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Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p

Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPHs potential role in CRC prevention.

The role of gut microbe-derived metabolites in the development of metabolic syndrome (MetS) remains unclear. This study aimed to evaluate the associations of gut microbe-derived metabolites and MetS traits in the cross-sectional Metabolic Syndrome In Men (METSIM) study. The sample included 10,194 randomly related men (age 57.65 ± 7.12 years) from Eastern Finland. Levels of 35 metabolites were tested for associations with 13 MetS traits using lasso and stepwise regression. Significant associations were observed between multiple MetS traits and 32 metabolites, three of which exhibited particularly robust associations. N-acetyltryptophan was positively associated with Homeostatic Model Assessment for Insulin Resistant (HOMA-IR) (β = 0.02, p = 0.033), body mass index (BMI) (β = 0.025, p = 1.3 × 10-16), low-density lipoprotein cholesterol (LDL-C) (β = 0.034, p = 5.8 × 10-10), triglyceride (0.087, p = 1.3 × 10-16), systolic (β = 0.012, p = 2.5 × 10-6) and diastolic blood pressure (β = 0.011, p = 3.4 × 10-6). In addition, 3-(4-hydroxyphenyl) lactate yielded the strongest positive associations among all metabolites, for example, with HOMA-IR (β = 0.23, p = 4.4 × 10-33), and BMI (β = 0.097, p = 5.1 × 10-52). By comparison, 3-aminoisobutyrate was inversely associated with HOMA-IR (β = -0.19, p = 3.8 × 10-51) and triglycerides (β = -0.12, p = 5.9 × 10-36). Mendelian randomization analyses did not provide evidence that the observed associations with these three metabolites represented causal relationships. We identified significant associations between several gut microbiota-derived metabolites and MetS traits, consistent with the notion that gut microbes influence metabolic homeostasis, beyond traditional risk factors.

ABSTRACT Previous studies have suggested a link between the gut microbiome and hypertension‐related traits like blood pressure. However, these reports are often limited by weak causal evidence. This study investigates the potential causal association between gut microbiota and hypertension‐related traits using Mendelian randomization with summary data from genome‐wide association studies. The inverse‐variance weighted method revealed that the Clostridium innocuum group (Odds ratio [OR]: 1.0047, 95% confidence interval [CI]: 1.0004–1.0090, p = 0.0336), Eubacterium fissicatena group (OR: 1.0047, 95% CI: 1.0005–1.0088, p = 0.0266), Lachnospiraceae FCS020 group (OR: 1.0063, 95% CI: 1.0004–1.0122, p = 0.0361), and Olsenella (OR: 1.0044, 95% CI: 1.0001–1.0088, p = 0.0430) were associated with an increased risk of hypertension. Conversely, Flavonifractor (OR: 0.9901, 95% CI: 0.9821–0.9982, p = 0.0166), Parabacteroides (OR: 0.9874, 95% CI: 0.9776–0.9972, p = 0.0121), and Senegalimassilia (OR: 0.9907, 95% CI: 0.9842–0.9974, p = 0.0063) were associated with a decreased risk of hypertension. External validation with the Guangdong Gut Microbiome Project confirmed a negative correlation between Parabacteroides and hypertension, potentially through metabolic pathways. These findings provide further evidence supporting the hypothesis that microbes and their metabolites play a role in blood pressure regulation. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is a prevalent inflammatory airway disease affecting over 10% of the global population, leading to considerable socio-economic impacts, especially in developing countries. The pathogenesis of CRS is multifactorial, involving potential contributions from both genetic and environmental factors. While the influence of allergic and autoimmune diseases on CRS has been observed, the causal relationships between these diseases and CRS remain unclear. We extracted data from large-scale genome-wide association studies (GWAS) and utilized a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationships between CRS and ten autoimmune and allergic diseases, including asthma, allergic rhinitis (AR), atopic dermatitis (AD), psoriasis, type 1 diabetes (T1D), hypothyroidism, celiac disease (CeD), multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Additionally, we conducted colocalization analysis to determine whether the allergic/autoimmune diseases showing statistical causal relationships with CRS are driven by the same genetic variants. The MR analysis identified that AR (OR = 1.30; 95% CI = 1.21–1.40; P = 3.26E−13), asthma (OR = 1.35; 95% CI = 1.25–1.45; P = 1.35E−14), and AD (OR = 1.17; 95% CI = 1.06–1.30; P = 0.003) were significantly associated with an increased risk of developing CRS. Interestingly, psoriasis (OR = 0.05; 95% CI = 0.01–0.37; P = 0.004) appeared to have a protective effect against CRS. Associations for T1D and hypothyroidism were also suggestive as potential risk factors for CRS. No significant associations in the reverse MR analysis, suggesting a one-directional relationship. Colocalization analysis indicated that asthma (PP.H4 = 0.99) shared the same genetic variant (IL-33 rs3939286) with CRS. In conclusion, our study confirmed the causal relationships between allergic and autoimmune diseases (AR, asthma, AD, and psoriasis) and CRS. Notably, we identified a shared genetic variant, rs3939286 in the IL-33 gene, between asthma and CRS, suggesting that targeting the IL-33 pathway may provide a therapeutic strategy for both diseases. [ABSTRACT FROM AUTHOR]

Alcohol is widely used but recognized as a risk factor for several adverse health outcomes based on observational studies. How alcohol affects lifespan remains controversial, with no trial to make such an assessment available or likely. We conducted a Mendelian randomization (MR) to assess the effect of alcohol on lifespan in men and women, including a possible role of smoking and education. Strong (p < 5e− 8), independent (r2 < 0.001) genetic predictors of alcohol consumption in 2,428,851 participants of European ancestry from the Sequencing Consortium of Alcohol and Nicotine use (GSCAN) consortium genome wide association study (GWAS) were applied to sex-specific GWAS of lifespan (paternal and maternal attained age) and age at recruitment to the UK Biobank. We used multivariable MR to allow for smoking and education, with systolic and diastolic blood pressure as control outcomes. Inverse variance weighted was the primary analysis with sensitivity analysis. Alcohol consumption decreased lifespan overall (− 1.09 years (logged alcoholic drinks per week), − 1.89 to − 0.3) and in men (− 1.47 years, − 2.55 to − 0.38), which remained evident after adjusting for smoking (− 1.81 years, − 3.3 to − 0.32) and education (− 1.85 years, − 3.12 to − 0.58). Estimates from sensitivity analysis were similar, and when using the genetic variant physiologically associated with alcohol use. Alcohol consumption was associated with higher blood pressure as expected. Our study indicates that alcohol does not provide any advantages for men or women but could shorten lifespan. Appropriate interventions should be implemented. [ABSTRACT FROM AUTHOR]

ABSTRACT Mendelian randomization uses genetic variants as instrumental variables to estimate the causal effect of exposure on outcome from observational data. A common challenge in Mendelian randomization is that many genetic variants are only modestly or even weakly associated with the exposure of interest, a setting known as many weak instruments. Conventional methods, such as the popular inverse‐variance weighted (IVW) estimator, could be heavily biased toward zero when the instrument strength is weak. To address this issue, the debiased IVW (dIVW) estimator and the penalized IVW (pIVW) estimator, which are shown to be robust to many weak instruments, were recently proposed. However, we find that the dIVW estimator tends to produce an exaggerated estimate of the causal effect, especially when the effective sample size is small. Although the pIVW estimator has better statistical properties, it is slightly more complex, and the idea behind this method is also a bit less intuitive. Therefore, we propose a modified debiased IVW (mdIVW) estimator that directly multiplies a shrinkage factor with the original dIVW estimator. After this simple modification, we prove that the mdIVW estimator not only has second‐order bias with respect to the effective sample size, but also has smaller variance and mean squared error than the preceding two estimators. We then extend the proposed method to account for the presence of instrumental variable selection and balanced horizontal pleiotropy. We demonstrate the improvement of the mdIVW estimator over the competing ones through extensive simulation studies and real data analysis. [ABSTRACT FROM AUTHOR]

A two‐sample Mendelian randomization (MR) analysis was utilized to assess the causal relationship between lipidomic profiles and the risk of intracranial aneurysms (IAs). Genetic variants related to lipidomic profiles (227 components) and IA [IA, aneurysmal subarachnoid hemorrhage (aSAH) only, unruptured IA (uIA) only] were obtained from published genome‐wide association studies (GWASs) or the IEU Open GWAS project and used as instrumental variables for MR analysis. The inverse‐variance weighted method was used in the primary analyses to derive causality estimates and was expressed as odds ratio (OR) with 95% confidence interval (CI). Of these 227 lipidomic profiles, only genetically predicted high levels of cholesterol to total lipids ratio in very small very‐low‐density lipoproteins (VLDL) [OR = 0.629 (95% CI, 0.504–0.786)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.637 (95% CI, 0.509–0.797)], ratio of docosahexaenoic acid to total fatty acids [OR = 0.691 (95% CI, 0.582–0.820)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.630 (95% CI, 0.522–0.760)] reduced the risk of aSAH, whereas genetically predicted high ratio of monounsaturated fatty acids to total fatty acids [OR = 1.471 (95% CI, 1.215–1.781)] increased the risk of aSAH. Moreover, genetically predicted high levels of cholesterol to total lipids ratio in very small VLDL [OR = 0.657 (95% CI, 0.542–0.798)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.663 (95% CI, 0.548–0.803)], free cholesterol to total lipids ratio in small VLDL [OR = 0.682 (95% CI, 0.560–0.832)], phospholipids to total lipids ratio in small VLDL [OR = 0.674 (95% CI, 0.548–0.830)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.678 (95% CI, 0.569–0.808)] reduced the risk of IA. The results of multivariable MR demonstrated that these causal associations persisted after adjusting for systolic blood pressure and cigarettes smoked per day. The effect of serum lipids on IA and aSAH may be mainly caused by subclasses of lipids such as VLDL. [ABSTRACT FROM AUTHOR]

