OBJECTIVE: To investigate the potential mechanisms of sepsis pathogenesis in intensive care unit (ICU), with a specific focus on the role of skin microbiota, and to evaluate the causal relationships between skin microbiota and ICU sepsis using Mendelian randomization (MR). METHODS: A two-sample MR analysis was performed using skin microbiota genome-wide association study (GWAS) summary data from German population cohorts as exposures, combined with ICU sepsis susceptibility and 28-day mortality GWAS summary data from the IEU OpenGWAS database as outcomes. The primary causal effect estimates were generated using the inverse variance weighted (IVW) method, supplemented by validation through MR-Egger and weighted median approaches. Heterogeneity and pleiotropy tests, along with sensitivity analyses, were conducted to evaluate the robustness of the results. RESULTS: Regarding risk of ICU sepsis, IVW analysis showed that order Pseudomonadales [odds ratio (OR) = 0.93, 95% confidence interval (95%CI) was 0.88-0.98], family Flavobacteriaceae (OR = 0.93, 95%CI was 0.90-0.96), and genus Acinetobacter (OR = 0.96, 95%CI was 0.93-0.99) were significantly negatively correlated with the risk of ICU sepsis (all P < 0.05). There was a significant positive correlation between the risk of ICU sepsis and the presence of β-Proteobacteria (OR = 1.05, 95%CI was 1.00-1.11) and Actinobacteria (OR = 1.05, 95%CI was 1.00-1.11), both P < 0.05. Regarding 28-day mortality of ICU sepsis, IVW analysis showed that phylum Bacteroidetes (OR = 0.92, 95%CI was 0.86-0.99), family Streptococcaceae (OR = 0.92, 95%CI was 0.85-0.98), family Flavobacteriaceae (OR = 0.90, 95%CI was 0.83-0.97), genus Streptococcus (OR = 0.92, 95%CI was 0.86-0.99), ASV016 [Enhydrobacter] (OR = 0.92, 95%CI was 0.87-0.98), and ASV042 [Acinetobacter] (OR = 0.92, 95%CI was 0.88-0.97) were significantly negatively correlated with the 28-day mortality of ICU sepsis (all P < 0.05); family Moraxellaceae (OR = 1.09, 95%CI was 1.00-1.18) and ASV008 [Staphylococcus] (OR = 1.08, 95%CI was 1.03-1.14) was significantly positively correlated with the 28-day mortality of ICU sepsis (both P < 0.05). Sensitivity analysis and MR-PRESSO showed no heterogeneity, pleiotropy, or horizontal pleiotropy between skin microbiota and ICU sepsis risk and 28-day mortality rate. Analysis of confounding factors showed that single nucleotide polymorphisms (SNPs) associated with relevant skin bacteria could independently and causally affect the risk of ICU sepsis or ICU sepsis related mortality rate, independent of other confounding factors. The Steiger test results indicated that the established causal relationship was not due to reverse causality. CONCLUSIONS Skin microbiota composition may influence both sepsis susceptibility and 28-day mortality in ICU settings. Family Flavobacteriaceae demonstrated protective effects against sepsis onset and mortality. These findings provide new perspectives for early detection and management strategies.
Humans ; Sepsis/mortality* ; Intensive Care Units ; Mendelian Randomization Analysis ; Microbiota ; Skin/microbiology* ; Genome-Wide Association Study ; Risk Factors ; Skin Microbiome

OBJECTIVE: Observational studies have found associations between inflammatory bowel disease (IBD) and the risk of dementia, including Alzheimer's dementia (AD) and vascular dementia (VD); however, these findings are inconsistent. It remains unclear whether these associations are causal. METHODS: We conducted a meta-analysis by systematically searching for observational studies on the association between IBD and dementia. Mendelian randomization (MR) analysis based on summary genome-wide association studies (GWASs) was performed. Genetic correlation and Bayesian co-localization analyses were used to provide robust genetic evidence. RESULTS: Ten observational studies involving 80,565,688 participants were included in this meta-analysis. IBD was significantly associated with dementia (risk ratio [ RR] =1.36, 95% CI = 1.04-1.78; I ² = 84.8%) and VD ( RR = 2.60, 95% CI = 1.18-5.70; only one study), but not with AD ( RR = 2.00, 95% CI = 0.96-4.13; I ² = 99.8%). MR analyses did not supported significant causal associations of IBD with dementia (dementia: odds ratio [ OR] = 1.01, 95% CI = 0.98-1.03; AD: OR = 0.98, 95% CI = 0.95-1.01; VD: OR = 1.02, 95% CI = 0.97-1.07). In addition, genetic correlation and co-localization analyses did not reveal any genetic associations between IBD and dementia. CONCLUSION Our study did not provide genetic evidence for a causal association between IBD and dementia risk. The increased risk of dementia observed in observational studies may be attributed to unobserved confounding factors or detection bias.
Humans ; Mendelian Randomization Analysis ; Inflammatory Bowel Diseases/complications* ; Dementia/etiology* ; Observational Studies as Topic ; Genome-Wide Association Study

