Objective:Based on multistage metabolomic profiling and Mendelian randomization analyses,the current study identified plasma metabolites that predicted the risk of developing gastric cancer(GC)and determined whether k...Objective:Based on multistage metabolomic profiling and Mendelian randomization analyses,the current study identified plasma metabolites that predicted the risk of developing gastric cancer(GC)and determined whether key metabolite levels modified the GC primary prevention effects.Methods:Plasma metabolites associated with GC risk were identified through a case-control study.Bi-directional two-sample Mendelian randomization analyses were performed to determine potential causal relationships utilizing the Shandong Intervention Trial(SIT),a nested case-control study of the Mass Intervention Trial in Linqu,Shandong province(MITS),China,the UK Biobank,and the Finn Gen project.Results:A higher genetic risk score for plasma L-aspartic acid was significantly associated with an increased GC risk in the northern Chinese population(SIT:HR=1.26 per 1 SD change,95%CI:1.07±1.49;MITS:HR=1.07,95%CI:1.00±1.14)and an increased gastric adenocarcinoma risk in Finn Gen(OR=1.68,95%CI:1.16±2.45).Genetically predicted plasma L-aspartic acid levels also modified the GC primary prevention effects with the beneficial effect of Helicobacter pylori eradication notably observed among individuals within the top quartile of L-aspartic acid level(P-interaction=0.098)and the beneficial effect of garlic supplementation only for those within the lowest quartile of L-aspartic acid level(P-interaction=0.02).Conclusions:Elevated plasma L-aspartic acid levels significantly increased the risk of developing GC and modified the effects of GC primary prevention.Further studies from other populations are warranted to validate the modification effect of plasma L-aspartic acid levels on GC prevention and to elucidate the underlying mechanisms.展开更多
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...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.展开更多
Objective Vitamin deficiencies,particularly in vitamins A,B12,and D,are prevalent across populations and contribute significantly to a range of health issues.While these deficiencies are well documented,the underlying...Objective Vitamin deficiencies,particularly in vitamins A,B12,and D,are prevalent across populations and contribute significantly to a range of health issues.While these deficiencies are well documented,the underlying etiology remains complex.Recent studies suggest a close link between the gut microbiota and the synthesis,absorption,and metabolism of these vitamins.However,the specific causal relationships between the gut microbiota composition and vitamin deficiencies remain poorly understood.Identifying key bacterial species and understanding their role in vitamin metabolism could provide critical insights for targeted interventions.Methods We conducted a two-sample Mendelian randomization(MR)study to assess the causal relationship between the gut microbiota and vitamin deficiencies(A,B12,D).The genome-wide association study data for vitamin deficiencies were sourced from the FinnGen biobank,and the gut microbiota data were from the MiBioGen consortium.MR analyses included inverse variance-weighted(IVW),MR‒Egger,weighted median,and weighted mode approaches.Sensitivity analyses and reverse causality assessments were performed to ensure robustness and validate the findings.Results After FDR adjustment,vitamin B12 deficiency was associated with the class Verrucomicrobiae,order Verrucomicrobiales,family Verrucomicrobiaceae,and genus Akkermansia.Vitamin A deficiency was associated with the phylum Firmicutes and the genera Fusicatenibacter and Ruminiclostridium 6.Additional associations for vitamin B12 deficiency included the Enterobacteriaceae and Rhodospirillaceae and the genera Coprococcus 2,Lactococcus,and Ruminococcaceae UCG002.Vitamin D deficiency was associated with the genera Allisonella,Eubacterium,and Tyzzerella 3.Lachnospiraceae and Lactococcus were common risk factors for both B12 and D deficiency.Sensitivity analyses confirmed the robustness of the findings against heterogeneity and horizontal pleiotropy,and reverse MR tests indicated no evidence of reverse causality.Conclusions Our findings reveal a possible causal relationship between specific gut microbiota characteristics and vitamin A,B12 and D deficiencies,providing a theoretical basis for addressing these nutritional deficiencies through the modulation of the gut microbiota in the future and laying the groundwork for related interventions.展开更多
Objective:Gut microbiota(GM)and blood metabolites are associated with the development of urticaria,yet their specific causal relationships in East Asian populations remain unclear.This study aims to elucidate the caus...Objective:Gut microbiota(GM)and blood metabolites are associated with the development of urticaria,yet their specific causal relationships in East Asian populations remain unclear.This study aims to elucidate the causal and mediating relationships among GM,blood metabolites,and urticaria in East Asians using Mendelian randomization(MR)analysis.Methods:Summary-level statistics for 500 GM taxa,112 blood metabolites,and urticaria were obtained from publicly available Genome-Wide Association Studies(GWAS)datasets.Bidirectional MR analyses were performed to examine causal associations among the GM,blood metabolites,and urticaria.The inverse variance weighted(IVW)method served as the primary analytical approach,supplemented by MR-Egger,weighted median,simple mode,and weighted mode methods.Sensitivity analyses included heterogeneity tests,horizontal pleiotropy assessments,and leave-one-out analyses.Mediation analysis was conducted to evaluate the potential mediating effects of blood metabolites on the causal pathways between GM and urticaria.Results:MR analyses identified 12 GM taxa exhibiting significant causal effects on urticaria susceptibility.Nine taxa,such as MF0017_galactose_degradation(OR=1.461,95%CI 1.098 to 1.944,P=0.009),were associated with increased urticaria risk.Three taxa,such as MF0001_arabinoxylan_degradation(OR=0.846,95%CI 0.737 to 0.973,P=0.019),showed protective effects with increased abundance.Additionally,6 blood metabolites demonstrated causal associations with urticaria.Notably,the risk of developing urticaria increases with rising fasting plasma glucose(FPG)levels(OR=1.971,95%CI 1.089 to 3.567,P=0.025).Mediation analysis further demonstrated that FPG partially mediated the protective effect of MF0001_arabinoxylan_degradation on urticaria,accounting for 11.30%of the total effect.Conclusion:This study has delineated specific GM taxa and blood metabolites that hold causal relevance to urticaria in East Asian populations.Notably,arabinogalactan degradation potentially mitigates urticaria risk via reducing FPG concentrations,offering genetic evidence to support therapeutic strategies targeting GM modulation and glucose regulation.展开更多
AIM:To investigate the causal relationship between dietary intake and myopia using Mendelian randomization(MR)analysis.METHODS:Genome-wide association study(GWAS)data from the IEU Open GWAS database were utilized to e...AIM:To investigate the causal relationship between dietary intake and myopia using Mendelian randomization(MR)analysis.METHODS:Genome-wide association study(GWAS)data from the IEU Open GWAS database were utilized to examine associations between myopia and various dietary factors.MR analysis,incorporating both univariable and multivariable approaches,assessed the impact of food intake on myopia risk through five analytical methods,with inverse variance weighted(IVW)serving as the primary reference.Sensitivity analyses,including heterogeneity assessment,horizontal pleiotropy evaluation,and leave-oneout analysis,were conducted to validate the MR findings.RESULTS:Univariable MR analysis identified a causal link between food intake and myopia.Consumption of breaded fish,canned soup,sweet biscuits,and certain fruits correlated with a lower risk of myopia,whereas intake of low-calorie hot chocolate and cereal was associated with an increased risk.Multivariable MR analysis further confirmed that breaded fish consumption exerted a direct protective effect against myopia,particularly when consumed alongside other dietary components.These findings highlight the intricate interplay between specific dietary factors and myopia development,offering valuable insights for further research.CONCLUSION:MR analysis provides evidence supporting a potential causal relationship between breaded fish intake and myopia,underscoring its relevance in targeted myopia prevention strategies.展开更多
