymyositis. These findings hold implications for planning prognosis and therapeutic strategies for polymyositis, offering novel insights for drug development., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Increasing evidence indicates a significant correlation between gut microbiota (GM) and susceptibility to chronic kidney disease (CKD). However, causal relationship presence remains uncertain. Mendelian randomization (MR) was applied to evaluate potential causal relation from GM to CKD. Genomic association analysis aggregates publicly online databases, utilizing Genome-Wide Association Study (GWAS) database focused on GM and CKD. For examination of potential causal connection from GM to CKD, a 2-way, 2-sample Mendelian randomization (MR) method was applied. Sensitivity analyses were utilized to scrutinize for heterogeneity, horizontal pleiotropy, MR outcomes resilience. Result from inverse variance weighting (IVW) method revealed that 10 microbiotas such as Porphyromonadaceae (OR = 1.351, 95% CI: 1.114-1.638, P = .002), Dorea (OR = 1.236, 95% CI: 1.040-1.468, P = .016), Ruminococcus torques group (OR = 1.290, 95% CI: 1.035-1.608, P = .024) are potential CKD risk factors. Five microbiotas, including the Prevotellaceae (OR = 0.814, 95% CI: 0.719-0.922, P = .001) are potential CKD protective factors. Sensitivity analyses reveal no horizontal pleiotropy or heterogeneity. Additionally, reverse MR results unveiled potential relation between CKD and disorders in 3 microbiotas, including Senegalimassilia. According to the investigation, MR method was employed to delve into reciprocal causal connection from GM to CKD. Our findings identified 15 types of GM causally linked to CKD, as well as CKD demonstrating causal associations with 3 types of GM. Further exploration of these associated GM types is hopeful to raise novel insights, for CKD preventing and early monitoring., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

In recent years, an increasing number of observational studies have reported the impact of amino acids on ovarian cancer. However, Mendelian randomization studies have not yet been conducted to explore the causal relationship between them in the context of ovarian cancer. This study conducted Mendelian randomization (MR) analysis of 20 amino acids in relation to ovarian cancer data from 2 different sources within the European population, using a two-sample MR approach. The primary results from the inverse variance weighting analysis were then subjected to a meta-analysis, followed by multiple testing correction for the meta-analysis thresholds. Finally, reverse causality testing was performed on the positively associated amino acids and ovarian cancer. MR analyses were conducted for 20 amino acids with ovarian cancer data from both the Finngen R10 and Open genome-wide association study databases. The inverse variance weighted results from these 2 analyses were then combined through meta-analysis, with multiple corrections applied to the significance thresholds of the meta-analysis results. The findings showed that only cysteine had a significant association with ovarian cancer, with an (odds ratio) odds ratio value of 0.507 (95% confidence interval: 0.335-0.767, P = .025). The P-value of the combined MR and meta-analysis, after multiple testing correction, was 0.025, indicating statistical significance (P < .05). Additionally, cysteine did not show a reverse causal relationship with ovarian cancer in either data source. Cysteine is a protective factor for ovarian cancer, potentially reducing the risk of ovarian cancer and slowing the progression of the disease., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To investigate the use of lipid-lowering drugs and abnormal serum lipid levels in patients at risk of sleep apnea syndrome. Three types of Mendelian randomization (MR) analyses were used. First, a 2-sample Mendelian randomization (TSMR) analysis was used to investigate the association between sleep apnea syndrome risk and serum lipid levels. Multivariate Mendelian randomization (MVMR) analysis was subsequently used to investigate the effects of confounding variables on SAS incidence of sleep apnea syndrome. Finally, drug-target Mendelian randomization (DMR) analysis was used to analyze the association between lipid-lowering drug use and sleep apnea syndrome risk. According to the TSMR analysis, the serum HDL-C concentration was negatively correlated with sleep apnea