Circulating immune cells and apolipoprotein A mediation: a Mendelian randomization study on hypertensive disorder of pregnancy.

Background: Studies using observational epidemiology have indicated that inflammation and immunological dysregulation are important contributors to placental and renal failure, which ultimately results in maternal hypertension. The potential causal relationships between the immunophenotypes and hypertensive disorder of pregnancy (HDP) are yet unclear. Methods: We conducted two-sample Mendelian randomization (MR) analyses to thoroughly examine the relationship between immunophenotypes and HDP. The GWAS data on immunological traits was taken from public catalog for 731 immunophenotypes and the summarized GWAS data in 4 types of HDP were retrieved from FinnGen database. The link between immune cell traits and HDP was examined through our study methodology, taking into account both direct relationships and mediation effects of apolipoprotein A (apoA). The inverse variance weighted (IVW) method served as the main analysis, while sensitivity analysis was carried out as a supplement. Results: We identified 14 highly correlative immunophenotypes and 104 suggestive possible factors after investigating genetically predicted immunophenotype biomarkers. According to the IVW analysis, there was a strong correlation between HDP and HLA DR on DC and plasmacytoid DC. Reverse MR analysis showed that there was no statistically significant effect of HDP on immune cells in our investigation. Mediation analysis confirmed that apoA mediates the interaction between HLA DR on DC and HDP. Conclusion: Our results highlight the complex interplay of immunophenotypes, apoA, and HDP. Moreover, the pathophysiological link between HLA DR on DC and HDP was mediated by the level of apoA.

Revealing the association between East Asian oral microbiome and colorectal cancer through Mendelian randomization and multi-omics analysis.

Background: Colorectal cancer (CRC) poses a global health threat, with the oral microbiome increasingly implicated in its pathogenesis. This study leverages Mendelian Randomization (MR) to explore causal links between oral microbiota and CRC using data from the China National GeneBank and Biobank Japan. By integrating multi-omics approaches, we aim to uncover mechanisms by which the microbiome influences cellular metabolism and cancer development. Methods: We analyzed microbiome profiles from 2017 tongue and 1915 saliva samples, and GWAS data for 6692 CRC cases and 27178 controls. Significant bacterial taxa were identified via MR analysis. Single-cell RNA sequencing and enrichment analyses elucidated underlying pathways, and drug predictions identified potential therapeutics. Results: MR identified 19 bacterial taxa significantly associated with CRC. Protective effects were observed in taxa like RUG343 and Streptococcus_umgs_2425, while HOT-345_umgs_976 and W5053_sp000467935_mgs_712 increased CRC risk. Single-cell RNA sequencing revealed key pathways, including JAK-STAT signaling and tyrosine metabolism. Drug prediction highlighted potential therapeutics like Menadione Sodium Bisulfite and Raloxifene. Conclusion: This study establishes the critical role of the oral microbiome in colorectal cancer development, identifying specific microbial taxa linked to CRC risk. Single-cell RNA sequencing and drug prediction analyses further elucidate key pathways and potential therapeutics, providing novel insights and personalized treatment strategies for CRC.

Mendelian Randomization Studies in Atherosclerotic Cardiovascular Diseases.

This review aimed to highlight the pivotal role of Mendelian randomization (MR) in advancing atherosclerotic cardiovascular disease (ASCVD) research-a field often hindered by the complexities and limitations of traditional studies. MR, which uses genetic variants as instrumental variables, provides a robust mechanism for inferring causality, offering insights untainted by the confounding factors and biases often prevalent in observational and randomized controlled trials. We explored the significant contributions of MR for elucidating the causal relationship between low-density lipoprotein cholesterol and ASCVD, and analyzed its assumptions and methodological nuances. We discussed issues surrounding instrumental variable selection, pleiotropy, and ethical considerations, in an effort to offer a balanced and insightful analysis. We highlighted the promising integration of MR with emerging technologies and global data sharing, as well as its potential to drive personalized medicine. This review provided a concise yet comprehensive journey into MR's transformative impact on ASCVD research, offering a blend of current insights and challenges, in addition to future prospects. We aimed to serve a valuable resource for those seeking to navigate the intricate pathways of causality and intervention in ASCVD, to aid the development of enhanced understanding and targeted treatment strategies in the future.

Causal Relationships between Lymphocyte Subsets and Risk of Coronary Artery Disease: A Two-Sample Mendelian Randomization Study.