Domain randomization is a widely adopted technique in deep reinforcement learning(DRL)to improve agent generalization by exposing policies to diverse environmental conditions.This paper investigates the impact of diff...Domain randomization is a widely adopted technique in deep reinforcement learning(DRL)to improve agent generalization by exposing policies to diverse environmental conditions.This paper investigates the impact of different reset strategies,normal,non-randomized,and randomized,on agent performance using the Deep Deterministic Policy Gradient(DDPG)and Twin Delayed DDPG(TD3)algorithms within the CarRacing-v2 environment.Two experimental setups were conducted:an extended training regime with DDPG for 1000 steps per episode across 1000 episodes,and a fast execution setup comparing DDPG and TD3 for 30 episodes with 50 steps per episode under constrained computational resources.A step-based reward scaling mechanism was applied under the randomized reset condition to promote broader state exploration.Experimental results showthat randomized resets significantly enhance learning efficiency and generalization,with DDPG demonstrating superior performance across all reset strategies.In particular,DDPG combined with randomized resets achieves the highest smoothed rewards(reaching approximately 15),best stability,and fastest convergence.These differences are statistically significant,as confirmed by t-tests:DDPG outperforms TD3 under randomized(t=−101.91,p<0.0001),normal(t=−21.59,p<0.0001),and non-randomized(t=−62.46,p<0.0001)reset conditions.The findings underscore the critical role of reset strategy and reward shaping in enhancing the robustness and adaptability of DRL agents in continuous control tasks,particularly in environments where computational efficiency and training stability are crucial.展开更多
Dear Editor,Observational studies in epidemiology have identified a correlation between hypothyroidism and cholelithiasis[1–2].However,the causal relationship between the two diseases remains unclear.To investigate t...Dear Editor,Observational studies in epidemiology have identified a correlation between hypothyroidism and cholelithiasis[1–2].However,the causal relationship between the two diseases remains unclear.To investigate the potential causal relationship,we employed a two-sample bidirectional Mendelian randomization(MR)analysis.展开更多
In recent years,Mendelian randomization(MR)has been increasingly utilized,leveraging genetic variants as instrumental variables.This approach significantly mitigates confounder effects and reverse causation,precisely ...In recent years,Mendelian randomization(MR)has been increasingly utilized,leveraging genetic variants as instrumental variables.This approach significantly mitigates confounder effects and reverse causation,precisely clarifying the causal links between exposures and outcomes.MR’s unique advantages have made it instrumental in medicine,especially in elucidating glaucoma’s etiology.It facilitates the identification of potential risk factors,laying the groundwork for developing preventative and therapeutic strategies against glaucoma.Recent MR research has delved into diverse potential glaucoma risk factors,including behavioral habits,metabolic profiles,and their causative linkage to the disease.This review encapsulates MR’s analysis in glaucoma etiology,heralding new avenues for understanding underlying mechanisms and establishing causality.展开更多
BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outc...BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.展开更多
Background:The aim of this study was to analyze the bi-directional causal relation-ship between lipid profile and characteristics related to muscle atrophy by using a bi-directional Mendelian randomization(MR)analysis...Background:The aim of this study was to analyze the bi-directional causal relation-ship between lipid profile and characteristics related to muscle atrophy by using a bi-directional Mendelian randomization(MR)analysis.Methods:The appendicular lean mass(ALM),whole body fat-free mass(WBFFM)and trunk fat-free mass(TFFM)were used as genome-wide association study(GWAS)data for evaluating muscle mass;the usual walking pace(UWP)and low grip strength(LGS)were used as GWAS data for evaluating muscle strength;and the triglycerides(TG),total cholesterol(TC),high density lipoprotein cholesterol(HDL),low density lipo-protein cholesterol(LDL),apolipoprotein A-1(Apo A-1),and apolipoprotein B(Apo B)were used as GWAS data for evaluating lipid profile.For specific investigations,we mainly employed inverse variance weighting for causal estimation and MR-Egger for pleiotropy analysis.Results:MR results showed that the lipid profile predicted by genetic variants was negatively correlated with muscle mass,positively correlated with UWP,and was not causally correlated with LGS.On the other hand,the muscle mass predicted by genetic variants was negatively correlated with lipid profile,the UWP predicted by genetic variants was mainly positively correlated with lipid profile,while the LGS pre-dicted by genetic variants had no relevant causal relationship with lipid profile.Conclusions:Findings of this MR analysis suggest that hyperlipidemia may affect muscle mass and lead to muscle atrophy,but has no significant effect on muscle strength.On the other hand,increased muscle mass may reduce the incidence of dyslipidemia.展开更多
Emerging evidence highlights the role of thyroid hormones in cancer,although findings are controversial.Research on thyroid-related traits in lung carcinogenesis is limited.Using UK Biobank data,we performed bidirecti...Emerging evidence highlights the role of thyroid hormones in cancer,although findings are controversial.Research on thyroid-related traits in lung carcinogenesis is limited.Using UK Biobank data,we performed bidirectional Mendelian randomization(MR)to assess causal associations between lung cancer risk and thyroid dysfunction(hypothyroidism and hyperthyroidism)or functional traits(free thyroxine[FT4]and normal-range thyroid-stimulating hormone[TSH]).Furthermore,in the smoking-behavior-stratified MR analysis,we evaluated the mediating effect of thyroid-related phenotypes on the association between smoking behaviors and lung cancer.We demonstrated significant associations between lung cancer risk and hypothyroidism(hazard ratio[HR]=1.14,95%confidence interval[CI]=1.03–1.26,P=0.009)and hyperthyroidism(HR=1.55,95%CI=1.29–1.87,P=1.90×10^(-6))in the UKB.Moreover,the MR analysis indicated a causal effect of thyroid dysfunction on lung cancer risk(ORinverse variance weighted[IVW]=1.09,95%CI=1.05–1.13,P=3.12×10^(-6)for hypothyroidism;ORIVW=1.08,95%CI=1.04–1.12,P=8.14×10^(-5)for hyperthyroidism).We found that FT4 levels were protective against lung cancer risk(ORIVW=0.93,95%CI=0.87–0.99,P=0.030).Additionally,the stratified MR analysis demonstrated distinct causal effects of thyroid dysfunction on lung cancer risk among smokers.Hyperthyroidism mediated the effect of smoking behaviors,especially the age of smoking initiation(17.66%mediated),on lung cancer risk.Thus,thyroid dysfunction phenotypes play causal roles in lung cancer development exclusively among smokers and act as mediators in the causal pathway from smoking to lung cancer.展开更多