OBJECTIVE: Several epidemiological observational studies have related particulate matter (PM) exposure to Inflammatory bowel disease (IBD), but many confounding factors make it difficult to draw causal links from observational studies. The objective of this study was to explore the causal association between PM _2.5 exposure, its absorbance, and IBD. METHODS: We assessed the association of PM _2.5 and PM _2.5 absorbance with the two primary forms of IBD (Crohn's disease [CD] and ulcerative colitis [UC]) using Mendelian randomization (MR) to explore the causal relationship. We conducted two-sample MR analyses with aggregated data from the UK Biobank genome-wide association study. Single-nucleotide polymorphisms linked with PM _2.5 concentrations or their absorbance were used as instrumental variables (IVs). We used inverse variance weighting (IVW) as the primary analytical approach and four other standard methods as supplementary analyses for quality control. RESULTS: The results of MR demonstrated that PM _2.5 had an adverse influence on UC risk (odds ratio [ OR] = 1.010; 95% confidence interval [ CI] = 1.001-1.019, P = 0.020). Meanwhile, the results of IVW showed that PM _2.5 absorbance was also causally associated with UC ( OR = 1.012; 95% CI = 1.004-1.019, P = 0.002). We observed no causal relationship between PM _2.5, PM _2.5 absorbance, and CD. The results of sensitivity analysis indicated the absence of heterogeneity or pleiotropy, ensuring the reliability of MR results. CONCLUSION Based on two-sample MR analyses, there are potential positive causal relationships between PM _2.5, PM _2.5 absorbance, and UC.
Humans ; Mendelian Randomization Analysis ; Particulate Matter/analysis* ; Polymorphism, Single Nucleotide ; Inflammatory Bowel Diseases/genetics* ; Air Pollutants/analysis* ; Crohn Disease/genetics* ; Colitis, Ulcerative/genetics* ; Genome-Wide Association Study ; Risk Factors ; Environmental Exposure

OBJECTIVE: Observational studies have shown inconsistent associations of loneliness or social isolation (SI) with ischemic heart disease (IHD), with unknown mediators. METHODS: Using data from genome-wide association studies of predominantly European ancestry, we performed a bidirectional two-sample Mendelian Randomization (MR) study to estimate causal effects of loneliness ( N = 487,647) and SI traits on IHD ( N = 184,305). SI traits included whether individuals lived alone, participated in various types of social activities, and how often they had contact with friends or family ( N = 459,830 to 461,369). A network MR study was conducted to evaluate the mediating roles of 20 candidate mediators, including metabolic, behavioral and psychological factors. RESULTS: Loneliness increased IHD risk ( OR= 2.129; 95% confidence interval [ CI]: 1.380 to 3.285), mediated by body fat percentage, waist-hip ratio, total cholesterol, and low-density lipoprotein cholesterol. For SI traits, only fewer social activities increased IHD risk ( OR= 1.815; 95% CI: 1.189 to 2.772), mediated by hypertension, high-density lipoprotein cholesterol, triglycerides, fasting insulin, and smoking cessation. No reverse causality of IHD with loneliness and SI was found. CONCLUSION These findings suggested more attention should be paid to individuals who feel lonely and have fewer social activities to prevent IHD, with several mediators as prioritized targets for intervention.
Loneliness/psychology* ; Humans ; Mendelian Randomization Analysis ; Social Isolation ; Myocardial Ischemia/etiology* ; Male ; Female ; Middle Aged ; Genome-Wide Association Study ; Risk Factors ; Aged