syndrome (OR = 0.904; 95% CI = 0.845-0.967; P = .003). Serum TG levels were positively correlated with sleep apnea syndrome (OR = 1.081; 95% CI = 1.003-1.163; P = .039). The association between serum HDL-C levels and sleep apnea syndrome in patients with MVMR was consistent with the results in patients with TSMR (OR = 0.731; 95% CI = 0.500-1.071; P = 3.94E-05). According to our DMR analysis, HMGCR and PCSK9, which act by lowering serum LDL-C levels, were inversely associated with the risk of sleep apnea syndrome (OR = 0.627; 95% CI = 0.511-0.767; P = 6.30E-06) (OR = 0.775; 95% CI = 0.677-0.888; P = .0002). LPL, that lowered serum TG levels, was positively associated with the risk of sleep apnea syndrome (OR = 1.193; 95% CI = 1.101-1.294; P = 1.77E-05). Our analysis suggested that high serum HDL-C levels may reduce the risk of sleep apnea syndrome. Low serum TG levels have a protective effect against sleep apnea syndrome. The DMR results suggested that the use of HMGCR lipid-lowering drugs (such as statins) and PCSK9 inhibitors has a protective effect against sleep apnea syndrome. However, LPL-based lipid-lowering drugs may increase the risk of sleep apnea syndrome., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Traditional observational studies have reported a positive association between constipation and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between constipation and CRC is scarce. In the study, 2-sample Mendelian randomization analysis was conducted to investigate the potential causal relationship between constipation and CRC. Analysis of the results showed that there was no causal association between constipation and CRC, either in European populations (CRC: odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.99-1.00, P = .49; rectal cancer: OR = 0.99, 95% CI = 0.99-1.00, P = .79) or in Asian populations (CRC: OR = 1.00, 95% CI = 0.99-1.01, P = .30). Also there was no inverse causal association between CRC and constipation, either in European populations (CRC: OR = 0.10, 95% CI = 2.76E-03-3.45, P = .20; rectal cancer: OR = 0.05, 95% CI = 9.14E-07-2.64E + 03, P = .59) or in Asian population (CRC: OR = 1.18, 95% CI = 0.92-1.52, P = .20), there was no horizontal diversity in the instrumental variables in the Mendelian randomization analyses of the present study (all F statistics >10), and no heterogeneity was found in the regression analyses. The findings from bidirectional 2-sample Mendelian randomization analyses indicate that there is no evidence of a bidirectional causal association between constipation and CRC. However, further investigation is warranted through additional clinical studies and trials to thoroughly explore the association between these 2 factors., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cysteine cathepsins are proteolytic enzymes crucial in various physiological and pathological processes, primarily operating within lysosomes. Their functions include protein degradation, immune system regulation, and involvement in various diseases. While some cysteine cathepsins play important roles in the immune system, their connection to autoimmune diseases remains unclear. This study proposes using Mendelian randomization to explore the causal relationship between cysteine cathepsins and autoimmune diseases. Single nucleotide polymorphisms (SNPs) for cysteine cathepsins were obtained from a publicly available genome-wide association study (GWAS) dataset, while outcome SNP data were sourced from 10 separate GWAS datasets. Mendelian randomization (MR) analysis employed the Wald ratio (WR) and inverse variance weighted (IVW) approach as primary methods, supplemented by the weighted median and MR-Egger methods. Heterogeneity was assessed using Cochran Q test, and sensitivity analysis was conducted using the MR-PRESSO method. The association strength between exposure and outcome was evaluated using odds ratios (OR) with 95% confidence intervals (CI). The study identified a potential positive correlation between elevated cathepsin B and psoriasis (Wald ratio OR = 1.449, 95% CI: 1.053-1.993, P = .0227). Elevated cathepsin F was potentially linked to ulcerative colitis (WR OR = 1.073, 95% CI: 1.021-1.127, P = .0056), ankylosing spondylitis (WR OR = 1.258, 95% CI: 1.082-1.463, P = .0029), and primary biliary cholangitis(PBC) (WR OR = 1.958, 95% CI: 1.326-2.889, P = .0007). Conversely, cathepsin H appeared protective against celiac disease (WR OR = 0.881, 95% CI: 0.838-0.926, P = 6.5e-7), though elevated levels may increase the risk of type 1 diabetes (IVW OR = 1.121, 95% CI: 1.053-1.194, P = .0003) and PBC (WR OR = 1.792, 95% CI: 1.062-3.024, P = .0288). Cathepsin Z was also associated with an increased risk of type 1 diabetes (IVW OR = 1.090, 95% CI: 1.006-1.181, P = .0349). The MR analysis suggests potential risks of cathepsin B with psoriasis, cathepsin F with ulcerative colitis, ankylosing spondylitis, and PBC, and cathepsin Z with type 1 diabetes. Conversely, cathepsin H may protect against celiac disease but could increase the risk of type 1 diabetes and PBC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