Background:Chronic obstructive pulmonary disease(COPD)is a prevalent respiratory ailment that has risen to become the foremost cause of mortality globally,and statins are a widely used class of lipid-modifying drugs.D...Background:Chronic obstructive pulmonary disease(COPD)is a prevalent respiratory ailment that has risen to become the foremost cause of mortality globally,and statins are a widely used class of lipid-modifying drugs.Data from some observational studies suggest an association between statins use and COPD.Objectives:The main objective of this study was to investigate whether lipids and apolipoproteins are bidirectionally causally associated with COPD at the genetic level using a Mendelian randomization(MR)design,and to determine the potential role of circulating inflammatory proteins as mediators in this association.Methods:The publicly available Genome-Wide Association Study(GWAS)database was utilised for the purposes of the analysis.The data on high-density lipoprotein(HDL-C),low-density lipoprotein(LDL-C),triglycerides(TG),apolipoprotein A-1(ApoA1),and apolipoprotein B(ApoB)were obtained from the UK BioBank,while the COPD dataset was obtained from the FinnGen BioBank R11(number of cases:21,617,number of controls:372,627).Furthermore,data were gathered on genetic variants linked to inflammatory processes,encompassing 91 circulating inflammatory proteins(n=14,823 individuals).A two-sample MR study was conducted using these data to assess the association between HDL-C,LDL-C,TG,ApoA1,and ApoB with the risk of COPD.Furthermore,in order to investigate the potential mediating influence of inflammatory factor alterations between lipids and COPD,a two-step Mendelian randomization(MR)mediation analysis was conducted.Results:The forward MR methods identified two lipids that were found to have a causal relationship with the development of COPD.An elevated level of LDL-C and ApoB was found to be associated with a diminished risk of COPD.Furthermore,the researchers identified circulating inflammatory factors that were determined to be the causal agents in the development of COPD.Mediation analysis indicated that the inflammatory protein S100-A12 may act as a mediator between the LDL-C and COPD pathways.Conclusion:The present MR study provides genetic evidence for a causal relationship between lipids and apolipoproteins and COPD,as well as identifying the inflammatory protein S100-A12 as a potential mediator of the COPD association.The findings offer valuable insights into the mechanistic studies of statins for COPD and potential targets for disease intervention and treatment.展开更多
Objective Pneumoconiosis,a lung disease caused by irreversible fibrosis,represents a significant public health burden.This study investigates the causal relationships between gut microbiota,gene methylation,gene expre...Objective Pneumoconiosis,a lung disease caused by irreversible fibrosis,represents a significant public health burden.This study investigates the causal relationships between gut microbiota,gene methylation,gene expression,protein levels,and pneumoconiosis using a multi-omics approach and Mendelian randomization(MR).Methods We analyzed gut microbiota data from MiBioGen and Esteban et al.to assess their potential causal effects on pneumoconiosis subtypes(asbestosis,silicosis,and inorganic pneumoconiosis)using conventional and summary-data-based MR(SMR).Gene methylation and expression data from Genotype-Tissue Expression and eQTLGen,along with protein level data from deCODE and UK Biobank Pharma Proteomics Project,were examined in relation to pneumoconiosis data from FinnGen.To validate our findings,we assessed self-measured gut flora from a pneumoconiosis cohort and performed fine mapping,drug prediction,molecular docking,and Phenome-Wide Association Studies to explore relevant phenotypes of key genes.Results Three core gut microorganisms were identified:Romboutsia(OR=0.249)as a protective factor against silicosis,Pasteurellaceae(OR=3.207)and Haemophilus parainfluenzae(OR=2.343)as risk factors for inorganic pneumoconiosis.Additionally,mapping and quantitative trait loci analyses revealed that the genes VIM,STX8,and MIF were significantly associated with pneumoconiosis risk.Conclusions This multi-omics study highlights the associations between gut microbiota and key genes(VIM,STX8,MIF)with pneumoconiosis,offering insights into potential therapeutic targets and personalized treatment strategies.展开更多
Objective 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 dysl...Objective 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.展开更多
AIM:To use two-sample Mendelian randomization(MR)method to study uveitis causal association with wet age-related macular degeneration(wAMD)risk from the genetic level.METHODS:Two-sample MR analysis was used to assess ...AIM:To use two-sample Mendelian randomization(MR)method to study uveitis causal association with wet age-related macular degeneration(wAMD)risk from the genetic level.METHODS:Two-sample MR analysis was used to assess the causal role of uveitis on wAMD risk,using the 8 genetic variants associated strongly with uveitis as instrumental variables.Besides,eight MR methods[inverse variance weighted(IVW),weighted median,MR-Egger regression,weighted mode,simple mode,robust adjusted profile score(RAPS),contamination inverse-variance weighted method,and debiased inverse-variance weighted method]were used to get the whole causal estimate for multiple instrumental single nucleotide polymorphism(SNPs).The MR analysis was based on Europeans.RESULTS:Uveitis was related to a higher risk of wAMD[odds ratio(OR):1.08,95%confidence interval(CI)1.03–1.12;P=1.03×10^(-3)]with the IVW method.No heterogeneity and directional pleiotropy were detected.On the contrary,no significant results were detected in reverse MR analysis.CONCLUSION:Uveitis is related to an increased risk of wAMD.Due to the high blindness rate of wAMD,understanding and controlling the risk factors of AMD is of great significance for reducing its incidence and early diagnosis and treatment.展开更多
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 observati...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.展开更多
BACKGROUND:This study aims to explore the causal relationship of body weight,body mass index(BMI),and waist circumference (WC) with the risk of cardiac arrest (CA) using two-sample Mendelian randomization (MR).METHODS...BACKGROUND:This study aims to explore the causal relationship of body weight,body mass index(BMI),and waist circumference (WC) with the risk of cardiac arrest (CA) using two-sample Mendelian randomization (MR).METHODS:Data were summarized using genome-wide association studies (GWAS).Twosample MR analyses were performed using the inverse variance weighting (IVW) method,the weighted median method,and the MR-Egger analysis.Heterogeneity test and sensitivity analysis were performed using Cochran’s Q test and the leave-one-out method,respectively.The Steiger test was used to detect reverse causality.Bayesian model-averaged MR was used to identify the most influential risk factors.RESULTS:A total of 13 GWAS data were collected for BMI,body weight and WC.IVW analyses showed a positive correlation of body weight,BMI,and WC with CA (all OR>1 and P<0.05),with MR-Egger and weighted median methods confirming the IVW findings.No horizontal pleiotropy or heterogeneity was observed.Sensitivity analysis indicated that no single nucleotide polymorphism(SNP) caused significant changes in overall causality.Bayesian model-averaged MR was also used to rank causality based on marginal inclusion probability (MIP),and the corresponding modelaveraged causal estimate (MACE) were confirmed,which indicated that WC (GWAS ID:ukb-b-9405)was the highest-ranked risk factor (MIP=0.119,MACE=0.011);its posterior probability was 0.057.A total of 14 sex-specific GWAS data on weight,BMI,and WC were analyzed in relationship with CA,and the MR results showed no significant effects of sex-specific factors.CONCLUSION:Body weight,BMI,and WC are causally associated with an increased risk of CA,with WC identified as the most important risk factor.展开更多