Background: Currently, the causal relationship between lymphocyte subsets and coronary artery disease (CAD) remains unclear. Therefore, we utilized Mendelian randomization (MR) to assess the association between lymphocyte subsets and CAD. Methods: We performed a two-sample MR analysis using publicly available genome-wide association studies (GWAS) datasets. The primary method of analysis to comprehensively evaluate causal effects was the inverse variance-weighted (IVW) method. The four additional MR approaches were MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analysis incorporated Cochran's Q and MR-Egger intercept tests to identify residual heterogeneity and potential horizontal pleiotropy, respectively. The MR-PRESSO distortion test was applied to identify potential pleiotropic outliers. Leave-one-out analysis confirmed that no single single-nucleotide polymorphism (SNP) significantly affected the MR estimate. We conducted reverse MR analysis to investigate the impact of variables correlated with outcomes in forward MR analysis. Results: The IVW method revealed a significant positive association between B cell count and CAD (odds ratio (OR) = 1.08 (95% CI: 1.04, 1.11), p = 2.67 × 10-5). A similar association was observed between B cell count and myocardial infarction (MI) (OR = 1.07 (95% CI: 1.03, 1.11), p = 5.69 × 10-4). Sensitivity analyses detected no outliers, heterogeneity, or pleiotropy. The reverse MR analysis was conducted to investigate the impact of CAD and MI on B cell count, and the IVW results showed no statistical significance. Conclusions: Our study suggests that a higher absolute B cell count is linked to an increased risk of CAD and MI.

Causal association between hyperthyroidism and risk of gastroesophageal reflux or esophageal cancer: a bidirectional Mendelian randomization investigation.

Background: Emerging observational studies indicated an association between hyperthyroidism and gastrointestinal disorders. However, it remains unclear whether this association is causal, particularly in the case of gastroesophageal reflux (GERD) and esophageal cancer. Methods: To assess the potential causal relationship between hyperthyroidism and GERD or esophageal cancer, we conducted a bidirectional 2-sample Mendelian randomization study. Independent genetic instruments for hyperthyroidism from the UK Biobank (N case=3,545 and N control=459,388) and public genome-wide association study (GWAS) dataset (N case=3,731 and N control=480,867) were used to investigate the association with esophageal cancer in the UK Biobank study (N case=740 and N control=372,016) and GERD in the public GWAS database (N case=20,381 and N control=464,217). Four different approaches (inverse variance weighted (IVW), weighted mode, MR-Egger, and weighted median regression) were used to ensure that our results more reliable. Additional sensitivity analyses were also performed to validate our results. Results: When hyperthyroidism was considered as the exposure factor, it appeared to act as a protective factor for GERD (ORIVW = 0.88, 95% CI, 0.79-0.99, P = 0.039), while as a risk factor for esophageal cancer (ORIVW = 1.03, 95% CI, 1.01-1.06, P = 0.003). However, there is no evidence supporting a reverse causal relationship between genetic susceptibility to hyperthyroidism and GERD or esophageal cancer. Conclusion: Our findings provided genetic evidence supporting bidirectional causal relationships between hyperthyroidism and GERD or esophageal cancer. These results substantiate certain discoveries from previous observational studies on a causal level and provide insight into relevant genetic susceptibility factors.

Impact of SGLT2 inhibitors on lower limb complications: a mendelian randomization perspective.

Background: While Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective in managing diabetes and reducing cardiovascular risk, concerns about their association with lower limb complications, including, osteomyelitis, ulcers, and peripheral artery disease (PAD), persist. This study employs Mendelian Randomization (MR) to assess the causal relationship between SGLT2 inhibitors and these lower limb safety outcomes. Methods: A two-sample drug-target MR approach was used, complemented by a one-sample MR and genetic association analysis. Six SNPs were selected as instrumental variables to proxy the effect of SGLT2 inhibition. Primary outcomes were major limb safety outcomes, including osteomyelitis, lower limb ulcers, PAD, and cellulitis. The primary analytical method was the generalized inverse variance-weighted (IVW) approach, along with several sensitivity analyses. Results: The MR analysis indicated no significant causal association between genetically proxied SGLT2 inhibition and most of the studied lower limb safety outcomes. However, a significant association with PAD was observed, necessitating careful interpretation due to discrepancies between IVW and MR-Egger results. Sensitivity analyses supported these findings, showing little evidence of heterogeneity or directional pleiotropy. Conclusion: This study suggests that SGLT2 inhibitors may not be significantly associated with an increased risk of most lower limb safety outcomes, including osteomyelitis, lower limb ulcers, and cellulitis, in patients with type 2 diabetes. However, the complex relationship with PAD highlights the need for further research. These findings contribute to the understanding of the safety profile of SGLT2 inhibitors, supporting their continued use in diabetes management while underlining the importance of continuous safety monitoring.