Introduction: The general population experiences mortality rates that are related to high levels of high-sensitivity C-reactive protein (hs-CRP). We aim to assess the linkage of longitudinal trajectories in hs-CRP levels with all-cause mortality in Chinese participants. Methods: We utilized data from the China Health and Retirement Longitudinal Study (CHARLS). The exposures were dynamic changes in the hs-CRP and cumulative hs-CRP from 2012 to 2015, and the outcome was all-cause mortality. All participants were categorized into four trajectories according to hs-CRP levels. Multivariable logistic regression analysis, adjusted for potential confounders, was employed to evaluate the relationship of different trajectories of hs-CRP with mortality risk. A two-sample Mendelian randomization (TSMR) method and SHapley Additive exPlanations (SHAP) for identifying determinants of mortality risk were also employed. Results: The study included 5,445 participants with 233 deaths observed, yielding a mortality proportion of 4.28%. Compared to individuals maintaining low, stable levels of hs-CRP (Class 1), individuals with sustained elevated levels of hs-CRP (Class 4), those experiencing a progressive rise in hs-CRP levels (Class 2), or those transitioning from elevated to reduced hs-CRP levels (Class 3) all faced a significantly heighted death risk, with adjusted Odds Ratios (ORs) ranging from 2.34 to 2.47 across models. Moreover, a non-linear relationship was found between them. Further TSMR analysis also supported these findings. SHAP showed that hs-CRP was the fifth most important determinant of mortality risk. Conclusions: Our study shows all-cause mortality increases with dynamic changes in hs-CRP levels among middle-aged and elderly adults in China, and cumulative hs-CRP shows an L-shaped relationship with all-cause mortality. [ABSTRACT FROM AUTHOR]

Background: There is evidence that inflammatory arthritis in the form of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and rheumatoid arthritis are both positively and negatively associated with certain female-specific cancers. However, the study results are very heterogeneous. Methods: Based on up to 375,814 European women, we performed an iterative two-sample Mendelian randomization to assess causal effects of the occurrence of the inflammatory arthritis on the risk of female-specific cancer in form of breast, endometrial, and ovarian cancer sites as well as their subtypes. Evidence was strengthened by using similar exposures for plausibility or by replication with a subsequent meta-analysis. P-values were Bonferroni adjusted. Results: Genetic liability to AS was associated with ovarian cancer (OR = 1.03; 95% CI: [1.01; 1.04]; =0.029) and liability to PsA with breast cancer (OR = 1.02; CI: [1.01; 1.04]; =0.002). Subgroup analyses revealed that the high-grade serous ovarian cancer (OR = 1.04; CI: [1.02; 1.06]; =0.015) and the ER- breast cancer (OR = 1.04; CI: [1.01; 1.07]; =0.118) appeared to drive the observed associations, respectively. No further associations were found between the remaining inflammatory arthritis phenotypes and female-specific cancers. Conclusions: This study suggests that AS is a risk factor for ovarian cancer, while PsA is linked to an increased breast cancer risk. These results are important for physicians caring women with inflammatory arthritis to advise their patients on cancer screening and preventive measures. [ABSTRACT FROM AUTHOR]

Background: Understanding genetic-metabolite associations has translational implications for informing cardiovascular risk assessment. Interrogating functional genetic variants enhances our understanding of disease pathogenesis and the development and optimization of targeted interventions. Methods: In this study, a total of 187 plasma metabolite levels were profiled in 4974 individuals of European ancestry of the GCAT| Genomes for Life cohort. Results of genetic analyses were meta-analysed with additional datasets, resulting in up to approximately 40,000 European individuals. Results of meta-analyses were integrated with reference gene expression panels from 58 tissues and cell types to identify predicted gene expression associated with metabolite levels. This approach was also performed for cardiovascular outcomes in three independent large European studies (N = 700,000) to identify predicted gene expression additionally associated with cardiovascular risk. Finally, genetically informed mediation analysis was performed to infer causal mediation in the relationship between gene expression, metabolite levels and cardiovascular risk. Results: A total of 44 genetic loci were associated with 124 metabolites. Lead genetic variants included 11 non-synonymous variants. Predicted expression of 53 fine-mapped genes was associated with 108 metabolite levels; while predicted expression of 6 of these genes was also associated with cardiovascular outcomes, highlighting a new role for regulatory gene HCG27. Additionally, we found that atherogenic metabolite levels mediate the associations between gene expression and cardiovascular risk. Some of these genes showed stronger associations in immune tissues, providing further evidence of the role of immune cells in increasing cardiovascular risk. Conclusions: These findings propose new gene targets that could be potential candidates for drug development aimed at lowering the risk of cardiovascular events through the modulation of blood atherogenic metabolite levels. [ABSTRACT FROM AUTHOR]

Background: Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear. Methods: We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer's Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer's Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites. Results: MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P < 0.005). Conclusions: Our study indicates that mtDNA-CN measured in blood is predictive of AD and is associated with AD biomarkers including plasma NFL particularly in females. Further, we illustrate that decreased mtDNA-CN possibly increases AD risk through dysregulation of mitochondrial lipid metabolism and inflammation. [ABSTRACT FROM AUTHOR]

To gain a clearer understanding of the relationship between venous leg ulcers (VLUs) and knee osteoarthritis (KOA), we performed a two‐sample, bidirectional Mendelian randomization (MR) analysis in this study. The present MR was carried out using summary data from publicly available genome‐wide association studies. After filtering single‐nucleotide polymorphism (SNP), we applied a variety of MR methods including inverse variance weighted (IVW), MR egger, weighted mode, and weighted median. IVW analysis revealed that the genetic association between VLUs and KOA was not significant (β = −0.017; SE 0.039; p = 0.658). In agreement with the IVW analysis, the findings of the weighted median estimator (β = −0.017; SE 0.052, p = 0.751), MR egger (β = 0.057; SE 0.084; p = 0.513), and weighted mode (β = 0.060; SE 0.078; p = 0.456) indicated the absence of a significant genetic association between VLUs and KOA. Furthermore, reverse causality analysis suggested a lack of genetic relationship between KOA and VLUs. In conclusion, the present MR study does not suggest a causal relationship or reverse causal relationship between VLUs and KOA. [ABSTRACT FROM AUTHOR]

In recent observational studies, a potential link between prostatitis and prostate cancer (PCa) has been hinted at, yet the causality remains ambiguous. In our endeavor to scrutinize the conceivable causal nexus between prostatitis and PCa, we embarked upon a Mendelian randomization (MR) study. MR circumvents arbitrary groupings by employing genetic variations that have a strong association with the exposure as instrumental variables to infer causal relationships between exposures and outcomes. The etiology of PCa remains elusive. Given that prostatitis and prostate cancer occupy the same anatomical region, MR can more effectively delineate their relationship by mitigating confounding variables. This method can indirectly elucidate disease correlations, thereby contributing to cancer prevention strategies. FinnGen Consortium data were used for the prostatitis genome-wide association study (GWAS), including 74,658 participants. UK biobank baseline data (ncase = 3436, ncontrol = 459574), European Bioinformatics Institute Database (ncase = 79148, ncontrol = 61106), and IEU openGWAS database (ncase = 79148, ncontrol = 61106) were used for PCa outcomes, mostly for European population samples. Data from the GWSAs for prostatitis were compared with data from the three GWASs for PCa, respectively, in an analysis of an MR. Utilizing the inverse variance weighting (IVW) methodology as our primary analytical framework, we delved into a meticulous exploration of the conceivable causal association between prostatitis and PCa. Furthermore, we deployed supplementary methodologies, including Maximum Likelihood, MR-Egger, weighted median, and MR-PRESSO, to thoroughly assess and scrutinize the causality aspect comprehensively. Cochran's Q statistic is employed as a metric to quantify the heterogeneity inherent in instrumental variables. The inverse variance weighted analysis revealed no discernible effect of prostatitis on PCa in the three PCa GWAS databases (odds ratio [OR]: 1.001, 95% Confidence Interval [CI]: 0.999–1.002, p = 0.28), (OR: 1.015, 95% CI: 0.981–1.050, p = 0.40), (OR: 1.015, 95% CI: 0.981–1.050, p = 0.40). Similarly, employing MR-Egger did not yield substantial evidence (OR: 0.999, 95% CI: 0.999–1.002, p = 0.89), (OR: 1.103, 95% CI: 1.006–1.209, p = 0.07), (OR: 1.103, 95% CI: 1.006–1.209, p = 0.07). The weighted median analysis also failed to provide convincing support for the impact of prostatitis on the incidence of PCa (OR: 1.001, 95% CI: 1.000-1.002, p = 0.064), (OR: 0.989, 95% CI: 0.946–1.034, p = 0.64), (OR: 0.989, 95% CI: 0.945–1.036, p = 0.65). The results of the MR showed no causality from prostatitis to PCa. [ABSTRACT FROM AUTHOR]