Background:Ankle-foot sprains are the most common musculoskeletal injuries,which can impair balance and theoretically increase the risk of falls,but still,there is a lack of evidence supporting the direct association ...Background:Ankle-foot sprains are the most common musculoskeletal injuries,which can impair balance and theoretically increase the risk of falls,but still,there is a lack of evidence supporting the direct association between ankle-foot sprains and the future risk of falls.Methods:UK Biobank cohort was utilized to measure the association between ankle-foot sprains and fall risk with covariates adjusted.Then,the two-sample Mendelian randomization(MR)analysis was applied based on the genetically predicated ankle-foot sprains from FinnGen to validate causal relationship.Finally,genetically predicated cerebellar neuroimaging features were used to explore the mediating role of maladaptive neuroplasticity between ankle-foot sprains and falls by two-step MR analyses.Results:Patients with ankle-foot sprains history exhibited a slightly increased risk of falls than the matched controls before and after adjustment for covariates(odd ratio[OR]ranged from 1.632 to 1.658).Two-sample MR analysis showed that ankle-foot sprains led to a higher risk of falls(OR=1.036)and a lower fractional anisotropy of superior cerebellar peduncle(SCP)(left,β=0.052;right,β=0.053).A trend of mediating effect was observed for the fractional anisotropy of right SCP in the causal effects of ankle-foot sprains on falls(β=0.003).Conclusion:The history of ankle-foot sprains is associated with a slightly increased risk of falls.These findings improve our understanding of the clinical consequences of ankle-foot sprains in terms of fall risk and suggest the importance of adopting more efficient strategies for managing residual functional deficits after the injuries.展开更多
Consecutive stresses,such as initial submergence during germination followed by water deficit during the seedling stage,pose significant challenges to direct-seeded rice cultivation.By Linkage disequilibrium analysis,...Consecutive stresses,such as initial submergence during germination followed by water deficit during the seedling stage,pose significant challenges to direct-seeded rice cultivation.By Linkage disequilibrium analysis,Sub1 and Dro1(Δbp:10 Mb),as well as Sub1 and TPP7(Δbp:6 Mb)were identified to exhibit long-range linkage disequilibrium(LRLD).Meta-QTL analysis further revealed that Sub1 and TPP7 co-segregated for tolerance to submergence at the germination and seedling stages.Based on this,we hypothesized that LRLD might influence plant responses to consecutive stresses.To test this hypothesis,we developed a structured recombinant inbred line population from a cross between Bhalum 2 and Nagina 22,with alleles(Sub1 and TPP7)in linkage equilibrium.Mendelian randomization analysis validated that the parental alleles,rather than the recombinant alleles of Sub1 and TPP7,significantly influenced 13 out of 41 traits under consecutive stress conditions.Additionally,16 minor additive effect QTLs were detected between the genomic regions,spanning Sub1 and TPP7 for various traits.A single allele difference between these genomic regions enhanced crown root number,root dry weight,and specific root area by 11.45%,15.69%,and 33.15%,respectively,under flooded germination conditions.Candidate gene analysis identified WAK79 and MRLK59 as regulators of stress responses during flooded germination,recovery,and subsequent water deficit conditions.These findings highlight the critical role of parental allele combinations and genomic regions between Sub1 and TPP7 in regulating the stress responses under consecutive stresses.Favourable haplotypes derived from these alleles can be utilized to improve stress resilience in direct-seeded rice.展开更多
Chronic diseases are major causes of global death and disability,significantly impacting individual health and imposing economic burdens.This study aims to investigate the causal relationship between physical activity...Chronic diseases are major causes of global death and disability,significantly impacting individual health and imposing economic burdens.This study aims to investigate the causal relationship between physical activity(PA)and the development of chronic diseases.Using a Mendelian randomization(MR)approach,we incorporated average PA and its subtypes(more than 450000 participants)as exposure measures and eight chronic diseases as outcome measures.Data were obtained from the European Genome-Wide Association Study(GWAS).The primary causal analysis technique employed was the inverse variance weighting(IVW)method,with MR-Egger,weighted median,weighted mode,and simple mode used to validate the results.Sensitivity analyses were performed to assess heterogeneity and pleiotropy.The IVW approach results show that vigorous physical activity(VPA)is associated with a modest reduction in the risk of major coronary heart disease(OR=0.95,95%CI:0.91–0.99,p=0.01).The causal directions of the other four MR methods are consistent with this result and validated by sensitivity analysis.No substantial associations were found between other levels of PA and chronic disease.Our findings underscore the importance of VPA in preventive cardiology and suggest its potential role in public health initiatives.Further research should explore the impact of PA on different demographic groups and the doseresponse relationship of VPA on heart health.展开更多
基金funded by the National Natural Science Foundation of China(No.82273704)Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2023ZD0501400-2023ZD0501402)+4 种基金Beijing Hospitals Authority’s Ascent Plan(DFL20241102)Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support(No.ZLRK202325)China Postdoctoral Science Foundation(2024M760152)Peking University Medicine Fund for World’s Leading Discipline or Discipline Cluster Development(No.BMU2022XKQ004)Science Foundation of Peking University Cancer Hospital(Nos.BJCH2024BJ02,XKFZ2410,BJCH2025CZ04,and 2022-27)。
文摘Objective:Based on multistage metabolomic profiling and Mendelian randomization analyses,the current study identified plasma metabolites that predicted the risk of developing gastric cancer(GC)and determined whether key metabolite levels modified the GC primary prevention effects.Methods:Plasma metabolites associated with GC risk were identified through a case-control study.Bi-directional two-sample Mendelian randomization analyses were performed to determine potential causal relationships utilizing the Shandong Intervention Trial(SIT),a nested case-control study of the Mass Intervention Trial in Linqu,Shandong province(MITS),China,the UK Biobank,and the Finn Gen project.Results:A higher genetic risk score for plasma L-aspartic acid was significantly associated with an increased GC risk in the northern Chinese population(SIT:HR=1.26 per 1 SD change,95%CI:1.07±1.49;MITS:HR=1.07,95%CI:1.00±1.14)and an increased gastric adenocarcinoma risk in Finn Gen(OR=1.68,95%CI:1.16±2.45).Genetically predicted plasma L-aspartic acid levels also modified the GC primary prevention effects with the beneficial effect of Helicobacter pylori eradication notably observed among individuals within the top quartile of L-aspartic acid level(P-interaction=0.098)and the beneficial effect of garlic supplementation only for those within the lowest quartile of L-aspartic acid level(P-interaction=0.02).Conclusions:Elevated plasma L-aspartic acid levels significantly increased the risk of developing GC and modified the effects of GC primary prevention.Further studies from other populations are warranted to validate the modification effect of plasma L-aspartic acid levels on GC prevention and to elucidate the underlying mechanisms.