Dietary factors and the incidence of intracranial aneurysms: a Mendelian randomization research.

BACKGROUND: Intracranial aneurysms (IAs) pose a significant threat to morbidity and mortality, yet their etiology remains inadequately comprehended. The present study employs Mendelian randomization (MR) to investigate the relationship among dietary elements with IAs, encompassing unruptured intracranial aneurysms (uIA) as well as aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The current study employed a double-sample MR test utilizing genome-wide association study (GWAS) summary data from the IEU and IAs' meta-analysis to investigate the genetically predicted consumption levels of various dietary factors using GWAS data. Causation was assessed by techniques of MR-Egger, weighted mode, and median, as well as IVW. To guarantee the accuracy of the results, pleiotropy and heterogeneity evaluations were also carried out. RESULTS: The findings of the study indicate a positive correlation between the intake of alcohol, lamb/mutton, and pork with the risk of IAs (IVW all p < 0.05). Conversely, a negative correlation was observed regarding dried fruit consumption and the risk of aSAH (IVW p < 0.05). There was only scant evidence supporting the association between alcohol intake frequency and an elevated risk of uIA (IVW method p < 0.05). The MR analysis outcomes were authenticated by the MR-PRESSO method and were deemed reliable. Furthermore, sensitivity calculations, such as pleiotropy and homogeneity test, leave-one-out evaluation, and funnel charts, validated the robustness of the results. CONCLUSIONS: The findings suggest that reducing alcohol, lamb/mutton, and pork intake, and increasing dried fruit intake may be potential strategies for the prevention of IAs and aSAH. Additional research is necessary to validate these outcomes and elucidate the underlying mechanisms.

Association between diet-derived antioxidants and asthma: Insights from the NHANES survey 2003-2018 and Mendelian randomization analysis.

BACKGROUND: Many studies have reported correlations between diet-derived antioxidants and asthma. Nevertheless, the probable association between diet-derived antioxidants and asthma remains a matter of discussion. OBJECTIVES: We explored the association between Diet-Derived Antioxidants and Asthma. METHODS: We used data from the 2003-2018 National Health and Nutrition Examination Survey (NHANES) to assess the relationship between diet-derived antioxidants and asthma and a two-sample Mendelian randomization (MR) study was employed to assess the causal associations between lifelong diet-derived circulating antioxidant levels and the risk of asthma. RESULTS: Participants with asthma were more likely to be young-to-middle-aged females, smokers, have lower income, belong to non-Hispanic Black ethnicity, have a high school education, have a BMI over 30. The dietary intakes of vitamin C, zinc, selenium, and CDAI were negatively associated with asthma risk (Vitamin C: OR = 0.76, 95 % CI: 0.63-0.91, P = 0.032; Zinc: OR = 0.86, 95 % CI: 0.75-1.00, P = 0.046; Selenium: OR = 0.85, 95 % CI: 0.73-0.98, P = 0.004; CDAI: OR = 0.80, 95 % CI: 0.65-0.97, P = 0.027). There was a significant nonlinear relationship between the dietary intake of vitamin C, zinc, and selenium and the risk of asthma (Pnon-linear < 0.05). However, no causal link between circulating antioxidants and asthma risk was found in the MR analysis. Sensitivity analyses supported the robustness of the results. CONCLUSION: In the observational study, we identified a negative correlation between the dietary intake of vitamin C, zinc, selenium, and CDAI and asthma risk, while our MR analyses did not find evidence to support a causal relationship between diet-derived antioxidants and the risk of asthma.

Association between Omega-3 fatty acids and autoimmune disease: Evidence from the umbrella review and Mendelian randomization analysis.