It remains unclear what causes esophageal cancer (EC), but blood metabolites have been connected to it. Our study performed a Mendelian randomization (MR) analysis to assess the causality from genetically proxied 1400 blood metabolites to EC level. A two-sample MR analysis was employed to evaluate the causal relationship between 1400 blood metabolites and EC. Initially, the EC genome-wide association study (GWAS) data (from Jiang L et al) were examined, leading to the identification of certain metabolites. Subsequently, another set of EC GWAS data from FINNGEN was utilized to validate the findings. Causality was primarily determined through inverse variance weighting, with additional support from the MR-Egger, weighted median, and MR-PRESSO models. Heterogeneity was assessed using the MR Cochran Q test. The MR-Egger intercept and MR-PRESSO global methods were employed to detect multicollinearity. In this study, Bonferroni corrected P value was used for significance threshold. We found 2 metabolites with overlaps, which are lipids. Docosatrienoate (22:3n3) was found to be causally associated with a decreased risk of EC, as evidenced by the EC GWAS data (from Jiang et al) (odds ratio [OR] = 0.620, 95% confidence interval [CI] = 0.390-0.986, P = .044) and the EC GWAS data (from FINNGEN) (OR = 0.77, 95% CI = 0.6-0.99, P = .042), these results were consistent across both data sets. Another overlapping metabolite, glycosyl-N-(2-hydroxyneuramoyl)-sphingosine, was associated with the risk of ES, with EC GWAS data (from Jiang L et al) (OR = 1.536, 95% CI = 1.000-2.360, P = .049), while EC GWAS data (from FINNGEN) (OR = 0.733, 95% CI = 0.574-0.937, P = .013), the 2 data had opposite conclusions. The findings of this study indicate a potential association between lipid metabolites (Docosatrienoate (22:3n3) and glycosyl-N-(2-hydroxynervonoyl)-sphingosine (d18:1/24:1 (2OH))) and the risk of esophageal carcinogenesis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

This study aims to investigate the connection between 25-hydroxyvitamin D (25(OH)D) levels and the prognosis of breast cancer with various estrogen receptor (ER) statuses. The summary statistics of 25(OH)D levels was obtained from a GWAS of 441,291 individuals and the information of breast cancer was collected from the Breast Cancer Association Consortium. We analyzed the causal association between 25(OH)D levels and breast cancer prognosis using a number of approaches, including inverse variance weighting (IVW). The heterogeneity test was performed using Cochran Q test. IVW, Mendelian randomization (MR)-Egger, and MR Pleiotropy RESidual Sum and Outlier methods were used for sensitivity analysis. In addition, a multivariate MR adjusted for total triglycerides, total cholesterol, and body mass index was used for further analysis. Two-sample MR results showed that 25(OH)D levels were not associated with prognosis in overall breast cancer (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.73-1.19, IVW exam) and estrogen receptor positive (ER+) breast cancers (OR = 1.12, 95% CI = 0.77-1.63, IVW exam) and were protective associated with prognosis in estrogen receptor negative (ER-) breast cancers (OR = 0.55, 95% CI = 0.34-0.87, IVW exam). Sensitivity analysis did not observe the presence of heterogeneity and horizontal pleiotropy. In multivariate MR analysis, after adjusting for total triglycerides, total cholesterol, and body mass index, the correlation between the protective relationship between 25(OH)D levels and the prognosis for ER- breast cancer remained and became increasingly significant (OR = 0.51, 95% CI = 0.31-0.83, P = .007). This study demonstrated a protective relationship between 25(OH)D levels and the prognosis of ER- breast cancer, but there was no connection between 