基金supported by the National Natural Science Foundation of China(82322059)the Chinese Academy of Medical·Sciences Innovation Fund for Medical Sciences(2021-I2M-1-010)+1 种基金the National Key Research and Development Program of China(2021YFC2500500)the National High Level Hospital Clinical Research Funding(2023-GSPRC-19).
文摘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.
文摘Objective Vitamin deficiencies,particularly in vitamins A,B12,and D,are prevalent across populations and contribute significantly to a range of health issues.While these deficiencies are well documented,the underlying etiology remains complex.Recent studies suggest a close link between the gut microbiota and the synthesis,absorption,and metabolism of these vitamins.However,the specific causal relationships between the gut microbiota composition and vitamin deficiencies remain poorly understood.Identifying key bacterial species and understanding their role in vitamin metabolism could provide critical insights for targeted interventions.Methods We conducted a two-sample Mendelian randomization(MR)study to assess the causal relationship between the gut microbiota and vitamin deficiencies(A,B12,D).The genome-wide association study data for vitamin deficiencies were sourced from the FinnGen biobank,and the gut microbiota data were from the MiBioGen consortium.MR analyses included inverse variance-weighted(IVW),MR‒Egger,weighted median,and weighted mode approaches.Sensitivity analyses and reverse causality assessments were performed to ensure robustness and validate the findings.Results After FDR adjustment,vitamin B12 deficiency was associated with the class Verrucomicrobiae,order Verrucomicrobiales,family Verrucomicrobiaceae,and genus Akkermansia.Vitamin A deficiency was associated with the phylum Firmicutes and the genera Fusicatenibacter and Ruminiclostridium 6.Additional associations for vitamin B12 deficiency included the Enterobacteriaceae and Rhodospirillaceae and the genera Coprococcus 2,Lactococcus,and Ruminococcaceae UCG002.Vitamin D deficiency was associated with the genera Allisonella,Eubacterium,and Tyzzerella 3.Lachnospiraceae and Lactococcus were common risk factors for both B12 and D deficiency.Sensitivity analyses confirmed the robustness of the findings against heterogeneity and horizontal pleiotropy,and reverse MR tests indicated no evidence of reverse causality.Conclusions Our findings reveal a possible causal relationship between specific gut microbiota characteristics and vitamin A,B12 and D deficiencies,providing a theoretical basis for addressing these nutritional deficiencies through the modulation of the gut microbiota in the future and laying the groundwork for related interventions.
基金supported by the Natural Science Foundation of Hunan Province,China(2024JJ7627).
文摘Objective:Gut microbiota(GM)and blood metabolites are associated with the development of urticaria,yet their specific causal relationships in East Asian populations remain unclear.This study aims to elucidate the causal and mediating relationships among GM,blood metabolites,and urticaria in East Asians using Mendelian randomization(MR)analysis.Methods:Summary-level statistics for 500 GM taxa,112 blood metabolites,and urticaria were obtained from publicly available Genome-Wide Association Studies(GWAS)datasets.Bidirectional MR analyses were performed to examine causal associations among the GM,blood metabolites,and urticaria.The inverse variance weighted(IVW)method served as the primary analytical approach,supplemented by MR-Egger,weighted median,simple mode,and weighted mode methods.Sensitivity analyses included heterogeneity tests,horizontal pleiotropy assessments,and leave-one-out analyses.Mediation analysis was conducted to evaluate the potential mediating effects of blood metabolites on the causal pathways between GM and urticaria.Results:MR analyses identified 12 GM taxa exhibiting significant causal effects on urticaria susceptibility.Nine taxa,such as MF0017_galactose_degradation(OR=1.461,95%CI 1.098 to 1.944,P=0.009),were associated with increased urticaria risk.Three taxa,such as MF0001_arabinoxylan_degradation(OR=0.846,95%CI 0.737 to 0.973,P=0.019),showed protective effects with increased abundance.Additionally,6 blood metabolites demonstrated causal associations with urticaria.Notably,the risk of developing urticaria increases with rising fasting plasma glucose(FPG)levels(OR=1.971,95%CI 1.089 to 3.567,P=0.025).Mediation analysis further demonstrated that FPG partially mediated the protective effect of MF0001_arabinoxylan_degradation on urticaria,accounting for 11.30%of the total effect.Conclusion:This study has delineated specific GM taxa and blood metabolites that hold causal relevance to urticaria in East Asian populations.Notably,arabinogalactan degradation potentially mitigates urticaria risk via reducing FPG concentrations,offering genetic evidence to support therapeutic strategies targeting GM modulation and glucose regulation.
基金Supported by Xi’an Science and Technology Program Project(No.24YXYJ0108)Support Projects of Xi’an Children’s Hospital(No.2024I07).