OBJECTIVE: To explore the causality between reproductive traits and risk of psoriasis by using a large Mendelian randomization (MR) study. METHODS: A two-sample MR study was performed using summarized statistics from the genome-wide association studies (GWAS) conducted in reproductive traits, as well as GWAS data on overall psoriasis, psoriatic arthritis (PsA), and psoriasis vulgaris (PV). Besides univariable MR (UVMR), multivariable MR and two-step MR was used to calculate the independent effects and quantify the proportion mediated by education or body mass index (BMI). RESULTS: Genetically predicted early age at first sexual intercourse (AFS) led to an increased risk of overall psoriasis [odds ratio ( OR) _UVMR: 0.54]; 36.13% of this effect was mediated through BMI and 47.79% through educational attainment. The direct negative casual association between age at first birth (AFB)-PsA was dominant ( OR _UVMR: 0.76), with 49.61% proportion of the mediation due to BMI. The mediating effect was found for BMI on the AFS-PV relationship, which accounted for 26.27% of the proportion. AFS was inversely associated with the risk of overall psoriasis and PV, with considerable mediation by BMI and educational attainment. CONCLUSION Early AFB may cause a higher risk of PsA, while the AFS-PsA association was fully mediated by BMI.
Humans ; Body Mass Index ; Psoriasis/etiology* ; Mendelian Randomization Analysis ; Educational Status ; Female ; Genome-Wide Association Study ; Risk Factors ; Male ; Reproduction ; Adult

OBJECTIVES: This study aimed to investigate the association between temporomandibular disorder (TMD) and insomnia using a two-sample Mendelian randomization (MR) approach. METHODS: Bidirectional MR analyses of two samples, TMD (n=377 277) and insomnia (n=375 359), were performed using genome-wide association study statistics published in the FinnGen database. Instrumental variables were first screened, and then inverse variance weighting (IVW) and MR-Egger were used as the main-effect assessment methods. Weighted median, weighted mode, and simple mode served as supplementary methods. We used IVW and MR-Egger to test for heterogeneity, as well as MR-Egger intercepts to assess the single nucleotide polymorphism (SNP) potential level of multiplicity effects. Sensitivity analyses were conducted based on leave-one-out to identify potentially influential SNPs. All analyses were conducted by using the two-sample MR R package and were considered statistically significant when P<0.05. RESULTS: MR analysis showed the presence of TMD on insomnia (OR=1.089, 95%CI: 1.017-1.166, P=0.014). Meanwhile, no effect of insomnia on TMD (OR=0.996, 95%CI: 0.964-1.029, P=0.816) was found. The sensitivity-analysis showed that no heterogeneity existed (P>0.05), and the presence of horizontal pleiotropy was not detected (P>0.05). Leave-one-out sensitivity analysis showed no single SNP, which may affect the causal relation. All findings indicated that the causal relationship between TMD and insomnia was not significantly affected by any individual SNP and that IV did not bias the results. CONCLUSIONS Results of MR analyses showed that TMD is a risk factor for insomnia, whereas insomnia is not a risk factor for TMD.
Humans ; Sleep Initiation and Maintenance Disorders/genetics* ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Temporomandibular Joint Disorders/complications* ; Genome-Wide Association Study