25(OH)D levels and the prognosis of ER+ breast cancer., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To investigate the potential link between gut microbiota and functional dyspepsia (FD). Genome-wide association studies (GWAS) of gut microbiota and FD were used in Mendelian randomization (MR) research. Using the GWAS of 18,340 people, instrumental variables related to gut microbiota as an exposure factor were identified. In a GWAS investigation, 189,695 control individuals and 4376 FD patients were included as outcome variables. The primary analysis technique was inverse variance weighted analysis. The reliability of MR analysis results is tested using sensitivity analysis. Two-sample Mendelian randomization analysis revealed the presence of 7 gut microbiota associated to FD. In the inverse variance weighted analysis method, Order Erysipelotrichales (odds ratio (OR): 1.301; 95% confidence interval (CI): 1.016, 1.665; P = .037), Family Erysipelotrichales (OR: 1.301; 95% CI: 1.016, 1.665; P = .037), Genus Haemophilus (OR: 1.236; 95% CI 1.059, 1.442; P = .007), Genus Ruminiclostridium 9 (OR: 1.422; 95% CI: 1.078, 1.877; P = .013), Genus Lachnospiraceae NK4A 136 group (OR: 1.297; 95% CI: 1.059, 1.589; P = .012) was positively associated with FD. Class Gammaproteobacteria (OR: 0.705; 95% CI: 0.522, 0.952; P = .022) and Genus Erysipelatoclostridium (OR: 0.747; 95% CI: 0.628, 0.888; P = .001) were found to be inversely related to FD. There was no evidence of pleiotropy or heterogeneity in the sensitivity analysis. Our research provides evidence for a possible link between FD and a number of gut microbiota. The role that gut microbiota plays in the development of FD requires more investigation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To clarify the causal relationship and potential mediators between educational attainment and carpal tunnel syndrome (CTS), as well as to evaluate whether educational attainment, cognition, and intelligence independently exert causal effects on CTS, we employed univariable Mendelian randomization (MR), multivariable MR, reverse MR, and 2-step MR approaches. Our research demonstrates that educational attainment exerts an independent causal effect on CTS, with this causal relationship being unidirectional. Five mediators were identified as significant influencers within the causal pathways connecting educational attainment and CTS. Targeting these mediators may be beneficial in the prevention of CTS., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

This study investigated the causal effect of gut microbiota on critical pneumonia. Data came from a large-scale gut microbiota data set (n = 18,340) and the critical pneumonia genome-wide genotyping array (cases n = 2758 and controls n = 42,8607). Inverse variance weighting was used as the primary Mendelian randomization (MR) analysis method. Weighted median, MR-Egger, simple model, weighted model, and MR-Egger, were used to evaluate robustness. Sensitivity analysis used Cochran Q test, MR-Egger intercept test, and MR-PRESSO. For critical pneumonia, inverse variance weighting estimates suggested that Class Verrucomicrobiae (OR = 0.415; 95% CI: 0.207, 0.833; P = .013), Family Verrucomicrobiaceae (OR = 0.415; 95% CI: 0.207, 0.833; P = .013), Genus Akkermansia (OR = 0.415; 95% CI: 0.207, 0.833; P = .013), Genus LachnospiraceaeFCS020group (OR = 0.449; 95% CI: 0.230, 0.890; P = .021), Genus Parasutterella (OR = 0.466; 95% CI: 0.233, 0.929; P = .030), Genus Prevotella7 (OR = 0.645; 95% CI: 0.432, 0.960; P = .031), Order Verrucomicrobiales (OR = 0.415; 95% CI: 0.207, 0.833; P = .013), and Phylum Cyanobacteria (OR = 0.510; 95% CI: 0.272, 0.956; P = .036) had a reduced risk, while Family Enterobacteriaceae (OR = 2.746; 95% CI: 1.008, 7.474; P = .048), Genus RuminococcaceaeUCG003 (OR = 2.811; 95% CI: 1.349, 5.851; P = .006) and Order Enterobacteriales (OR = 2.746; 95% CI: 1.008, 7.474; P = .048) were associated with an increased risk. Sensitivity analyses confirmed that the aforementioned correlations were robust., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Observational studies have reported associations between atopic diseases, including allergic rhinitis (AR), asthma, atopic dermatitis (AD), and inflammatory bowel disease (IBD), but the causal relationship remains unknown. We utilized pooled data from genome-wide association studies, qualified instrumental variables were screened according to the 3 