文摘AIM:To investigate the causal relationship between dietary intake and myopia using Mendelian randomization(MR)analysis.METHODS:Genome-wide association study(GWAS)data from the IEU Open GWAS database were utilized to examine associations between myopia and various dietary factors.MR analysis,incorporating both univariable and multivariable approaches,assessed the impact of food intake on myopia risk through five analytical methods,with inverse variance weighted(IVW)serving as the primary reference.Sensitivity analyses,including heterogeneity assessment,horizontal pleiotropy evaluation,and leave-oneout analysis,were conducted to validate the MR findings.RESULTS:Univariable MR analysis identified a causal link between food intake and myopia.Consumption of breaded fish,canned soup,sweet biscuits,and certain fruits correlated with a lower risk of myopia,whereas intake of low-calorie hot chocolate and cereal was associated with an increased risk.Multivariable MR analysis further confirmed that breaded fish consumption exerted a direct protective effect against myopia,particularly when consumed alongside other dietary components.These findings highlight the intricate interplay between specific dietary factors and myopia development,offering valuable insights for further research.CONCLUSION:MR analysis provides evidence supporting a potential causal relationship between breaded fish intake and myopia,underscoring its relevance in targeted myopia prevention strategies.
基金supported by the Deputyship for Research&Innovation,Ministry of Education in Saudi Arabia(Project No.MoE-IF-UJ-R2-22-04220773-1).
文摘Domain randomization is a widely adopted technique in deep reinforcement learning(DRL)to improve agent generalization by exposing policies to diverse environmental conditions.This paper investigates the impact of different reset strategies,normal,non-randomized,and randomized,on agent performance using the Deep Deterministic Policy Gradient(DDPG)and Twin Delayed DDPG(TD3)algorithms within the CarRacing-v2 environment.Two experimental setups were conducted:an extended training regime with DDPG for 1000 steps per episode across 1000 episodes,and a fast execution setup comparing DDPG and TD3 for 30 episodes with 50 steps per episode under constrained computational resources.A step-based reward scaling mechanism was applied under the randomized reset condition to promote broader state exploration.Experimental results showthat randomized resets significantly enhance learning efficiency and generalization,with DDPG demonstrating superior performance across all reset strategies.In particular,DDPG combined with randomized resets achieves the highest smoothed rewards(reaching approximately 15),best stability,and fastest convergence.These differences are statistically significant,as confirmed by t-tests:DDPG outperforms TD3 under randomized(t=−101.91,p<0.0001),normal(t=−21.59,p<0.0001),and non-randomized(t=−62.46,p<0.0001)reset conditions.The findings underscore the critical role of reset strategy and reward shaping in enhancing the robustness and adaptability of DRL agents in continuous control tasks,particularly in environments where computational efficiency and training stability are crucial.
基金by grants from the Jiangsu Province 333 High-level Talent Training Project(Grant No.LGY2016010)the Nanjing Science and Technology Development Plan(Grant No.201715003)the Jiangsu Province Six Talent Peaks(Grant No.WSN-030).
文摘Dear Editor,Observational studies in epidemiology have identified a correlation between hypothyroidism and cholelithiasis[1–2].However,the causal relationship between the two diseases remains unclear.To investigate the potential causal relationship,we employed a two-sample bidirectional Mendelian randomization(MR)analysis.
基金Supported by Shenzhen Science and Technology Program(No.JCYJ20220530152005013,No.JCYJ20230807114605011)Sanming Project of Medicine in Shenzhen(No.SZZYSM202411007).
文摘In recent years,Mendelian randomization(MR)has been increasingly utilized,leveraging genetic variants as instrumental variables.This approach significantly mitigates confounder effects and reverse causation,precisely clarifying the causal links between exposures and outcomes.MR’s unique advantages have made it instrumental in medicine,especially in elucidating glaucoma’s etiology.It facilitates the identification of potential risk factors,laying the groundwork for developing preventative and therapeutic strategies against glaucoma.Recent MR research has delved into diverse potential glaucoma risk factors,including behavioral habits,metabolic profiles,and their causative linkage to the disease.This review encapsulates MR’s analysis in glaucoma etiology,heralding new avenues for understanding underlying mechanisms and establishing causality.
文摘BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.
基金Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2021A1515220030Hunan Provincial Clinical Medical Technology Innovation Guiding Project,Grant/Award Number:2020SK53307+2 种基金Hunan Provincial Health Commission,Grant/Award Number:20201902Natural Science Foundation of Hunan Province,Grant/Award Number:2020JJ8043Project of Hunan Provincial Health,Grant/Award Number:c2019133。
文摘Background:The aim of this study was to analyze the bi-directional causal relation-ship between lipid profile and characteristics related to muscle atrophy by using a bi-directional Mendelian randomization(MR)analysis.Methods:The appendicular lean mass(ALM),whole body fat-free mass(WBFFM)and trunk fat-free mass(TFFM)were used as genome-wide association study(GWAS)data for evaluating muscle mass;the usual walking pace(UWP)and low grip strength(LGS)were used as GWAS data for evaluating muscle strength;and the triglycerides(TG),total cholesterol(TC),high density lipoprotein cholesterol(HDL),low density lipo-protein cholesterol(LDL),apolipoprotein A-1(Apo A-1),and apolipoprotein B(Apo B)were used as GWAS data for evaluating lipid profile.For specific investigations,we mainly employed inverse variance weighting for causal estimation and MR-Egger for pleiotropy analysis.Results:MR results showed that the lipid profile predicted by genetic variants was negatively correlated with muscle mass,positively correlated with UWP,and was not causally correlated with LGS.On the other hand,the muscle mass predicted by genetic variants was negatively correlated with lipid profile,the UWP predicted by genetic variants was mainly positively correlated with lipid profile,while the LGS pre-dicted by genetic variants had no relevant causal relationship with lipid profile.Conclusions:Findings of this MR analysis suggest that hyperlipidemia may affect muscle mass and lead to muscle atrophy,but has no significant effect on muscle strength.On the other hand,increased muscle mass may reduce the incidence of dyslipidemia.
基金funded by the National Natural Science Foundation of China(Grant Nos.82220108002 to F.C.,82273737 to R.Z.,82473728 to Y.W.)the US National Institutes of Health(Grant Nos.CA209414,HL060710,ES000002 to D.C.C.,CA209414,CA249096 to Y.L.)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).R.Z.was partially supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young-Level Academic Leadership Training Program of Nanjing Medical University.