Background: We investigated the potential relationship between age-related conditions, particularly sarcopenia and ischemic stroke (IS), through a twosample Mendelian randomization (MR) study. Methods: We conducted a two-sample bidirectional MR study to investigate the relationship between sarcopenia and stroke. Genetic instruments for sarcopenia were derived from the UK Biobank, while data on IS and its subtypes were obtained from the MEGASTROKE consortium. Inverse variance weighting (IVW) served as the primary analytical method. Additionally, heterogeneity and pleiotropy were assessed to ensure the robustness of the findings. Results: The analysis indicates a negative correlation between appendicular lean mass (ALM) and small vessel stroke (SVS; OR = 0.790, 95% CI: 0.703--0.888, p < 0.001), a positive correlation with cardioembolic stroke (CES; OR = 1.165, 95% CI: 1.058--1.284, p = 0.002), and no causal relationship with any ischemic stroke (AIS) or large artery stroke (LAS). Additionally, SVS is negatively associated with right-hand grip strength (OR = 0.639, 95% CI: 0.437--0.934, p = 0.021), while AIS, LAS, and CES do not exhibit a causal relationship with grip strength. Furthermore, no causal relationship was identified between left-hand grip strength, usual walking pace, and IS or its subtypes. MR analysis reveals only a negative association between CES and usual walking pace (OR = 0.989, 95% CI: 0.980--0.998, p = 0.013), with no associations found between other IS subtypes and sarcopenia-related traits. Conclusion: This study demonstrates that a reduction in ALM and right-hand grip strength is associated with SVS, whereas decreased ALM may serve as a protective factor against CES. Conversely, our analysis suggests that CES can impact walking speed. Overall, these findings provide valuable insights into the prevention and treatment of these conditions. [ABSTRACT FROM AUTHOR]

Introduction: The intricate roles of immune cells and inflammatory factors in cancer, particularly their association with the risk of bladder cancer, are not well understood. Methods: This study aimed to clarify potential causal relationships between these elements and the development of bladder cancer using genome-wide association study (GWAS) summary statistics for 731 immune cell phenotypes and 91 circulating inflammatory factors (cases=2,053; controls=287,137). The primary analytical approach was Inverse Variance Weighting (IVW), supplemented by MR-Egger regression, weighted median, and weighted mode analyses. Sensitivity analyses included Cochran Q test, MR-Egger intercept test, and Leave-one-out test. Results: The findings indicated that monocytes are positively correlated with an increased risk of bladder cancer. On the contrary, double-negative (DN) T cells, HLA DR+CD8br, and CD28 on CD28+CD45RA+CD8br T cells exhibited an inverse correlation, suggesting a possible protective effect. Furthermore, inflammatory factors IL-20, IL-22RA1, and Eotaxin were significantly associated with an increased risk of bladder cancer. Discussion: These results suggest that certain immune cell phenotypes and inflammatory factors may play a role in the development of bladder cancer and could serve as potential biomarkers for assessing tumor risk. The findings also offer new insights into the pathogenesis of bladder cancer, indicating a need for further investigation. [ABSTRACT FROM AUTHOR]

Background: Extensive observational data suggest a link between celiac disease (CeD) and osteoporosis, but the causality and mediating mechanism remain undetermined. Herein, we performed a Mendelian randomization (MR) study to address these concerns. Methods: We obtained the summary-level statistics for CeD from a large genome-wide association study (GWAS) comprising 4,533 cases and 10,750 controls of European ancestry. The GWAS data for osteoporosis-related traits and inflammatory cytokines were derived from the UK Biobank, FinnGen, IEU OpenGWAS database, or GWAS catalog. Two-sample MR with the inverse variance-weighted methods were employed to evaluate the genetic association between CeD and osteoporosis-related traits. The potential inflammatory mediators from CeD to osteoporosis were explored using twostep mediation analyses. Results: The primary MR analyses demonstrated causal associations between genetically predicted CeD and osteoporosis (odds ratio [OR]: 1.110, 95% confidence interval [CI]: 1.043-1.182, p=0.001), total body bone mineral density (β: -0.025, p=0.039), and osteoporotic fracture (OR: 1.124, 95% CI: 1.009-1.253, p=0.034). Extensive sensitivity analyses consolidated these findings. Among the candidate inflammatory cytokines, only interleukin-18 was observed to mediate the effects of CeD on osteoporosis, with an indirect OR of 1.020 (95% CI: 1.000-1.040, p=0.048) and a mediation proportion of 18.9%. The mediation effects of interleukin-18 could be validated in other datasets (OR: 1.015, 95% CI: 1.001-1.029, p=0.041). Bayesian colocalization analysis supported the role of interleukin-18 in osteoporosis. Conclusion: The present MR study reveals that CeD is associated with an increased risk of developing osteoporosis, which may be partly mediated by upregulation of interleukin-18. [ABSTRACT FROM AUTHOR]

Background: Coffee is a widely consumed beverage with potential benefits for various chronic diseases. Its effect on reducing erectile dysfunction (ED) risk is unclear. This Mendelian randomization (MR) study investigates the impact of coffee/caffeine consumption on ED. Methods: Two sets of coffee consumption-associated genetic variants at the genome-wide significance level were obtained from recent studies of coffee consumption. Taking into account other sources of caffeine, genetic variants associated with caffeine consumption from tea were also obtained. The inverse variance weighted (IVW) method was utilized as the primary analysis. Sensitivity analysis methods and meta-analysis methods were performed to confirm the robustness of the results, while the genetic variants associated with confounders, e.g., diabetes and hypertension, were excluded. Results: Genetically predicted coffee/caffeine consumption was unlikely to be associated with the risk of ED in the Bovijn datasets, with similar directional associations observed in the FinnGen datasets. The combined odds ratio for ED was 1.011 (95% CI 0.841-1.216, p=0.906) for coffee consumption from the genome-wide meta-analysis, 1.049 (95% CI 0.487-2.260, p=0.903) for coffee consumption from the genome-wide association study, and 1.061 (95% CI 0.682-1.651, p=0.793) for caffeine from tea. Conclusion: Using genetic data, this study found no association between coffee/caffeine consumption and the risk of ED. [ABSTRACT FROM AUTHOR]

Background: Previous research has established connections between gut microbiota, immune modulation, and several virus-related diseases. However, no study has explored the relationships between gut microbiota and herpes zoster and postherpetic neuralgia (PHN). Methods: A total of 205 taxa of gut microbiota were regarded as exposures. The occurrences of herpes zoster and PHN were selected as outcomes. The causal effects of gut microbiota on herpes zoster and PHN were estimated with multiple methods for two-sample Mendelian randomization, such as inverse variance weighted (IVW), MR–Egger, and weighted median. All results were subjected to FDR correction to prevent from possibility of multiple comparison. Results: Among the significant findings, four taxa and one genus were identified as facilitators of herpes zoster and PHN, respectively. Conversely, six genera and eleven taxa were found to inhibit herpes zoster and PHN, respectively. The causal effect of the Tyzzerella 3 was confirmed through FDR correction, making it a key focus in this study. Specifically, it was found to causally facilitate herpes zoster primarily with IVW (OR 1.420, 95% CI 1.174–1.718, p < 0.001, q = 0.039), as there is no heterogeneity or horizontal pleiotropy found. Conclusions: With investigation of the causal association between gut microbiota, and herpes zoster/PHN, significant findings were identified in 22 different taxa. Among them, Tyzzerella 3 keeps significant after multiple comparison correction, and displays potential to facilitate the occurrence of herpes zoster. [ABSTRACT FROM AUTHOR]

Background: The relationship between gut microbiota and coagulation defects, purpura, and other hemorrhagic conditions (CPH) is currently unclear, with causal links yet to be firmly established. Objective: The causal relationships between gut microbiota and CPH, along with the potential mediating role of immune cells, were studied using Mendelian randomization analysis. Methods: Data on 412 gut microbiota species, 731 immune cell types, and CPH were methodologically compiled from genome-wide association studies and the FinnGen database. A 2-sample Mendelian randomization approach in 2 stages was used and the causal links between gut microbiota and CPH were statistically analyzed, assessing the potential mediation by immune cells. Sensitivity and reliability were ensured through heterogeneity and pleiotropy tests. Results: The abundance of Alistipes putredinis (odds ratio [OR]=0.77, 95% confidence interval [CI] 0.64-0.93, P=0.006) was negatively correlated with CPH, whereas the abundance of Bacteroides stercoris (OR=1.25, 95%CI 1.09-1.45, P=0.002) was positively correlated with the risk of CPH. There was no evidence of reverse causality or the potential mediating effects of 731 immune cell types. The abundance of Proteobacteria (OR=0.81, 95%CI 0.71-0.92, P=0.001) and Coprococcus sp. ART55/1 (OR=0.87, 95%CI 0.80-0.96, P=0.005) was negatively associated with the risk of CPH, whereas the abundance of Enterobacteriales/Enterobacteriaceae (OR=1.36, 95%CI 1.12-1.64, P=0.002) was positively correlated with the risk of CPH, with no evidence of reverse causality. Furthermore, CD38 levels on CD3-CD19 cells can serve as a mediating factor for the influence of Proteobacteria on the pathogenesis of CPH, with a mediating effect ratio of 7.26%. Conclusions: An increase in Proteobacteria abundance leads to a decrease in CD38 expression on CD3-CD19-cells, thereby reducing the risk of developing CPH. CD3 expression on naive CD4+ in mature T cells serves as a mediating factor for the influence of Enterobacteriales/Enterobacteriaceae on the pathogenesis of CPH, whereas IgD CD38br AC expression on B cells serves as a mediating factor for the influence of Coprococcus sp. ART55/1 on the pathogenesis of CPH. The mediating effect is opposite to the overall trend and has a relatively small impact. No significant heterogeneity or pleiotropy was observed. [ABSTRACT FROM AUTHOR]