BACKGROUND: Autoimmune diseases are a group of disorders characterized by abnormal immune responses that mistakenly target and attack healthy cells, tissues, and organs, resulting in inflammation and tissue damage. Omega-3 fatty acids possess anti-inflammatory activities and may decrease abnormal immune activity. However, the role of omega-3 fatty acids in various autoimmune diseases is still unclear. This umbrella review and Mendelian randomization (MR) study aims to summarize the highest available evidence on omega-3 fatty acids and autoimmune disease. METHODS: We conducted an umbrella review by searching electronic databases to identify systematic reviews and meta-analyses. The selection criteria included systematic reviews with or without meta-analysis, which evaluated omega-3 fatty acids as the exposure and autoimmune disease as the outcome variable. Two authors independently assessed the overlapping and quality of the reviews using the AMSTAR-2 tool. We also performed MR studies to investigate the potential causal effect of fatty acids on the risk of various autoimmune diseases, utilizing data from the meta-analysis of the UKB-TOPMed and FinnGen cohorts. RESULT: The umbrella review identified 21 studies (8 systematic reviews and 13 meta-analyses) on 9 autoimmune diseases and 30 diseases in the MR study. AMSTAR 2 categorized the quality of evidence in six studies as critically low, six studies as low, eight studies as moderate, and one as high-quality evidence. The consistent result between the review and the MR study demonstrated the benefit of omega-3 fatty acids on rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Additionally, in our summary review, omega-3 fatty acids can improve disease activity and inflammation biomarkers; however, MR studies provided no consistent evidence for the causal effects of omega-3 fatty acids on psoriasis, multiple sclerosis (MS), type 1 diabetes (T1D), IgA nephropathy (IgAN), juvenile idiopathic arthritis (JIA), Crohn's disease (CD), and ulcerative colitis (UC). CONCLUSION: The current study presented solid evidence highlighting the advantageous impact of omega-3 fatty acids on SLE and RA. This was achieved through the reduction of disease risk, the decrease of disease activity, and the mitigation of inflammatory biomarkers. To stratify another autoimmune illness, it is necessary to carry out rigorous evaluations to surpass the existing findings and enhance understanding in this domain.

Comprehensive analysis of aging-related gene expression patterns and identification of potential intervention targets.

PURPOSE: This study aims to understand the molecular mechanisms underlying the aging process and identify potential interventions to mitigate age-related decline and diseases. METHODS: This study utilized the GSE168753 dataset to conduct comprehensive differential gene expression analysis and co-expression module analysis. Machine learning and Mendelian randomization analyses were employed to identify core aging-associated genes and potential drug targets. Molecular docking simulations and mediation analysis were also performed to explore potential compounds and mediators involved in the aging process. RESULTS: The analysis identified 4164 differentially expressed genes, with 1893 upregulated and 2271 downregulated genes. Co-expression analysis revealed 21 modules, including both positively and negatively correlated modules between older age and younger age groups. Further exploration identified 509 aging-related genes with distinct biological functions. Machine learning and Mendelian randomization analyses identified eight core genes associated with aging, including DPP9, GNAZ, and RELL2. Molecular docking simulations suggested resveratrol, folic acid, and ethinyl estradiol as potential compounds capable of attenuating aging through modulation of RELL2 expression. Mediation analysis indicated that eosinophil counts and neutrophil count might act as mediators in the causal relationship between genes and aging-related indicators. CONCLUSION: This comprehensive study provides valuable insights into the molecular mechanisms of aging and offers important implications for the development of anti-aging therapeutics. Key Messages What is already known on this topic - Prior research outlines aging's complexity, necessitating precise molecular targets for intervention. What this study adds - This study identifies novel aging-related genes, potential drug targets, and therapeutic compounds, advancing our understanding of aging mechanisms. How this study might affect research, practice, or policy - Findings may inform targeted therapies for age-related conditions, influencing future research and clinical practices.

Association between lipid-lowering agents with intervertebral disc degeneration, sciatica and low back pain: a drug-targeted mendelian randomized study and cross-sectional observation.