文摘Emerging evidence highlights the role of thyroid hormones in cancer,although findings are controversial.Research on thyroid-related traits in lung carcinogenesis is limited.Using UK Biobank data,we performed bidirectional Mendelian randomization(MR)to assess causal associations between lung cancer risk and thyroid dysfunction(hypothyroidism and hyperthyroidism)or functional traits(free thyroxine[FT4]and normal-range thyroid-stimulating hormone[TSH]).Furthermore,in the smoking-behavior-stratified MR analysis,we evaluated the mediating effect of thyroid-related phenotypes on the association between smoking behaviors and lung cancer.We demonstrated significant associations between lung cancer risk and hypothyroidism(hazard ratio[HR]=1.14,95%confidence interval[CI]=1.03–1.26,P=0.009)and hyperthyroidism(HR=1.55,95%CI=1.29–1.87,P=1.90×10^(-6))in the UKB.Moreover,the MR analysis indicated a causal effect of thyroid dysfunction on lung cancer risk(ORinverse variance weighted[IVW]=1.09,95%CI=1.05–1.13,P=3.12×10^(-6)for hypothyroidism;ORIVW=1.08,95%CI=1.04–1.12,P=8.14×10^(-5)for hyperthyroidism).We found that FT4 levels were protective against lung cancer risk(ORIVW=0.93,95%CI=0.87–0.99,P=0.030).Additionally,the stratified MR analysis demonstrated distinct causal effects of thyroid dysfunction on lung cancer risk among smokers.Hyperthyroidism mediated the effect of smoking behaviors,especially the age of smoking initiation(17.66%mediated),on lung cancer risk.Thus,thyroid dysfunction phenotypes play causal roles in lung cancer development exclusively among smokers and act as mediators in the causal pathway from smoking to lung cancer.
基金supported by the Key Support Project of Regional Innovation and Development Joint Fund of National Natural Science Foundation of China(U20A20398)the National Natural Science Foundation of China(82104454,82374399)+1 种基金the Clinical Medical Research Transformation Project of Anhui Province(202304295107020111)the Natural Science Research Key Project of Anhui Provincial Department of Education(KJ2021A0542).
文摘Background:Chronic obstructive pulmonary disease(COPD)is a prevalent respiratory ailment that has risen to become the foremost cause of mortality globally,and statins are a widely used class of lipid-modifying drugs.Data from some observational studies suggest an association between statins use and COPD.Objectives:The main objective of this study was to investigate whether lipids and apolipoproteins are bidirectionally causally associated with COPD at the genetic level using a Mendelian randomization(MR)design,and to determine the potential role of circulating inflammatory proteins as mediators in this association.Methods:The publicly available Genome-Wide Association Study(GWAS)database was utilised for the purposes of the analysis.The data on high-density lipoprotein(HDL-C),low-density lipoprotein(LDL-C),triglycerides(TG),apolipoprotein A-1(ApoA1),and apolipoprotein B(ApoB)were obtained from the UK BioBank,while the COPD dataset was obtained from the FinnGen BioBank R11(number of cases:21,617,number of controls:372,627).Furthermore,data were gathered on genetic variants linked to inflammatory processes,encompassing 91 circulating inflammatory proteins(n=14,823 individuals).A two-sample MR study was conducted using these data to assess the association between HDL-C,LDL-C,TG,ApoA1,and ApoB with the risk of COPD.Furthermore,in order to investigate the potential mediating influence of inflammatory factor alterations between lipids and COPD,a two-step Mendelian randomization(MR)mediation analysis was conducted.Results:The forward MR methods identified two lipids that were found to have a causal relationship with the development of COPD.An elevated level of LDL-C and ApoB was found to be associated with a diminished risk of COPD.Furthermore,the researchers identified circulating inflammatory factors that were determined to be the causal agents in the development of COPD.Mediation analysis indicated that the inflammatory protein S100-A12 may act as a mediator between the LDL-C and COPD pathways.Conclusion:The present MR study provides genetic evidence for a causal relationship between lipids and apolipoproteins and COPD,as well as identifying the inflammatory protein S100-A12 as a potential mediator of the COPD association.The findings offer valuable insights into the mechanistic studies of statins for COPD and potential targets for disease intervention and treatment.
基金the Central Guidance for Regional Science and Technology Development Projects(YDZJSX2024B010)Research project of Shanxi Provincial Health Commission(2024067)。
文摘Objective Pneumoconiosis,a lung disease caused by irreversible fibrosis,represents a significant public health burden.This study investigates the causal relationships between gut microbiota,gene methylation,gene expression,protein levels,and pneumoconiosis using a multi-omics approach and Mendelian randomization(MR).Methods We analyzed gut microbiota data from MiBioGen and Esteban et al.to assess their potential causal effects on pneumoconiosis subtypes(asbestosis,silicosis,and inorganic pneumoconiosis)using conventional and summary-data-based MR(SMR).Gene methylation and expression data from Genotype-Tissue Expression and eQTLGen,along with protein level data from deCODE and UK Biobank Pharma Proteomics Project,were examined in relation to pneumoconiosis data from FinnGen.To validate our findings,we assessed self-measured gut flora from a pneumoconiosis cohort and performed fine mapping,drug prediction,molecular docking,and Phenome-Wide Association Studies to explore relevant phenotypes of key genes.Results Three core gut microorganisms were identified:Romboutsia(OR=0.249)as a protective factor against silicosis,Pasteurellaceae(OR=3.207)and Haemophilus parainfluenzae(OR=2.343)as risk factors for inorganic pneumoconiosis.Additionally,mapping and quantitative trait loci analyses revealed that the genes VIM,STX8,and MIF were significantly associated with pneumoconiosis risk.Conclusions This multi-omics study highlights the associations between gut microbiota and key genes(VIM,STX8,MIF)with pneumoconiosis,offering insights into potential therapeutic targets and personalized treatment strategies.
文摘Objective 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.
基金Supported by the National Natural Science Foundation of China(No.82201163)Natural Science Foundation Youth Foundation of Shaanxi Province(No.2023-JC-QN-0861)Shaanxi Province Key Research and Development Program(No.2021SF-332).
文摘AIM:To use two-sample Mendelian randomization(MR)method to study uveitis causal association with wet age-related macular degeneration(wAMD)risk from the genetic level.METHODS:Two-sample MR analysis was used to assess the causal role of uveitis on wAMD risk,using the 8 genetic variants associated strongly with uveitis as instrumental variables.Besides,eight MR methods[inverse variance weighted(IVW),weighted median,MR-Egger regression,weighted mode,simple mode,robust adjusted profile score(RAPS),contamination inverse-variance weighted method,and debiased inverse-variance weighted method]were used to get the whole causal estimate for multiple instrumental single nucleotide polymorphism(SNPs).The MR analysis was based on Europeans.RESULTS:Uveitis was related to a higher risk of wAMD[odds ratio(OR):1.08,95%confidence interval(CI)1.03–1.12;P=1.03×10^(-3)]with the IVW method.No heterogeneity and directional pleiotropy were detected.On the contrary,no significant results were detected in reverse MR analysis.CONCLUSION:Uveitis is related to an increased risk of wAMD.Due to the high blindness rate of wAMD,understanding and controlling the risk factors of AMD is of great significance for reducing its incidence and early diagnosis and treatment.