Introduction: A potential link between venous thromboembolism and the risk of ovarian cancer has been identified in clinical practice. However, it is unclear whether there is a causal relationship between the two. In this study, we applied a univariate two-sample Mendelian randomization method to explain the possible link between venous thromboembolism and ovarian cancer pathogenesis at the genetic level, and pointed out that lipid metabolism and ovarian cancer pathogenesis have innovative basic experimental directions. Objective: This study explored the causal effect between a history of venous thromboembolism and the risk of ovarian cancer. Methods: Genome-Wide Association Study (GWAS) data of venous thromboembolism patients (n = 9176) of the same ethnicity were selected as study exposures, and GWAS data of ovarian cancer patients (n = 1218) of the same ethnicity were selected as study exposures. In this study, univariate two-sample Mendelian randomization analysis (UVMR) was performed separately using inverse variance weighted (IVW), MR-Egger regression, and weighted median (WM) to assess causal effects. In this study, Cochran's Q test, MR-Egger regression intercept term, MR-PRESSO, and leave-one-out method were used for sensitivity analysis to assess the stability and reliability of the results. Results: The GWAS data screened in this study were all European ethnicity data. In this study, we found that genetically predicted history of venous thromboembolism was associated with an upward trend in ovarian cancer incidence, and the results of Weighted median, Simple mode, Weighted mode, and MR Egger showed a similar trend (OR = 1.0006, 95% CI: 1.00007–1.0013, p < 0.05). There was no heterogeneity of results (p = 0.18) and no horizontal pleiotropy (p = 0.77). The instrumental variables selected for venous thromboembolism in this study were all strong instrumental variables (F = 669.7). The results of the sensitivity analysis remained consistent. Conclusion: The results of this study indicate that patients with a history of venous thromboembolism are at increased risk of developing ovarian cancer and point to possible associations between lipid metabolism genes, such as CYP4V2, and the development of ovarian cancer, which provide interesting directions for further basic research. [ABSTRACT FROM AUTHOR]

Background: Beta-2 microglobulin (b2M) is acknowledged as a prognostic biomarker for B-cell malignancies. However, insights into the impact of b2M on B-cell malignancy risk, and vice versa, are limited. Methods: We conducted a genome-wide meta-analysis (GWMA), bidirectional two-sample Mendelian randomization (TSMR) analysis, and pathway enrichment analysis to explore the causal relationship between b2M and B-cell malignancies and the underlying biological processes. Results: The GWMA identified 55 lead SNPs across five genomic regions (three novel: WDR72, UMOD, and NLRC5) associated with b2M. In the UKB, genetically predicted b2M showed a positive association with diffuse large B-cell lymphoma (DLBCL; odds ratio [OR]: 1.742 per standard deviation increase in b2M; 95% confidence interval [CI]: 1.215--2.498; P = 3.00 x 10-3; FDR = 7.50 x 10-3) and Hodgkin lymphoma (HL; OR: 2.270; 95% CI: 1.525--3.380; P = 5.15 x 10-5; FDR =2.58 x 10-4). However, no associations were found with follicular lymphoma (FL), chronic lymphoid leukemia (CLL), or multiple myeloma (MM). Reverse TSMR analysis revealed no association between genetically predicted B-cell malignancies and b2M. In FinnGen, b2M was found to be associated with an increased risk of DLBCL (OR: 2.098; 95% CI: 1.358-3.242; P = 8.28 x 10-4; FDR = 4.14 x 10-3), HL (OR: 1.581; 95% CI: 1.167-2.142; P = 3.13 x 10-3; FDR = 5.22 x 10-3), and FL (OR: 2.113; 95% CI: 1.292-3.455; P = 2.90 x 10-3; FDR = 5.22 x 10-3). However, no association was found with CLL or MM. Reverse TSMR analysis indicated that genetically predicted DLBCL, FL, and MM may perturb b2M levels. Pathway enrichment analysis suggested that the innate immune system represents a convergent biological process underlying b2M, DLBCL, and HL. Conclusions: Our findings suggested that elevated levels of b2M were associated with an increased risk of DLBCL and HL, which is potentially linked to dysfunction of the innate immune system. [ABSTRACT FROM AUTHOR]

Introduction and objectives: Recent studies have indicated a potential association of hypertension with Hashimoto's thyroiditis (HT) and other autoimmune diseases, yet the impact of antihypertensive drugs on HT risk is not well understood. Methods: We employed a drug-target Mendelian randomization approach to investigate the prolonged impact of 9 classes of antihypertensive medications on HT susceptibility in European and Asian populations. Genetic variants close to or within genes associated with the drug targets and systolic blood pressure (SBP) were utilized to mimic the effects of antihypertensive medications. We focused on drugs linked to a lower risk of coronary artery disease for our main analysis. We gathered genetic data on SBP and HT risk from comprehensive genomewide association studies available for European and Asian groups. For a supplementary analysis, we used expression quantitative trait loci (eQTLs) related to drug target genes as proxies. Results: Our analysis revealed that the use of calcium channel blockers (CCBs) is linked to a reduced risk of HT in both European (OR [95% CI]: 0.96 [0.95 to 0.98] per 1 mmHg decrease in SBP; p = 3.51×10-5) and Asian populations (OR [95% CI]: 0.28 [0.12, 0.66]; p = 3.54×10-3). Moreover, genetically mimicking the use of loop diuretics (OR [95% CI]: 0.94 [0.91, 0.97]; p = 3.57×10-5) and thiazide diuretics (0.98 [0.96, 0.99]; p = 3.83×10-3) showed a significant association with a decreased risk of HT only in European population. These outcomes were confirmed when eQTLs were employed to represent the effects of antihypertensive medications. Conclusion: The study suggests that CCBs and diuretics could potentially reduce the risk of HT in different populations. Additional research is needed to assess the feasibility of repurposing antihypertensive medications for the prevention of HT. [ABSTRACT FROM AUTHOR]

Background: Endometrial carcinoma (EC) remain a malignancy with incompletely understood risk factors. To address this knowledge gap, we employed mendelian randomization study to investigate potential protective and risk elements associated with endometrial cancer. Methods: We conducted a two-sample Mendelian randomization (MR) study using genetic association data for overall EC and its subtypes from a large-scale genome-wide association study (GWAS). This GWAS encompassed 12,906 EC patients and 108,979 healthy controls. The EC cases were further categorized into 8758 endometrioid and 1230 non-endometrioid subtypes. To serve as instrumental variables, we identified independent genetic variants strongly associated with 5 lifestyle factors and 14 metabolic factors from relevant GWASs. Subsequently, we conducted univariable Mendelian randomization (MR) analyses. Results: Our study revealed the relationship among EC with lifetime smoking index (OR: 1.43; 95% CI 1.05–1.96), frequency of alcohol consumption (OR:1.23; 95% CI 1.04–1.45), body mass index (BMI) (OR:1.82; 95% CI 1.64–2.01), type 2 diabetes mellitus (T2DM) (OR:1.06; 95% CI 1.00–1.12), and fasting insulin (OR:1.97; 95% CI 1.30–2.98). Conversely, inverse associations with EC were observed for education level (OR:0.72, 95% CI 0.62–0.83), moderate-level physical exercise (OR 0.35, 95% CI 0.15–0.84), and low-density lipoproteins (LDL) (OR 0.91, 95% CI 0.84–0.99). Conclusions: Our findings underscore a causal association between genetically predicted lifetime smoking index, alcohol intake frequency, BMI, T2DM, and fasting insulin with EC risk. Furthermore, our study highlights the potential protective effects of a high education level, moderate-intensity physical exercise, and LDL reduction against EC risk. This MR analysis provided valuable insights into underlying EC risk mechanisms and paved new ways for EC prevention strategies. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease with a very poor prognosis. Existing drugs for the treatment of IPF are still insufficient. Therefore, there is still a need to explore new drug targets for preventing and treating IPF. Methods: We included quantitative trait loci (QTL) for genes, DNA methylation, and proteins in plasma, as well as the summary statistics for IPF. Genetic variants located within 500 kb of the gene and strongly associated with plasma exposure were used as instrumental variables. The causal association between plasma exposures and IPF was primarily estimated using summary-data-based Mendelian randomization (SMR) analysis. Five other MR methods and sensitivity analyses were employed to validate the SMR results. Bayesian tests for colocalization between QTL and IPF risk loci further strengthen the MR results. Results: We identified three genes and five DNA methylation sites causally associated with IPF by SMR analysis, validation of MR analysis, sensitivity analysis, and colocalization analysis. BTRC and LINC01252 were negatively associated with IPF risk (OR: 0.30, 95% CI: 0.17–0.54, FDRSMR = 0.029; OR: 0.85, 95% CI: 0.78–0.92, FDRSMR = 0.043), and RIPK4 was positively associated with IPF risk (OR: 2.60, 95% CI: 1.64–4.12, FDRSMR = 0.031). cg00045227 (OR8U8, OR: 1.16, 95% CI: 1.08–1.24, FDRSMR = 0.010), cg00577578 (GBAP1, OR: 1.23, 95% CI: 1.12–1.36, FDRSMR = 0.014), cg14222479 (ARPM1, OR: 3.17, 95% CI: 1.98–5.08, FDRSMR = 0.001), and cg19263494 (PMF1, OR: 1.20, 95% CI: 1.10–1.30, FDRSMR = 0.012) were positively associated with the risk of IPF, whereas cg07163735 (MAPT, OR: 0.22, 95% CI: 0.11–0.45, FDRSMR = 0.013) was negatively correlated with the risk of IPF. Conclusions: This study demonstrated that genetically determined plasma levels of the BTRC, RIPK4, and LINC01252 genes, as well as methylation levels of cg00045227 (OR8U8), cg00577578 (GBAP1), cg07163735 (MAPT), cg14222479 (ARPM1), and cg19263494 (PMF1), have causal influences on the risk of IPF. [ABSTRACT FROM AUTHOR]