BACKGROUND: Abnormal lipid metabolism is linked to intervertebral disc degeneration (IVDD), sciatica, and low back pain (LBP), but it remains unclear whether targeted interventions can prevent these issues. This study investigated the causal effects of lipid-lowering drug use on IVDD, sciatica, and LBP development. METHODS: Single-nucleotide polymorphisms (SNPs) linked to total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and non-high-density-lipoprotein cholesterol (non-HDL-C) were obtained from the Global Lipids Genetics Consortium's genome-wide association study (GWAS). Genes near HMGCR, PCSK9, and NPC1L1 were selected to represent therapeutic inhibition targets. Using Mendelian randomization (MR) focusing on these drug targets, we identified causal effects of PCSK9, HMGCR, and NPC1L1 on the risk of developing IVDD, sciatica, and LBP, with coronary heart disease risk serving as a positive control. Using summary data from Mendelian randomization (SMR) analysis, we evaluated potential therapeutic targets for IVDD, sciatica, and LBP through protein quantitative trait loci (pQTL). The genetic associations with IVDD, sciatica, LBP, and coronary heart disease were derived from FinnGen (discovery) and UK Biobank (replication). Additionally, a cross-sectional observational study was performed using data from the National Health and Nutrition Examination Survey (NHANES) to further investigate the connection between LBP and statin use, with a sample size of 4343 participants. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to assess the outcomes. RESULTS: The NHANES-based cross-sectional study indicated that non-statin use was associated with an increased risk of developing LBP (OR = 1.29, 95% CI [1.04, 1.59], P = 0.019). Moreover, Inverse-variance weighting (IVW) analysis revealed that NPC1L1-mediated reductions in TC, LDL-C, and non-HDL-C concentrations were associated with a decreased risk of developing IVDD (P = 9.956E-03; P = 3.516E-02; P = 1.253E-04). Similarly, PCSK9-mediated reductions in LDL-C and TC concentrations were linked to a lower risk of developing sciatica (P = 3.825E-02; P = 2.709E-02). Sensitivity analysis confirmed the stability and reliability of the MR results. MST1 (macrophage stimulating 1) levels was inversely associated with IVDD, sciatica, and LBP risks. CONCLUSION: The results of cross-sectional study suggested that non-use of statins was positively correlated with LBP. The results of Mendelian randomization study suggest that NPC1L1 could lower the risk of developing IVDD by reducing TC, LDL-C, and non-HDL-C levels. Additionally, PCSK9 may reduce the risk of developing sciatica by lowering LDL-C and TC levels. In contrast, HMGCR appears to have no significant effect on IVDD, sciatica, or LBP development. Nonetheless, further research is needed to verify these preliminary results. MST1 warrants further exploration as a potential therapeutic target. It is necessary to do further research to validate these findings.

Identifying therapeutic targets for primary ovarian insufficiency through integrated genomic analyses.

BACKGROUND: Primary ovarian insufficiency (POI) is a disorder characterized by the premature decline in ovarian function, leading to significant fertility and health impacts on women under 40. The unclear etiology of POI hinders the development of effective treatments, highlighting the need for novel therapeutic targets. METHODS: This study employed genome-wide association analysis (GWAS) integrated with expression quantitative trait loci (eQTL) data from the GTEx and eQTLGen databases. Mendelian randomization (MR) and colocalization analyses were conducted to investigate causal relationships between genetic variants and POI and to identify potential therapeutic targets. RESULTS: We identified 431 genes with available index cis-eQTL signals, of which four (HM13, FANCE, RAB2A, and MLLT10) were significantly associated with POI. Colocalization analysis revealed strong evidence for FANCE and RAB2A, indicating their potential as therapeutic targets. Subsequent druggability assessments identified FANCE and RAB2A as promising candidates for POI treatment, supported by their involvement in DNA repair and autophagy regulation, respectively. CONCLUSIONS: Our study establishes a causal link between specific genes and POI, highlighting FANCE and RAB2A as potential drug targets. These findings provide a foundation for future research and therapeutic development, aiming to improve outcomes for women with POI. Validation in further trials is necessary to confirm these potential targets.

Identification of novel targets associated with cholesterol metabolism in nonalcoholic fatty liver disease: a comprehensive study using Mendelian randomization combined with transcriptome analysis.

Background: There is limited research on cholesterol metabolism-related genes (CM-RGs) in non-alcoholic fatty liver disease (NAFLD), despite hypercholesterolemia being a recognized risk factor. The role of CM-RGs in NAFLD remains unclear. Methods: The differentially expressed genes (DEGs) between NAFLD and control were acquired by differential expression analysis. The differentially expressed genes associated with cholesterol metabolism (DE-CM-RGs) were identified and functional enrichment analyses were performed. Protein-protein interaction network analysis and a two-sample Mendelian randomization study were utilized for identifying hub genes. Nomogram model, competing endogenous RNA and messenger RNA-drug networks were established. In addition, immunoinfiltration analysis was performed. Results: We identified four hub genes (MVK, HMGCS1, TM7SF2, and FDPS) linked to NAFLD risk. MVK and TM7SF2 were protective factors, HMGCS1 and FDPS were risk factors for NAFLD. The area under the curve values of nomograms in GSE135251 and GSE126848 were 0.79 and 0.848, respectively. The gene set enrichment analysis indicated that hub genes participated in calcium signaling pathways and biosynthesis of unsaturated fatty acids. NAFLD patients showed increased CD56dim NK cells and Th17. Tretinoin, alendronate, zoledronic acid, and quercetin are potential target agents in NAFLD. Conclusion: Our study has linked cholesterol metabolism genes (MVK, HMGCS1, TM7SF2, and FDPS) to NAFLD, providing a promising diagnostic framework, identifying treatment targets, and offering novel perspectives into its mechanisms.