Based on the traditional Chinese medicine(TCM) theory of "kidney-brain interaction", a two-sample Mendelian randomization(MR) analysis was conducted to investigate the causal effects of chronic kidney disease(CKD) on Alzheimer's disease(AD) and analyze the potential mechanisms of kidney-tonifying and essence-replenishing TCM to improve AD. From the perspective that CKD is closely related to the core pathogenesis of AD, namely "kidney deficiency, essence loss, and marrow reduction", genome-wide association study(GWAS) data was used, with the inverse variance weighting(IVW) method as the main approach to reveal the causal association between CKD and AD. Sensitivity analysis was conducted to evaluate the robustness of the results. To further investigate the causal effects of CKD on AD, two different AD datasets were used as outcomes, and the urinary albumin-to-creatinine ratio(UACR) data was used as the exposure for a supplementary analysis. On this basis, the modern scientific mechanism of the kidney-tonifying and essence-replenishing method for improving AD was further explored. The IVW analysis show that CKD(ieu-b-2: OR=1.084, 95%CI[1.011, 1.163], P=0.024; ieu-b-5067: OR=1.001, 95%CI[1.000, 1.001], P=0.002) and UACR(ieu-b-2: OR=1.247, 95%CI[1.021, 1.522], P=0.031; ieu-b-5067: OR=1.001, 95%CI[1.000, 1.003], P=0.015) both have significant causal effects on AD in different datasets, with CKD increasing the risk of AD. The sensitivity analysis further confirmed the reliability of the results. Genetic studies have shown that CKD has a significant causal effect on AD, suggesting that controlling CKD is an important intervention measure for preventing and treating AD. Therefore, further research on CKD's role in AD is crucial in clinical practice. The research enriches the theoretical implication of "kidney-brain interaction", deepens the understanding of AD' etiology, and provides further insights and directions for the prevention and treatment of AD with TCM, specifically from a kidney-based perspective.
Humans ; Alzheimer Disease/genetics* ; Renal Insufficiency, Chronic/genetics* ; Kidney/metabolism* ; Brain/physiopathology* ; Genome-Wide Association Study ; Medicine, Chinese Traditional ; Mendelian Randomization Analysis

OBJECTIVES: To clarify the causal relationship between the level of cytoplasmic unactivated mineralocorticoid receptor (MR) and the development of tubulointerstitial nephritis (TIN), and to evaluate the impact of MR on dyslipidemia, particularly secondary hyperlipemia, in patients with diabetic kidney disease. METHODS: We conducted a two-sample Mendelian randomization study using genome-wide association study (GWAS) summary data. Genetic variants associated with MR levels were selected as exposures, with TIN and lipid profiles [including low-density lipoprotein cholesterol (LDL-C), triglyceride, and high-density lipoprotein cholesterol] as outcomes. A two-step Mendelian randomization approach was used to assess TIN as a mediator, employing inverse variance weighted regression as the primary analysis, supplemented by Mendelian randomization-Egger, weighted median, and sensitivity analyses. RESULTS: Cytoplasmic unactivated MR level exhibited a significant causal association with a decreased risk of TIN (OR = 0.8598, 95% CI [0.7775-0.9508], P < 0.001). Although no significant causal relationship was identified between MR level and secondary hyperlipemia, a potential association of cytoplasmic unactivated MR level with lower LDL-C levels was observed (OR = 0.9901, 95% CI [0.9821-0.9983], P = 0.018). Additionally, TIN exhibited causal links with secondary hyperlipemia (OR = 1.0016, 95% CI [1.0002-1.0029], P = 0.020) and elevated LDL-C (OR = 1.0111, 95% CI [1.0024-1.0199], P = 0.012), particularly LDL-C in European males (OR = 1.0230, 95% CI [1.0103-1.0358], P < 0.001). Inverse Mendelian randomization analysis revealed causal relationships between TIN and genetically predicted triglyceride (OR = 0.7027, 95% CI [0.6189-0.7978], P < 0.001), high-density lipoprotein cholesterol (OR = 1.1247, 95% CI [1.0019-1.2626], P = 0.046), and LDL-C (OR = 0.8423, 95% CI [0.7220-0.9827], P = 0.029). Notably, TIN mediated 16.7% of the causal association between MR and LDL-C levels. CONCLUSIONS MR plays a critical role in the development of TIN and lipid metabolism, highlighting the potential of MR-antagonists in reducing renal damage and lipid metabolism-associated complications.
Humans ; Mendelian Randomization Analysis ; Nephritis, Interstitial/metabolism* ; Receptors, Mineralocorticoid/genetics* ; Lipid Metabolism/genetics* ; Genome-Wide Association Study ; Male ; Female ; Polymorphism, Single Nucleotide ; Dyslipidemias/metabolism*