Objective: Early identification of modifiable risk factors is crucial for the prevention of constipation. This study systematically investigated the relationship between genetically predicted modifiable risk factors and constipation. Methods: The inverse variance weighting (IVW) method was employed as the primary analytical approach. For similar exposure indicators, the multivariate Mendelian randomization (MVMR) method was used to adjust for potential biases in univariate MR analysis. The robustness of the results was further evaluated using the MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis. Bonferroni correction was applied to reduce the false positive rate in the results. Results: The IVW analysis indicated a significant causal association between genetically predicted gastroesophageal reflux disease [OR (95% CI) = 1.192 (1.079–1.315), P = 0.0005], atorvastatin use [OR (95% CI) = 16.995 (3.327–86.816), P = 0.0007], and constipation. Additionally, there was a potential causal association between education level [OR (95% CI) = 0.859 (0.767–0.964), P = 0.009], major depressive disorder [OR (95% CI) = 1.206 (1.041–1.399), P = 0.013], hypothyroidism [OR (95% CI) = 2.299 (1.327–3.985), P = 0.003], and aspirin use [OR (95% CI) = 4.872 (1.174–20.221), P = 0.029] with constipation. No causal associations were found for the other included indicators. Sensitivity analysis demonstrated the absence of evidence for heterogeneity and pleiotropy in any positive results. Conclusion: This study identified several risk factors that could be targeted for the prevention of constipation, offering valuable insights for public health policies. [ABSTRACT FROM AUTHOR]

Although observational clinical studies have established an association between Intestinal Diseases (IDS) and Anal Diseases (ADS), the causal relationship is still not fully understood due to the limitations of observational studies. Genome-wide association study (GWAS) statistical data for IDS and ADS were obtained from publicly available databases. To assess the causal effects of IDS on ADS, we conducted Mendelian randomization analysis. The inverse variance weighted method indicated that Inflammatory bowel disease (IBD) had a significant causal relationship with three kinds of ADS: Anorectal abscess (ARB), Haemorrhoidal disease (HEM), and Fissure and fistula of anal and rectal regions (FISSANAL). Crohn's disease (CD) and Ulcerative colitis (UC) also showed significant causal effects with three ADS: ARB, HEM, and FISSANAL. Furthermore, a potential link between CD and BNA(Benign neoplasm of anus and anal canal), Irritable bowel syndrome (IBS) and HEM, Colorectal cancer (CRC) and BNA, and Celiac disease and MNA (Malignant neoplasm of anus and anal canal) was observed. This comprehensive MR analysis highlight the significant and increased risk of common Anal Diseases (ARB, FISSANAL, and HEM) in patients with IBD, CD, and UC. Additionally, potential positive causal associations emerged between IBS and HEM, CRC and BNA, as well as between celiac disease and MNA. [ABSTRACT FROM AUTHOR]

Observational studies have shown some association between cannabis use disorder (CUD) and neurological disorders, but their causal relationship is unclear. In this study, we tested the potential causal relationship between CUD and three common neurological disorders using two-sample Mendelian randomization (TSMR) and multivariate MR (MVMR) methods. Thirty-two genetic loci were extracted as exposure factors from the largest genome-wide association study (GWAS) summary statistics for CUD to date. TSMR results showed that genetic prediction of CUD with all stroke, ischemic stroke, large-artery atherosclerotic stroke, migraine with aura, and Alzheimer's disease (AD) had a positive causal relationship (P < 0.05), which was not found in several other diseases. The association between CUD and stroke, ischemic stroke, and AD in the MVMR study may have been influenced by confounding factors (P > 0.05). Subgroup analyses highlighted a causal relationship between genetically predicted CUD and large-artery atherosclerotic stroke (OR = 1.169; 95%CI 1.030–1.328; P = 0.016) and migraine with aura (OR = 1.142; 95% 1.021–1.278; P = 0.020). Our further functional mapping and annotation enrichment analyses using FUMA suggest that the brain-gut axis may serve as another layer of explanation for the existence of an association between CUD and neurological disorders. [ABSTRACT FROM AUTHOR]

For a long time, the decline in lung function has been regarded as a potential factor associated with the risk of osteoporosis (OP). Although several observational studies have investigated the relationship between lung function and OP, their conclusions have been inconsistent. Given that Mendelian randomization (MR) studies can help reduce the interference of confounding factors on outcomes, we adopted this approach to explore the causal relationship between lung function and OP at the genetic level. To investigate the potential causality between lung function (FVC, FEV1, FEV1/FVC, PEF) and OP, we conducted a MR analysis employing three approaches: inverse variance weighted (IVW), MR-Egger, and weighted median. We used Cochran's Q test to detect potential heterogeneity, MR-Egger regression to evaluate directional pleiotropy, and the MR-PRESSO method to evaluate horizontal pleiotropy. In addition, we used MR-PRESSO and MR radial methods to exclude SNPs exhibiting pleiotropic outliers. Upon identification of potential outliers, we removed them and subsequently ran MR analysis again to assess the reliability of our findings. The MR analysis suggested that there was no causal effect of lung function (FVC, PEF, FEV1/FVC, FEV1) on OP, which is consistent with the. results after excluding potential outliers using MR-PRESSO and MR radial. methods. Sensitivity analysis confirmed the reliability and consistency of these. results. The study concluded that there is no causal link between lung function and OP. The association found in observational studies might be attributable to shared risk factors. [ABSTRACT FROM AUTHOR]

ABSTRACT Esophageal adenocarcinoma and diet are not well understood to be associated. We conducted Mendelian randomization analysis using 18 dietary factors as exposures (primarily including fruit consumption, vegetable consumption, alcohol consumption, meat consumption, tea intake, fish intake, etc.), with esophageal adenocarcinoma as the outcome. The IVW method was the leading method used for detecting causal links. Cochran's Q test was utilized to assess heterogeneity, the intercept of the MR‐Egger method was used to assess the presence of horizontal pleiotropy, and the existence of outliers was identified via the MR‐Presso method. This study identified that both alcohol intake frequency (OR = 1.375, p = 0.0216) and coffee intake (OR = 2.680, p = 0.0304) were linked to a heightened risk of esophageal adenocarcinoma, while raw vegetable/salad consumption (OR = 0.117, p = 0.0258) and dried fruit intake (OR = 0.229, p = 0.00235) were associated with a decreased risk of esophageal adenocarcinoma. After FDR correction, only dried fruit intake (q = 0.0423) remained statistically significant. However, there was no evidence linking the other 14 dietary variables to esophageal adenocarcinoma. This study observed that alcohol consumption and coffee intake increase the risk of esophageal adenocarcinoma, while the intake of dried fruits rather than fresh fruits and raw vegetable intake rather than cooked vegetable intake reduce the risk of esophageal adenocarcinoma. Other dietary factors were not associated with the risk of esophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion The Composite Dietary Antioxidant Index (CDAI) measures the antioxidant capacity of the diet, which is believed to provide protection against various diseases, including depression, osteoporosis, and papillomavirus infection, by neutralizing harmful oxidative stress. However, the relationship between CDAI and infertility is not well understood. This research aims to explore the potential correlations between CDAI and the risk of infertility.This research harnessed data from the National Health and Nutrition Examination Survey (NHANES) to execute a cross‐sectional analysis involving 8263 US women aged 20–45. Each participant was subjected to two distinct 24‐h dietary recall interviews. We calculated the CDAI using average daily antioxidant intake. Infertility was assessed using a standardized questionnaire. The association between CDAI and infertility was examined using weighted multiple logistic regression models, while nonlinear correlations were explored through restricted cubic splines. To affirm the robustness of our findings, sensitivity and subgroup analyses were performed using unweighted logistic regression. Additionally, to ascertain the causal influence of circulating antioxidant levels on infertility, a two‐sample univariable Mendelian randomization (MR) analysis was conducted, using the inverse variance weighted (IVW) method as the primary analytic approach.Participants who were infertile exhibited lower CDAI levels compared to their fertile counterparts. When confounding variables were accounted for in the multivariate weighted logistic regression model, an inverse relationship was observed between CDAI and infertility, with the odds ratio for the highest versus lowest quartile being 0.55 (0.33–0.90, P = 0.02). However, the IVW method indicated that genetically predicted elevated levels of CDAI did not significantly correlate with infertility.Cross‐sectional observational studies indicate that antioxidants from diets might diminish infertility risks. However, findings from MR studies do not confirm a causal connection. Additional prospective research is required to elucidate this association further. [ABSTRACT FROM AUTHOR]