Integrative multi-omics summary-based mendelian randomization identifies key oxidative stress-related genes as therapeutic targets for atrial fibrillation and flutter.

Background: Atrial fibrillation (AF) is a prevalent cardiac arrhythmia associated with substantial morbidity and mortality. Oxidative stress (OS) has been implicated in the pathogenesis of AF, suggesting that targeting OS-related genes could offer novel therapeutic opportunities. This study aimed to identify causal OS-related genes contributing to AF through a comprehensive multi-omics Summary-based Mendelian Randomization (SMR) approach. Methods: This study integrated data from genome-wide association studies (GWAS) with methylation quantitative trait loci (mQTL), expression QTL (eQTL), and protein QTL (pQTL) to explore the relationships between oxidative stress-related (OS-related) genes and AF risk. Genes associated with oxidative stress and AF were obtained from the Nielsen et al. study (discovery) and the FinnGen study (replication). The SMR analysis and HEIDI test were utilized to assess causal associations, followed by Bayesian co-localization analysis (PPH4 > 0.5) to confirm shared causal variants. Multi-omics data were employed to analyze the associations within mQTL-eQTL pathways. A two-sample MR analysis was conducted for sensitivity verification. The significance of findings was determined using a false discovery rate (FDR) < 0.05 and p_HEIDI > 0.01. Results: At the DNA methylation level, 19 CpG sites near 7 unique genes were found to have causal effects on AF and strong co-localization evidence support (PPH4 > 0.70). At the gene expression level, six oxidative stress-related genes from eQTLGen and three from GTEx (v8), including TNFSF10, CDKN1A, ALOX15, TTN, PTK2, ALB, KCNJ5, and CASQ2, were found to have causal effects on AF in the sensitivity and co-localization analyses (PPH4 > 0.50). At the circulating protein level, both ALAD (OR 0.898, 95% CI 0.845-0.954, PPH4 = 0.67) and APOH (OR 0.896, 95% CI 0.844-0.952, PPH4 = 0.93) were associated with a lower risk of AF, and APOH was validated in the replication group. After integrating the multi-omics data between mQTL and eQTL, we identified two oxidative stress-related genes, TTN and CASQ2. The methylation of cg09915519 and cg10087519 in TTN was associated with higher expression of TTN and a lower risk of AF, which aligns with the negative effect of TTN gene expression on AF risk. TTN may play a protective role in AF. Conclusion: This study identified several OS-related genes, particularly TTN, as having causal roles in AF, which were verified across three-omics pathways. The findings underscore the importance of these genes in AF pathogenesis and highlight their potential as therapeutic targets. The integration of multi-omics data provides a comprehensive understanding of the molecular mechanisms underlying AF, paving the way for targeted therapeutic strategies.

Bidirectional two-sample Mendelian randomization analysis investigates causal associations between cathepsins and inflammatory bowel disease.

Background: Cathepsins, key regulators of the pathology of gastrointestinal disorders such as inflammatory bowel disease (IBD), are a target protease that has attracted much attention in recent years. IBD is a chronic and relapsing inflammatory disorder of the gut. Traditional studies have shown a correlation between cathepsin and the risk of IBD, while the causal relationship remains unclear. Methods: This study utilized Mendelian randomization techniques to evaluate the causal relationships between eleven cathepsins and the subtypes of IBD, such as ulcerative colitis (UC) and Crohn's disease (CD). We also performed a series of sensitivity analyses to validate the primary Mendelian randomization (MR) results, including Cochran's Q test, the MR-PRESSO global test, and the MR pleiotropy test. Results: The forward MR analyses showed no significant association between cathepsins and IBD. Reverse Mendelian randomization analyses suggested that UC might lead to elevated cathepsin G levels [inverse-variance weighted (IVW): p = 0.038, b = 9.966], and CD might cause a decrease in cathepsin B levels [IVW: p = 0.002, b = -10.525] and cathepsin L1 levels [IVW: p = 0.045, b = -4.742]. Conclusions: Our findings offer novel and comprehensive evidence on the impact of UC or CD on cathepsins, potentially providing valuable insights into the treatment and prognosis of IBD.