基金supported by the National Natural Science Foundation of China(No.82303169)the Key Research and Development Program of Shaanxi(No.2021ZDLSF02-06).
文摘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.
基金This study is supported by the National Natural Science Foundation of China (No. 82072127)。
文摘BACKGROUND:This study aims to explore the causal relationship of body weight,body mass index(BMI),and waist circumference (WC) with the risk of cardiac arrest (CA) using two-sample Mendelian randomization (MR).METHODS:Data were summarized using genome-wide association studies (GWAS).Twosample MR analyses were performed using the inverse variance weighting (IVW) method,the weighted median method,and the MR-Egger analysis.Heterogeneity test and sensitivity analysis were performed using Cochran’s Q test and the leave-one-out method,respectively.The Steiger test was used to detect reverse causality.Bayesian model-averaged MR was used to identify the most influential risk factors.RESULTS:A total of 13 GWAS data were collected for BMI,body weight and WC.IVW analyses showed a positive correlation of body weight,BMI,and WC with CA (all OR>1 and P<0.05),with MR-Egger and weighted median methods confirming the IVW findings.No horizontal pleiotropy or heterogeneity was observed.Sensitivity analysis indicated that no single nucleotide polymorphism(SNP) caused significant changes in overall causality.Bayesian model-averaged MR was also used to rank causality based on marginal inclusion probability (MIP),and the corresponding modelaveraged causal estimate (MACE) were confirmed,which indicated that WC (GWAS ID:ukb-b-9405)was the highest-ranked risk factor (MIP=0.119,MACE=0.011);its posterior probability was 0.057.A total of 14 sex-specific GWAS data on weight,BMI,and WC were analyzed in relationship with CA,and the MR results showed no significant effects of sex-specific factors.CONCLUSION:Body weight,BMI,and WC are causally associated with an increased risk of CA,with WC identified as the most important risk factor.
基金supported by the National Natural Science Foundation of China[No.81871823,81971583,81671652,8207090113]National Key R&D Program of China[No.2018YFC1312900]+3 种基金Natural Science Foundation of Shanghai[No.20ZR1406400]Science and Technology Commission of Shanghai Municipality[No.18JC1410403]Shanghai Municipal Science and Technology Major Project[No.2017SHZDZX01,2018SHZDZX01]Shanghai Science and Technology Committee[No.22dz1204700].
文摘Background:Ankle-foot sprains are the most common musculoskeletal injuries,which can impair balance and theoretically increase the risk of falls,but still,there is a lack of evidence supporting the direct association between ankle-foot sprains and the future risk of falls.Methods:UK Biobank cohort was utilized to measure the association between ankle-foot sprains and fall risk with covariates adjusted.Then,the two-sample Mendelian randomization(MR)analysis was applied based on the genetically predicated ankle-foot sprains from FinnGen to validate causal relationship.Finally,genetically predicated cerebellar neuroimaging features were used to explore the mediating role of maladaptive neuroplasticity between ankle-foot sprains and falls by two-step MR analyses.Results:Patients with ankle-foot sprains history exhibited a slightly increased risk of falls than the matched controls before and after adjustment for covariates(odd ratio[OR]ranged from 1.632 to 1.658).Two-sample MR analysis showed that ankle-foot sprains led to a higher risk of falls(OR=1.036)and a lower fractional anisotropy of superior cerebellar peduncle(SCP)(left,β=0.052;right,β=0.053).A trend of mediating effect was observed for the fractional anisotropy of right SCP in the causal effects of ankle-foot sprains on falls(β=0.003).Conclusion:The history of ankle-foot sprains is associated with a slightly increased risk of falls.These findings improve our understanding of the clinical consequences of ankle-foot sprains in terms of fall risk and suggest the importance of adopting more efficient strategies for managing residual functional deficits after the injuries.
基金supported by the Director General,Indian Council of Agricultural Research(ICAR),New Delhithe Director,ICAR-National Rice Research Institute,Cuttack.
文摘Consecutive stresses,such as initial submergence during germination followed by water deficit during the seedling stage,pose significant challenges to direct-seeded rice cultivation.By Linkage disequilibrium analysis,Sub1 and Dro1(Δbp:10 Mb),as well as Sub1 and TPP7(Δbp:6 Mb)were identified to exhibit long-range linkage disequilibrium(LRLD).Meta-QTL analysis further revealed that Sub1 and TPP7 co-segregated for tolerance to submergence at the germination and seedling stages.Based on this,we hypothesized that LRLD might influence plant responses to consecutive stresses.To test this hypothesis,we developed a structured recombinant inbred line population from a cross between Bhalum 2 and Nagina 22,with alleles(Sub1 and TPP7)in linkage equilibrium.Mendelian randomization analysis validated that the parental alleles,rather than the recombinant alleles of Sub1 and TPP7,significantly influenced 13 out of 41 traits under consecutive stress conditions.Additionally,16 minor additive effect QTLs were detected between the genomic regions,spanning Sub1 and TPP7 for various traits.A single allele difference between these genomic regions enhanced crown root number,root dry weight,and specific root area by 11.45%,15.69%,and 33.15%,respectively,under flooded germination conditions.Candidate gene analysis identified WAK79 and MRLK59 as regulators of stress responses during flooded germination,recovery,and subsequent water deficit conditions.These findings highlight the critical role of parental allele combinations and genomic regions between Sub1 and TPP7 in regulating the stress responses under consecutive stresses.Favourable haplotypes derived from these alleles can be utilized to improve stress resilience in direct-seeded rice.
文摘Chronic diseases are major causes of global death and disability,significantly impacting individual health and imposing economic burdens.This study aims to investigate the causal relationship between physical activity(PA)and the development of chronic diseases.Using a Mendelian randomization(MR)approach,we incorporated average PA and its subtypes(more than 450000 participants)as exposure measures and eight chronic diseases as outcome measures.Data were obtained from the European Genome-Wide Association Study(GWAS).The primary causal analysis technique employed was the inverse variance weighting(IVW)method,with MR-Egger,weighted median,weighted mode,and simple mode used to validate the results.Sensitivity analyses were performed to assess heterogeneity and pleiotropy.The IVW approach results show that vigorous physical activity(VPA)is associated with a modest reduction in the risk of major coronary heart disease(OR=0.95,95%CI:0.91–0.99,p=0.01).The causal directions of the other four MR methods are consistent with this result and validated by sensitivity analysis.No substantial associations were found between other levels of PA and chronic disease.Our findings underscore the importance of VPA in preventive cardiology and suggest its potential role in public health initiatives.Further research should explore the impact of PA on different demographic groups and the doseresponse relationship of VPA on heart health.