Background: The causal relationship between cathepsins and neurological diseases remains uncertain. To address this, we utilized a two-sample Mendelian randomization (MR) approach to assess the potential causal effect of cathepsins on the development of neurological diseases. Methods: This study conducted a two-sample two-way MR study using pooled data from published genome-wide association studies to evaluate the relationship between 10 cathepsins (B, D, E, F, G, H, L2, O, S, and Z) and 7 neurological diseases, which included ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and epilepsy. The analysis employed various methods such as inverse variance weighting (IVW), weighted median, MR Egger regression, MR pleiotropy residual sum and outlier, Cochran Q statistic, and leave-one-out analysis. Results: We found a causal relationship between cathepsins and neurological diseases, including Cathepsin B and Parkinson's disease (IVW odds ratio (OR): 0.89, 95% confidence interval (CI): 0.83, 0.95, p = 0.001); Cathepsin D and Parkinson's disease (OR: 0.80, 95%CI: 0.68, 0.95, p = 0.012); Cathepsin E and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.09, p = 0.015); Cathepsin O and ischemic stroke (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.021). Reverse MR analyses revealed that multiple sclerosis and Cathepsin E (OR: 1.05, 95%CI: 1.01, 1.10, p = 0.030). There is currently no significant relationship has been found between other cathepsins and neurological diseases. Conclusion: Our study reveals a causal relationship between Cathepsins B, D, E, and O and neurological diseases, offering valuable insights for research aimed at improving the diagnosis and treatment of such conditions. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is a major microvascular complication of diabetes and a leading cause of blindness worldwide. The pathogenesis of DR involves complex interactions between metabolic disturbances, immune cells, and proteolytic enzymes such as cathepsins (CATs). Despite various studies, the precise roles of different CATs, metabolites, and vitamins in DR remain unclear. Method: In this study, we employed Mendelian Randomization (MR) to assess causal relationships using genetic instruments selected based on genome-wide association studies (GWAS). We employed two-sample and mediation MR to explore the causal effects between nine CATs, immune cells, metabolites, vitamins, and DR. Additionally, the study also incorporated data from the NHANES survey to explore the associated relationship between vitamins and DR. We utilized cross-sectional data from the NHANES to analyze the association between vitamin intake and diabetic retinopathy (DR), adjusting for potential confounders to strengthen the validity of our findings. Results: The MR analysis identified CAT H as a significant risk factor for both NPDR and PDR, with no evidence of reverse causality. Additionally, 62 immune cell traits were found to have causal relationships with NPDR and 49 with PDR. Enrichment analysis revealed that metabolic pathways such as sphingolipid metabolism are crucial in DR progression. Vitamins B6 and E were significantly associated with a reduced risk of PDR. Cross-sectional data indicated that vitamins B1, B2, B6, B12, and E progressively decreased with DR severity. Conclusion: This study is the first to identify CAT H as a key risk factor for DR, while vitamins B6 and E showed significant protective effects, particularly against PDR. These findings suggest that CAT H, along with vitamins B6 and E, could serve as therapeutic targets for DR. Further validation through larger, multi-center studies is recommended to enhance the accuracy and applicability of these findings. [ABSTRACT FROM AUTHOR]

Purposes: Gastric cancer (GC) is one of the most common malignant tumors threatening human beings and has a poor prognosis. Therefore, exploring unveiled biomarkers or therapeutic targets for the diagnosis and treatment of GC is crucial. Methods: A total of 5772 protein quantitative trait loci (pQTL) were aggregated from four latest large-scale proteomics cohorts. Two-sample Mendelian randomization (two-sample MR) was utilized to identify the causal effect of blood plasma proteins on GC. Heterogeneity, pleiotropy, and directionality analyses were employed to evaluate proteins identified via two-sample MR. The robustness of results was further validated via colocalization. The drug targets of proteins were evaluated to reveal the compounds that can interfere with these proteins. Results: Ten proteins with potential causations in relation to GC were identified: LY6D, SLURP1, MLN, PSCA, THSD1, CFTR, PPM1B, KDM3A, TSC1, and HCG22. Among these proteins, LY6D, SLURP1, and THSD1 were considered as the most reliable biomarkers of GC due to their significant H4 posterior probabilities in colocalization analysis and absence of pleiotropy. Compound 35, nitrosamide, and 0175029-0000 were potential drugs or small molecules targeting LY6D, SLURP1, and THSD1, respectively. Conclusion: This study identified several plasma proteins as potential biomarkers of GC and provided data support and new insights into the early diagnosis, intervention, and therapeutic targets of GC. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the causal relationship between cervical carcinoma in situ and antibody-mediated immune responses, providing a scientific basis for the prevention and treatment of cervical carcinoma in situ. Methods: A bidirectional Mendelian Randomization (MR) approach was utilized, leveraging two Genome-Wide Association Studies (GWAS) related to cervical carcinoma in situ and antibody-mediated immune responses to collect Single Nucleotide Polymorphism (SNP) data. Multiple statistical methods, including the inverse-variance weighted (IVW) method, MR-Egger regression, weighted median, and weighted mode, were utilized. Antibody-mediated immune response-related SNPs were used as instrumental variables (IVs) for a forward MR analysis of cervical carcinoma in situ, while cervical carcinoma in situ-related SNPs served as IVs for a reverse MR analysis of antibody-mediated immune responses. Results: The forward MR analysis revealed significant causal associations between two SNPs, GCST90006901 (P = 0.012, OR (95%CI) = 1.167(1.034–1.317)) and GCST90006909 (P < 0.001, OR (95%CI) = 1.805(1.320–2.467)), within antibody-mediated immune responses and the occurrence of cervical carcinoma in situ. The reverse MR analysis demonstrated that cervical carcinoma in situ exerts influence on multiple SNPs associated with antibody-mediated immune responses. Specifically, GCST90006891 (P = 0.018, OR (95%CI) = 1.164(1.027–1.319)) and GCST90006894 (P = 0.048, OR (95%CI) = 1.074 (1.001–1.153)) showed positive effects, while GCST90006899 (P = 0.022, OR (95%CI) = 0.935(0.882–0.990)) and GCST90006911 (P = 0.0193, OR (95%CI) = 1.226(1.034–1.454)) exhibited distinct trends of influence. Conclusion: The Mendelian Randomization analysis indicates a clear causal relationship between antibody-mediated immune responses and the prevalence of cervical carcinoma in situ, with cervical carcinoma in situ also exerting a certain degree of influence on antibody-mediated immune responses. This finding provides important insights into the interaction mechanism between the two and suggests avenues for developing effective prevention and control strategies. [ABSTRACT FROM AUTHOR]

Objectives: Thyroid dysfunction is commonly associated with the risk of infertility in both females and males. However, recent randomized controlled trials have demonstrated that thyroid function levels in females are not significantly related to infertility, and evidence on the association between male thyroid function and infertility is limited. We aim to investigate the association between thyroid function levels and infertility in both females and males. Method: A two-sample Mendelian randomization study was conducted using four methods, with the inverse variance weighted method (IVW) as the primary approach. Data on thyroid function as the exposure were obtained from the ThyroidOmics Consortium and UK Biobank, including over 700,000 individuals from a large meta-analysis of genome-wide association studies for thyroid function and dysfunction. The outcome data for infertility in both sex encompassed more than 70,000 individuals from the FinnGen Consortium. All participants were adults of European ancestry. The MR Egger regression intercept and Cochran's Q test were employed to evaluate directional pleiotropy and heterogeneity. Results: The results indicated no causal effect of thyroid-stimulating hormone (TSH) and free tetraiodothyronine (fT4) on female and male infertility. Furthermore, no causal association between hypo- and hyperthyroidism and infertility were identified. Notably, we observed a causal relationship between high TSH and endometriosis-related infertility (OR=0.82, 95% CI: 0.74-0.91, P = 1.49E-04). Conclusions: This study did not find evidence for casual relationship between thyroid function levels and risk of infertility. The findings suggest that overall thyroid function levels may not be a significant predictor of infertility risk. [ABSTRACT FROM AUTHOR]

Background: To better understand the preventive or therapeutic clinical interventions that may be supported by the association between rheumatoid arthritis (RA) and postural deformities including hallux valgus, flat foot, and scoliosis, this study was conducted using Mendelian randomization (MR) analysis. It aimed to investigate whether RA is causally associated with postural deformities in European populations. Methods: Summary-level data on RA and postural deformities were obtained from the IEU OpenGWAS project and Finngen database, respectively. LDSC regression analysis was conducted to assess the genetic correlation between these diseases. The inverse variance weighting (IVW) method was employed as the primary approach for two-sample MR analyses to evaluate causality. Supplementary methods included MR-Egger, maximum likelihood, weighted median, and cML-MA. To test for potential horizontal pleiotropy, we performed the MR-Egger intercept test, cML-MA, and secondary analyses after excluding confounders. Additionally, mediation analyses were conducted using two-step MR. Results: The IVW method revealed RA to be causally associated with hallux valgus (OR 1.132, 95% CI 1.087-1.178, P < 0.001) and flat foot (OR 1.197, 95% CI 1.110-1.291, P < 0.001). Among postural deformities, hallux valgus was causally associated with flat foot (OR 1.823, 95% CI 1.569-2.119, P < 0.001) and scoliosis (OR 1.150, 95% CI 1.027-1.287, P < 0.05). No significant horizontal pleiotropy was detected. Moreover, mediation analyses indicated that hallux valgus mediates the effect of RA on flat foot (mediation effect 0.024, 95% CI 0.005-0.044, P < 0.05), with a mediation proportion of 41.31%. Conclusion: These findings indicate a potential causal association between genetically predicted RA and both hallux valgus and flat foot. Furthermore, hallux valgus serves as a mediator in the pathway from RA to flat foot. This underscores the importance of early screening and preventive treatment of foot deformities in RA patients. Further research is necessary to determine the applicability of these findings in non-European populations. [ABSTRACT FROM AUTHOR]