Causal relationship between non-alcoholic fatty liver disease and sarcopenia: a bidirectional Mendelian randomization study.

Introduction: A correlation between non-alcoholic fatty liver disease and sarcopenia is demonstrated, but the causality remains unclear. Our study aims to clarify the point of genetics between non-alcoholic fatty liver disease (NAFLD) and sarcopenia at the level of gene prediction through two-sample Mendelian randomization (MR) analysis. Methods: The study employed the two-sample MR approach to investigate the bi-directional causality between NAFLD and sarcopenia. Published summary statistics were used to obtain instrumental variables (IVs) at the genome-wide significance level. Results: IVW analysis showed that the risk of NAFLD was reduced when walking pace was increased (OR = 0.435, 95%CI 0.240-0.789, p = 0.006); Increasing appendicular lean mass (ALM) decreased the risk of NAFLD (OR = 0.906, 95%CI 0.838-0.980, p = 0.014); Those older than 60 were more likely to suffer from NAFLD if they had low grip strength (OR = 1.411, 95%CI 1.087-1.830, p = 0.0012). In the reverse MR study, weight median analysis showed that NAFLD caused a decrease in ALM (OR = 0.953, 95%CI 0.957-0.994, p = 0.001); whereas NAFLD showed no correlation with usual walking pace or grip strength (all with p > 0.05). MR-Egger regression analysis showed that there was no horizontal pleiotropy in the SNPs (all with p > 0.05). Conclusion: The characteristics related to sarcopenia (usual walking pace, appendicular lean mass and low hand grip strength) may play a causal role in the development of nonalcoholic fatty liver disease, although the underlying mechanisms need to be further investigated. The presence of specific single nucleotide polymorphisms (SNPs) such as rs3747207, rs429358, and rs73001065 has been identified in the PNPLA3, APOE, and MAU2 proteins. These genetic markers represent potential targets for future interventions aimed at addressing, managing, or mitigating the risk of NAFLD.

Causal Effects of Gut Microbiota and Metabolites on Chronic Obstructive Pulmonary Disease: A Bidirectional Two Sample Mendelian Randomization Study.

Background: Recent evidence suggests that the gut microbiome and metabolites are intricately involved in Chronic Obstructive Pulmonary Disease (COPD) pathogenesis, yet the precise causal relationships remain unclear due to confounding factors and reverse causation. This study employs bidirectional two-sample Mendelian Randomization (MR) to clarify these connections. Methods: Summary data from publicly available Genome-Wide Association Studies (GWAS) concerning the gut microbiome, metabolites, and COPD were compiled. The selection of genetic instrumental variables (Single Nucleotide Polymorphisms, or SNPs) for MR analysis was conducted meticulously, primarily utilizing the Inverse Variance Weighting (IVW) method, supplemented by MR-Egger regression and the Weighted Median (WM) approach. The evaluation of heterogeneity and horizontal pleiotropy was performed using Cochran's Q test, the MR-Egger intercept test, and the MR-PRESSO global test. Sensitivity analyses, including leave-one-out tests, were conducted to verify the robustness of our results. And the mediation effect of gut microbiota-mediated changes in metabolites on the causal relationship with COPD was analyzed. Results: Our study identified nine significant gut microbiota taxa and thirteen known metabolites implicated in COPD pathogenesis. Moreover, associations between the onset of COPD and the abundance of five bacterial taxa, as well as the concentration of three known metabolites, were established. These findings consistently withstood sensitivity analyses, reinforcing their credibility. Additionally, our results revealed that gut microbiota contribute to the development of COPD by mediating changes in metabolites. Conclusion: Our bidirectional Two-Sample Mendelian Randomization analysis has revealed reciprocal causal relationships between the abundance of gut microbiota and metabolite concentrations in the context of COPD. This research holds promise for identifying biomarkers for early COPD diagnosis and monitoring disease progression, thereby opening new pathways for prevention and treatment. Further investigation into the underlying mechanisms is essential to improve our understanding of COPD onset.

The Causal Effects between Mood Swings and Gastrointestinal Diseases: A Mendelian Randomization Study.