hypotheses of MR, and bidirectional causality between atopic diseases and IBD was assessed using 2-sample Mendelian randomization analysis (2SMR). The results of our study suggest that AR increased the risk of Crohn disease (CD) (IVW OR = 1.19, 95% CI = 1.02-1.39, P = .026), ulcerative colitis (UC) (IVW OR = 1.14, 95% CI = 1.01-1.29, P = .031) and overall IBD (IVW OR = 1.15, 95% CI = 1.03-1.28, P = .015); Asthma increased the risk of CD (IVW OR = 7.66, 95% CI = 1.58-37.20, P = .012), UC (IVW OR = 3.81, 95% CI = 1.09-13.32, P = .036) and overall IBD (IVW OR = 5.13, 95% CI = 1.48-17.70, P = .010); AD increased the risk of CD (IVW OR = 1.19, 95% CI = 1.02-1.39, P = .023) and overall IBD (IVW OR = 1.14, 95% CI = 1.03-1.28, P = .015) risk. In reverse causality, only CD increased the risk of AR (IVW OR = 1.02, 95% CI = 1.00-1.05, P = .031). This study shows that atopic diseases of AR and asthma are causally related to IBD and its subtypes, and AD is causally related to IBD (which may be attributed to CD). Of the reverse causality, only CD was causally related to AR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Many previous observational studies have disputed whether there is a link between uric acid and stroke. And the causal relationship between uric acid and stroke is unclear. To determine whether there is a causal relationship between uric acid and stroke by using mendelian randomization (MR). Uric acid dataset was obtained from Anna Kottgen et al, with a sample size of 110,347 people, including 2450,548 single nucleotide polymorphisms (SNPs). Stroke pooled data from Malik R et al, publicly available in MEGASTROKE genome-wide association study, included meta-analysis data from 40,585 stroke patients and 406,111 control patients, totaling 8211,693 SNPs. The summary data of genome-wide association study of uric acid and stroke were collected from publicly available online databases. Inverse variance weighting was used to determine the causal relationship between uric acid and stroke. MR-Egger and weighted median model were used for supplementary analysis. Results were then analyzed for heterogeneity, pleiotropy, and sensitivity to ensure no statistical pleiotropy and to reduce bias. A total of 27 SNPs were included in this study after the disequilibrium instrumental variables were excluded. Check the PhenoScanner database for SNPs associated with confounders. In the end, a total of 8 SNPs were excluded. Two SNPs were excluded because the correction direction was the same. Since the F statistic is >10, rs10761587 and rs1825043 are excluded. Finally, 15 SNPs were selected as uric acid instrumental variables. Inverse variance weighting-fixed effect model suggested that there was no causal relationship between uric acid and stroke (odds ratio = 1.004, 95% confidence interval = 0.940, 1.072). MR-Egger and weighted median model also showed the same result. In addition, the results of this study were robust without heterogeneity and pleiotropy. This MR study suggests no support of a causal relationship between uric acid and stroke., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

During the coronavirus disease 2019 (COVID-19) pandemic, the incidence of type 1 diabetes mellitus (T1DM) has increased. Additionally, evidence suggests that individuals with diabetes mellitus may have increased susceptibility to severe acute respiratory syndrome coronavirus 2 infection. However, the specific causal relationships and interaction mechanisms between T1DM and COVID-19 remain unclear. This study aims to investigate the causal relationship between T1DM and COVID-19, utilizing differential gene expression and Mendelian randomization analyses. Differentially expressed gene sets from datasets GSE156035 and GSE171110 were intersected to identify shared genes, analyzed for functional enrichment. Mendelian randomization models were employed to assess causal effects, revealing no direct causal link between T1DM and COVID-19 in the European population (P > .05). Notably, DNA replication and sister chromatid cohesion 1 (DSCC1) showed negative causal associations with both diseases (T1DM: OR = 0.943, 95% CI: 0.898-0.991, P = .020; COVID-19: OR = 0.919, 95% CI: 0.882-0.958, P < .001), suggesting a protective effect against their comorbidity. This genetic evidence highlights DSCC1 as a potential target for monitoring and managing the co-occurrence of T1DM and COVID-19., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)