Background: The gut-brain axis has garnered increasing attention, with observational studies suggesting its involvement in the disease activity and progression of inflammatory bowel disease (IBD), but the precise mechanisms remain unclear. Materials and methods: In this study, we aimed to investigate "novel proteins" underlying IBD in the brain using a comprehensive multi-omics analysis approach. We performed integrated analyses of proteomics and transcriptomics in the human prefrontal cortex (PFC) tissue, coupled with genome-wide association studies (GWAS) of IBD, crohn's disease (CD), and ulcerative colitis (UC). This included performing protein-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR), and colocalization analysis to identify brain proteins associated with IBD and its subtypes. Results: PWAS analyses identified and confirmation 9, 9, and 6 brain proteins strongly associated with IBD, CD, and UC, respectively. Subsequent MR analyses revealed that increased abundance of GPSM1, AUH, TYK2, SULT1A1, and FDPS, along with corresponding gene expression, led to decreased risk of IBD. For CD, increased abundance of FDPS, SULT1A1, and PDLIM4, along with corresponding gene expression, also decreased CD risk. Regarding UC, only increased abundance of AUH, along with corresponding gene expression, was significantly associated with decreased UC risk. Further TWAS and colocalization analyses at the transcriptome level supported strong associations of SULT1A1 and FDPS proteins with reduced risk of IBD and CD. Conclusion: The two "novel proteins," SULT1A1 and FDPS, are strongly associated with IBD and CD, elucidating their causal relationship in reducing the risk of IBD and CD. This provides new clues for identifying the pathogenesis and potential therapeutic targets for IBD and CD. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) is a complex autoimmune disorder, although some medications are available for its treatment. However, the long-term efficacy of these drugs remains unsatisfactory. Therefore, there is a need to develop novel drug targets for IBD treatment. Methods: We conducted two-sample Mendelian randomization (MR) analysis using Genome-Wide Association Study (GWAS) data to assess the causal relationships between plasma proteins and IBD and its subtypes. Subsequently, the presence of shared genetic variants between the identified plasma proteins and traits was explored using Bayesian co-localization. Phenome-wide MR was used to evaluate evaluated adverse effects, and drug target databases were examined for therapeutic potential. Results: Using the Bonferroni correction (P < 3.56e-05), 17 protein-IBD pairs were identified. Notably, the genetic associations of IBD shared a common variant locus (PP.H4 > 0.7) with five proteins (MST1, IL12B, HGFAC, FCGR2A, and IL18R1). As a subtype of IBD, ulcerative colitis shares common variant loci with FCGR2A, IL12B, and MST1. In addition, we found that ANGPTL3, IL18R1, and MST1 share a common variant locus with Crohn's disease. Furthermore, phenome-wide MR analysis revealed that except for ANGPTL3, no other proteins showed potential adverse effects. In the drug database, identified plasma proteins such as FCGR2A and IL18R1 were found to be potential drug targets for the treatment of IBD and its subtypes. Conclusion: Six proteins (FCGR2A, IL18R1, MST1, HGFAC, IL12B, and ANGPTL3) were identified as potential drug targets for the treatment of IBD and its subtypes. [ABSTRACT FROM AUTHOR]

Aim Materials and Methods Results Conclusions The aim was to investigate the causal relationship between puberty timing and plasma metabolites, accounting for birth weight, childhood and adulthood adiposity.The meta‐analysis of genome‐wide association studies (GWAS) for puberty timing was extracted from the ReproGen Consortium, involving 329 345 women of European ancestry. Summary data for 174 plasma metabolites were retrieved from a recently conducted cross‐platform GWAS that involved a meta‐analysis of three cohort studies (i.e. the Fenland, European Prospective Investigation into Cancer‐Norfolk and INTERVAL studies) and three publicly available studies and included up to 86 507 participants. We conducted a two‐sample Mendelian randomization (MR) analysis to infer the causal relationship of puberty timing on 174 plasma metabolites, complemented by a two‐step and multivariable Mendelian randomization (MVMR) analysis to assess direct and indirect effects. Additionally, summary‐level data from the UK Biobank were used for our replication analysis.The results of the two‐sample MR provide moderate evidence supporting a causal relationship between puberty timing and 23 of 174 plasma metabolites (i.e. 7 acylcarnitines, 8 amino acids, 2 biogenic amines and 6 lysophosphatidylcholines). Even after single‐nucleotide polymorphisms associated with birth weight and childhood adiposity were excluded, causal effects persisted for 16 metabolites (i.e. 8 acylcarnitines, 4 amino acids, 2 biogenic amines and 2 lysophosphatidylcholines). The two‐step MR analysis provided evidence that the relationship between puberty timing and plasma metabolites was mediated by adulthood adiposity. Additionally, moderate evidence emerged for an independent causal effect of puberty timing on 10 metabolites through an MVMR analysis (i.e. 5 acylcarnitines, 2 amino acids, 1 biogenic amine, 1 lysophosphatidylcholine and 1 phosphatidylcholine). Furthermore, the replication analysis suggested the robustness of our results.In summary, our study provides compelling evidence that puberty timing has a causal influence on certain plasma metabolites, although this influence is largely mediated by adulthood adiposity. [ABSTRACT FROM AUTHOR]

Major depression is a public health problem facing the world. This study aimed to identify the risk factors for major depression and clarify their causal effects. Data from the National Health and Nutrition Examination Survey (NHANES). Multifactorial logistic regression analysis was used to calculate the effect of each variable on major depression. Subgroup analyses and interaction tests were conducted to observe the stability of the association between them. Nonlinear correlations were explored using restricted cubic spline plots. The causal effects of serum Klotho on major depression were assessed using Mendelian randomization (MR) analysis. A total of 8359 participated in the study. After adjusting for all covariates, the risk of having major depression was 1.47 times higher for each unit rise in serum Klotho (OR = 1.47, 95 % CI = 1.07–2.02; P = 0.0183). MR analysis showed no causal relationship between serum Klotho levels and risk of major depression (OR = 1.09, 95 % CI = 0.91–1.30; P = 0.4120). Sensitivity analysis verified the reliability of the results. Serum Klotho is positively associated with an increased risk of major depression in the U.S. population, but MR analyses did not show genetic causality between Klotho and major depression in individuals of European ancestry. Based on the results of the current study, no indication maintaining high levels of Klotho may increase the risk of major depression. The main limitation of this study is the inconsistency of the cross-sectional study and the MR population. • Serum Klotho was first observed as a risk factor for major depression, but MR findings suggest no causal relationship. • J-shaped association between serum Klotho and major depression. • This study combines comprehensive data from a large-sample cross-sectional survey and a genomic analysis system. • No indication that serum Klotho may help improve major depression. [ABSTRACT FROM AUTHOR]

The objective of this study was to analyze the causal relationship between Neuroticism and aortic aneurysm using Mendelian randomization (MR). The study aimed to establish a foundation for the development of effective prevention and treatment strategies. Genetic association data for Neuroticism were obtained from the UK Biobank, which included 393,411 individuals and 11,968,760 single nucleotide polymorphisms (SNPs). Genetic association data for aortic aneurysm were obtained from a genome-wide association study (GWAS), which included 479,194 individuals and 24,191,825 SNPs. Heterogeneity was assessed using the Cochran's Q statistic test. The study also utilized the MR Pleiotropy RESidual Sum and Outlier (Mr-PRESSO) test, as well as the MR-Egger regression method, to examine horizontal pleiotropy and determine the reliability of the findings through the leave-one-out method. Forward MR analysis showed that the risk of aortic aneurysm was elevated in individuals with genetically predicted Neuroticism compared to those without Neuroticism (OR = 1.1315, 95 % CI: 1.0269–1.2468; P = 0.0126). The Cochran's Q test showed no heterogeneity (P > 0.05), and the MR-PRESSO test did not identify instrumental variables of horizontal pleiotropy (P > 0.05). The MR analysis remained robust after removing SNPs one by one. Inverse MR analysis did not observe an association between aortic aneurysm and having Neuroticism OR = 1.030, 95 % CI: 0.9459–1.118, P = 0.488). Our study has established a clear causal relationship between genetically determined Neuroticism and the development of aortic aneurysms. It is therefore important to intensify screening and prevention efforts for aortic aneurysms in neurotic patients. It also opens new avenues for exploring the disease's pathogenesis. • Existing Evidence Gap: Psych trait-cardiovascular studies common, but few MR analyses explore neuroticism-aortic aneurysm link. • Novel Contribution: Forward MR shows higher neuroticism genetically linked to increased aortic aneurysm risk. • Clinical Significance: Findings suggest intensified screening & prevention for aortic aneurysms in neurotic individuals. • Future Directions: Study prompts deeper investigation into aortic aneurysm mechanisms & discovery of new genetic pathways. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disorder with multiple causes, including genetic and environmental factors. Despite advances in treatment, there remains a need to identify novel therapeutic targets. A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets for psoriasis. Data on cis-expression quantitative trait loci were obtained from the eQTLGen Consortium (n = 31,684). Summary statistics for psoriasis (outcome) were sourced from the GWAS Catalog with a sample size of 484,598, including 5,427 cases and 479,171 controls. Colocalization analysis was used to assess whether psoriasis risk and gene expression were driven by shared single nucleotide polymorphisms. Drug prediction and molecular docking were utilized to validate the pharmacological value of the drug targets. The MR analysis found that 81 drug targets were significantly associated, and two (TYK2 and PRSS36) were supported by colocalization analysis (PP.H4 > 0.80). Phenome-wide association studies did not show any associations with other traits at the gene level. Biologically, these genes were closely related to immune function. Molecular docking revealed strong binding with drugs and proteins, as supported by available structural data. This study validated TYK2 as a drug target for psoriasis, in line with its existing clinical use, including the development of decucravacitinib. PRSS36 is a potential novel target requiring further investigation. [ABSTRACT FROM AUTHOR]