Background: Numerous studies have examined the links between mental disorders such as depression and bipolar disorder, and gastrointestinal (GI) diseases. However, few studies have investigated the link between mood swings and GI diseases. Given the impact of mood swings on various conditions and the growing comprehension of the gut-brain axis, this study aims to explore their causal relationship using Mendelian randomization (MR) methods. Methods: Single-nucleotide polymorphisms (SNPs) associated with mood swings were obtained from a recent study. SNPs associated with GI diseases were identified from the FinnGen project. We conducted two-sample bidirectional MR analyses using three methods, primarily the inverse variance weighting (IVW) method. Furthermore, we performed sensitivity analyses and false discovery rate (FDR) analysis to validate the accuracy and robustness of the results. Results: Bidirectional MR analysis revealed significant causal effects between mood swings and GI diseases according to the IVW method (odds ratio (OR): 1.213; 95% confidence interval (CI): 1.118-1.316; P = 3.490e-6; P FDR = 8.730e-5). Mood swings were linked to an increased risk for 11 of 24 diseases, including five upper GI diseases (gastroesophageal reflux disease (GERD), acute gastritis, gastroduodenal ulcer, duodenal ulcer, and functional dyspepsia), two lower GI diseases (diverticular disease of the intestine and irritable bowel syndrome (IBS)) and four hepatobiliary and pancreatic diseases (nonalcoholic fatty liver disease (NAFLD), chronic pancreatitis, acute pancreatitis, and pancreatic cancer). Inverse MR analysis showed no causal relationship between 24 GI diseases and mood swings. Conclusions: This comprehensive MR analysis suggests that genetically predicted mood swings may be a risk factor in the development of GI diseases. Interventions for mood swings may help to treat GI diseases.

Unravel the distinct effects of adiposity at different life stages on COVID-19 susceptibility and severity: A life-course Mendelian randomization study.

Childhood obesity is widely recognized as a risk factor for numerous health conditions, particularly cardiovascular disease. However, it remains unclear whether childhood adiposity directly affects the risk of COVID-19 in later life. We aimed to investigate the causal effects of early life adiposity on COVID-19 susceptibility and severity. We used genetic instruments from large-scale genome-wide association studies to examine the relationships between birth weight, childhood and adulthood adiposity indicators (including body mass index [BMI], obesity, and body size), and COVID-19 outcomes. Univariable and multivariable Mendelian randomization (MR) analyses were used to obtain the causal estimates. Univariable MR analyses found that childhood BMI and obesity were positively associated with COVID-19 risk and severity in adulthood, however, the significant associations were attenuated to null after further adjusting for adulthood adiposity indicators in multivariable MR analyses. In contrast, our analysis revealed strong evidence of a genetically predicted effect of childhood obesity on COVID-19 hospitalization (OR 1.08, 95% CI: 1.01-1.15, p = 2.12E-2), which remained robust even after adjusting for adulthood obesity and potential lifestyle confounders. Our results highlight the importance of promoting healthy weight management throughout life to reduce the risk of COVID-19.

Lower Incidence of Dementia Following Cancer Diagnoses: Evidence from a Large Cohort and Mendelian Randomization Study.

BACKGROUND: The reported inverse association between cancer and subsequent Alzheimer's disease and related dementias (ADRD) remains uncertain. OBJECTIVES: To investigate the association between these common conditions of old age and explore possible causal factors. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We conducted a large population-based cohort analysis using data from 3,021,508 individuals aged 60 and over in the UK Clinical Practice Research Datalink (CPRD), over a period up to 30 years (1988-2018). Cox proportional hazards models were fitted to estimate hazard ratios (HR) for risk of dementia associated with previous cancer diagnosis. Competing risk models were employed to account for competing risk of death. Two-sample Mendelian Randomization analysis based on meta-analysis data from large-scale GWAS studies was also conducted. RESULTS: In the CPRD cohort, 412,903 participants had cancer diagnosis and 230,558 were subsequently diagnosed with dementia over a median follow-up period of 7.9 years. Cancer survivors had a 25% lower risk of developing dementia (HR=0.75, 95% CI:0.74-0.76) after adjustment for potential confounders. Accounting for competing risk of death provided a sub-distribution HR of 0.56 (95% CI:0.55-0.56). Results were consistent for prevalent and incident cancer and different common cancer types. Two-sample Mendelian Randomization analysis, using 357 cancer-related instrumental single-nucleotide polymorphisms (SNPs) revealed evidence of vertical pleiotropy between genetically predicted cancer and reduced risk of Alzheimer's disease (OR=0.97,95% CI:0.95-0.99). CONCLUSION: Our results provide strong epidemiological evidence of the inverse association between cancer and risk of ADRD and support the potential causal nature of this association via genetic instruments. Further investigations into the precise underlying biological mechanisms may reveal valuable information for new therapeutic approaches.