OBJECTIVE: To explore the potential causal relationship between intervertebral disc degeneration and certain autoimmune diseases. METHODS: Genome-wide association study (GWAS) data of 5 autoimmune diseases were obtained from large-scale GWAS databases. Data on internal vertebral disc degeneration (IVDD) were derived from the FinnGen consortium, which included 294, 770 controls and 41, 669 cases. A two-sample bidirectional Mendelian randomization (MR) analysis was performed to investigate the potential causal relationship between the 5 autoimmune diseases and IVDD. Multiple analytical methods were adopted, including MR methods such as inverse variance weighting(IVW), MR-Egger, weighted median, weighted mode, and simple mode. Cochran's Q test, leave-one-out analysis, and MR-Egger intercept test were conducted to assess heterogeneity, robustness, and pleiotropy. For the robustness of the results, MR-PRESSO was used to detect outliers, and MR analysis was re-conducted after removing the outliers. RESULTS: The MR analysis results showed that there might be a bidirectional causal relationship between ankylosing spondylitis(AS) and IVDD:AS on IVDD, OR=1.038, 95%CI (1.024, 1.053), P=0.000;and IVDD on AS, OR=2.117, 95%CI(1.065, 4.207), P=0.032. There might be a positive correlation between IVDD and rheumatoid arthritis(RA) as well as systemic lupus erythematosus(SLE):IVDD on RA, OR=1.184, 95%CI(1.071, 1.309), P=0.001;and IVDD on SLE, OR=1.678, 95%CI(1.187, 2.372), P=0.003. There was no significant correlation between ulcerative colitis(UC), autoimmune thyroiditis(ATD) and IVDD. After removing outliers by MR-PRESSO and re-conducting MR analysis, the results did not change qualitatively. Sensitivity analysis indicated that the results were robust to potential sources of bias. CONCLUSION AS and IVDD may be risk factors for each other, and IVDD may be a potential risk factor for RA and SLE. These findings provide a basis for guiding the prevention and combined diagnosis and treatment of IVDD, AS, RA, and SLE, while the specific underlying mechanisms still require further experimental basic research.
Humans ; Intervertebral Disc Degeneration/etiology* ; Mendelian Randomization Analysis ; Autoimmune Diseases/complications* ; Genome-Wide Association Study ; Spondylitis, Ankylosing/genetics* ; Arthritis, Rheumatoid/genetics*

OBJECTIVE: To screen out the key metabolites related to diabetic foot (DF) by integrating genome-wide association studies (GWAS) and metabolome genome-wide association studies (mGWAS). METHODS: The literature databases such as PubMed and China national knowledge infrastructure(CNKI), as well as genomics databases such as PAN UKBB, FinnGen, and IEU Open GWAS were systematically retrieved from database estobilishment to November 2024 on DF-related single nucleotide polymorphisms and genome-wide association studies. DF-single nucleotide polymorphism-metabolite network was constructed by mGWAS package and mGWAS-Explorer platform. The causal relationship between key factors was evaluated by two-sample Mendelian randomization. The genetic correlation between DF and 575 metabolites (source:IEU Open GWAS) was evaluated by linkage disequilibrium score regression. In vitro experiments were conducted to induce injury of human umbilical vein endothelial cells with 30 mM glucose and intervene with 20 μM γ-tocopherol. Changes in cell migration, scratch healing and tube formation function were detected. RESULTS: Twenty-senen literatures on single nucleotide polymorphism literatures and 3 studies on GWAS were included. Genetic analysis results showed DF-related single nucleotide polymorphisms were enriched in vascular endothelial dysfunction-related pathways (such as fluid shear stress and atherosclerosis). The results of metabolic network analysis screened out 19 associated metabolites, among which 12 such as γ -tocopherol and pyruvate had significant genetic correlations with DF. Mendelian randomization suggested matrix metalloproteinase-9(MMP-9) might be a potential driver of DF (β=0.658, P=0.063 8), and the occurrence of DF could reduce the level of high-density lipoprotein (β=-0.002, P=0.015 2). The results of in vitro experiments confirmed that γ -tocopherol could improve endothelial dysfunction induced by high glucose, specifically manifested as an increase in the number of cell migrations, improvement in the scratch healing rate, and recovery of tubule formation ability (P<0.05). CONCLUSION DF has a genetic basis centered on vascular endothelial dysfunction, and its occurrence can lead to further metabolic disorders. The key single nucleotide polymorphism loci integrated provided molecular markers for the risk stratification of foot ulcers in diabetic patients. In addition, γ -tocopherol has demonstrated clinical application potential as a therapeutic drug for DF by significantly improving the function of vascular endothelial cells in a high-glucose environment.
Humans ; Diabetic Foot/drug therapy* ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Genomics ; Metabolomics ; Metabolome