The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37–0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry. [ABSTRACT FROM AUTHOR]

Researchers have conducted extensive research on the correlation between brain resting-state functional activities (RSFA) and migraine. However, we still do not fully understand the exact nature of the causal relationship between these RSFA and migraine. We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the causal association between migraine and RSFA. We gathered summary statistics from genome-wide association studies for 191 resting-state functional magnetic resonance imaging phenotypes. We employed various analytical methods for bidirectional two-sample MR analyses. This included inverse variance weighted, weighted median, MR Egger, and the constrained maximum likelihood approaches. We also conducted pleiotropy and heterogeneity analyses to evaluate the robustness and reliability. We found the functional connectivity between the default mode and the central executive network (OR = 1.39, p = 4.77 × 10−4, FDR corrected p value = 0.040) and the intensity of spontaneous brain activity in the calcarine or lingual gyrus within the visual network (OR = 0.74, p = 5.94 × 10−4, FDR corrected p value = 0.040) having a causal effect on the risk of migraine. Our MR analysis provided genetic support for these networks, which may play an important role in influencing migraine susceptibility. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia (SP) is an aging-related loss of muscle mass and function, affecting the respiratory system. However, the causality of the association between sarcopenia on lung diseases remains elusive. Methods: The bidirectional univariate Mendelian randomization (UVMR), multivariate MR (MVMR) analysis, and mediation MR were utilized to systematically investigate the genetic causal relationship of SP and 11 respiratory diseases. Independent genomic variants related to sarcopenia or respiratory diseases were identified as instrumental variables (IVs), and the summary level data of genome-wide associated studies (GWAS) were obtained from the UK biobank and FinnGen. MVMR analysis was conducted to explore the mediation effects of body mass index (BMI), Alcohol Use Disorders Identification Test (AUDIT), smoking, education attainment (EA), physical activity, and Type 2 Diabetes Mellitus (T2DM). Results: Forward UVMR analysis based on the primary method revealed that pneumoconiosis was associated with a higher risk of appendicular lean mass (ALM) (OR = 1.01, p = 0.03), and BMI (10.65%), smoking (10.65%), and physical activity (17.70%) had a mediating role in the effect of pneumoconiosis on ALM. In reverse MR analysis, we found that genetically predicted ALM was significantly associated with an increased risk of pulmonary embolism (PE) (OR = 1.24, p = 7.21E-05). Chronic obstructive pulmonary disease (COPD) (OR = 0.98, p = 0.002) and sarcoidosis (OR = 1.01, p = 0.004) were identified to increase the loss of left-hand grip strength (HGS). Conversely, the increase in left- HGS presented a protective effect on chronic bronchitis (CB) (OR = 0.35, p = 0.03), (OR = 0.80, p = 0.02), and asthma (OR = 0.78, p = 0.04). Similarly, the loss of the right-HGS elevated the risk of low respiratory tract infection (LRTI) (OR = 0.97, p = 0.02) and bronchiectasis (OR = 1.01, p = 0.03), which is also an independent protective factor for LRTI and asthma. In the aspects of low HGS, the risk of LRTI was increased after MVMR analysis, and the risk of sarcoidosis and pneumoconiosis was elevated in the reverse analysis. Lastly, asthma was found to be related to the loss of the usual walking pace, and the reverse MR analysis suggested a causal relationship between the usual walking pace and LRTI (OR = 0.32, p = 2.79 × 10−5), asthma (OR = 0.24, p = 2.09 × 10−6), COPD (OR = 0.22, p = 6.64 × 10−4), and PE(OR = 0.35, p = 0.03). Conclusions: This data-driven MR analysis revealed SP was bidirectional causally associated with lung diseases, providing genetic evidence for further mechanistic and clinical studies to understand the crosstalk between SP and lung diseases. [ABSTRACT FROM AUTHOR]

Background: Although healthy lifestyle has been linked with a reduced risk of cardiovascular diseases (CVDs), the potential metabolic mechanism underlying this association remains unknown. Methods: We included 161,018 CVD-free participants from the UK Biobank. Elastic net regression was utilized to generate a healthy lifestyle-related metabolic signature. The Cox proportional hazards model was applied to investigate associations of lifestyle-related metabolic signature with incident CVDs, and mediation analysis was conducted to evaluate the potential mediating role of metabolic profile on the healthy lifestyle-CVD association. Mendelian randomization (MR) analysis was conducted to detect the causality. Results: During 13 years of follow-up, 17,030 participants developed incident CVDs. A healthy lifestyle-related metabolic signature comprising 123 metabolites was established, and it was inversely associated with CVDs. The hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.81, 0.84) for CVD, 0.83 (95% CI: 0.81, 0.84) for ischemic heart disease (IHD), 0.86 (95% CI: 0.83, 0.90) for stroke, 0.86 (95% CI: 0.82, 0.89) for myocardial infarction (MI), and 0.75 (95% CI: 0.72, 0.77) for heart failure (HF) per standard deviation increase in the metabolic signature. The metabolic signature accounted for 20% of the association between healthy lifestyle score and CVD. Moreover, MR showed a potential causal association between the metabolic signature and stroke. Conclusions: Our study revealed a potential link between a healthy lifestyle, metabolic signatures, and CVD. This connection suggests that identifying an individual's metabolic status and implementing lifestyle modifications may provide novel insights into the prevention of CVD. [ABSTRACT FROM AUTHOR]

Background: Understanding the causal relations between dietary habits and stroke is crucial for prioritizing public health interventions and developing effective health strategies. This study utilized Mendelian randomization (MR) analysis to examine the causal associations between 20 dietary habits and various stroke subtypes, aiming to identify potential mediators and evaluate the proportions of mediation. Methods: A two-sample MR analysis was conducted to examine the causal relationships between dietary habits and stroke incidence. Mediation analysis, two-step MR (TSMR), and multivariable MR (MVMR) were employed to identify potential mediators. Genetic data pertaining to dietary habits and stroke were obtained from extensive genome-wide association study (GWAS) consortia. The inverse variance-weighted (IVW) method served as the primary analytical approach, with the additional scrutiny of significant correlations conducted through the Egger regression, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), and weighted median techniques. Results: Our analyses indicated that genetically predicted intakes of dried fruits, cheese, cereal, oily fish, and hot drink temperatures were protective against stroke, whereas higher intakes of lamb/mutton, poultry, and added salt significantly elevated stroke risk. Specifically, dried fruit consumption demonstrated a protective effect against total stroke (β = −0.009, p = 0.013), ischemic stroke (β = −0.475, p = 0.003), and small-vessel ischemic stroke (β = −0.682, p = 0.033) through reductions in BMI levels, accounting for mediated proportions of 3.2%, 17.1%, and 8.5%, respectively. Furthermore, cheese intake provided a protective effect against ischemic stroke (β = −0.275, p = 0.003) by decreasing BMI and increasing HDL-C levels, with mediated proportions of 30.5% and 6.5%. Together, BMI and HDL-C accounted for 34.9% of the beneficial effect of cheese intake on reducing the risk of ischemic stroke. In contrast, an increased salt intake exhibited a positive association with large-artery ischemic stroke (β = 0.432, p = 0.033) through BMI elevation, with a mediated proportion of 10.9%. Conclusions: Our findings provide compelling evidence supporting causal relationships between dietary habits and stroke subtypes, while identifying mediators and evaluating the proportions of mediation. Adhering to a low-calorie, nutrient-dense diet enriched with dried fruits, cheese, and cereal, along with reduced salt and poultry consumption, could potentially mitigate stroke risk. [ABSTRACT FROM AUTHOR]

Background: Existing epidemiological data indicated a correlation between thyroid cancer (THCA) and the risk of secondary primary malignancies (SPMs). However, the correlation does not always imply causality. Methods: The Mendelian randomization (MR) analyses were performed to investigate the causal relationships between THCA and SPMs based on international multicenter data. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. The Cancer Genome Atlas (TCGA) was used to explore potential mechanisms shared by THCA and bladder cancer (BLCA). Results: Summary datasets of genome-wide association studies (GWAS) on 30 types of cancers were obtained from the United Kingdom Biobank (UKB) and FinnGen database. Meta-analysis of the UKB and FinnGen results revealed that THCA was significantly positively correlated with BLCA (OR = 1.140; 95% CI, 1.072-1.212; P < 0.001). Four genes, including WNT3, FAM171A2, MLLT11, and ULBP1, were identified as key genes shared by both TCHA and BLCA. Correlation analysis indicated that THCA may increase the risk of secondary BLCA through augmentation of N2 neutrophil infiltration. Conclusions: This study showed that THCA was causally related to BLCA. It is recommended to conduct more rigorous screenings for BLCA during the followup of THCA patients. [ABSTRACT FROM AUTHOR]