Mendelian randomization analysis of causal relationship between cheese intake and diabetic retinopathy

AIM:To assess whether there is a possible causal link between the intake of cheese and the risk of diabetic retinopathy(DR)utilizing a two-sample Mendelian randomization(MR)analysis.METHODS:The research data were obtained from summary statistics of genome-wide association studies(GWAS).Genetic loci closely related to cheese intake were extracted as instrumental variables(IVs),and DR was the outcome variable.The data were extracted from individuals of European ethnicity.The data of cheese intake consisted of 451486 samples with 9851867 single nucleotide polymorphisms(SNPs),while the DR data consisted of 206234 samples with 16380446 SNPs.Sixty-one genetic loci closely related to cheese intake were selected as IVs.MR analysis was performed by inverse-variance weighted(IVW)method and MR-Egger regression respectively.The causal relationship between cheese intake and DR was evaluated using odds ratios(ORs)and 95%confidence intervals(CIs).Egger-intercept test was used to test horizontal pleiotropy and sensitivity analysis was performed by leave-one-out test.RESULTS:The P value of the IVW method was less than 0.05,indicating a significant negative correlation between cheese intake and DR.MR-Egger regression showed that the intercept was 0.01 with a standard error of 0.022,and a P-value of 0.634,indicating no evidence of horizontal pleiotropy affecting the IVs related to the exposure factors.Besides,heterogeneity tests confirmed the absence of heterogeneity,and the“leave-one-out”sensitivity analysis demonstrated that the results were stable.CONCLUSION:Cheese intake is causally negatively correlated with the occurrence of DR,and cheese intake could reduce the risk of DR.

Diabetes mellitus and prostate cancer risk:A mendelian randomization analysis

BACKGROUND Some studies have directed towards an association between diabetes mellitus(DM)and prostate cancer(PCa);however,this specific relationship remains inconclusive.In recent years,Mendelian randomization(MR)has become a widely used analytical method for inferring epidemiological causes.AIM To investigated the potential relationship between DM and PCa using MR.METHODS We downloaded relevant data on"diabetes"and"PCa"from the IEU OpenGWAS project database,performed three different methods to conduct MR,and carried out sensitivity analysis for verification.RESULTS The results indicated that DM was an independent risk factor for PCa.The odds ratio(OR)values obtained using the inverse variance weighted method in this study were as follows:OR=1.018(95%confidence interval:1.004-1.032),P=0.014.CONCLUSION We found that DM could increase the incidence rate of PCa.

Modifiable factors mediating the effects of educational attainment on gestational diabetes mellitus: A two-step Mendelian randomization study

BACKGROUND Although there is currently a wealth of evidence to indicate that maternal educational attainment is associated with gestational diabetes mellitus(GDM),the specific modifiable risk factors that mediate the causal relationship between these two variables have yet to be identified.AIM To identify the specific modifiable risk factors that mediate the causal relationship between the level of maternal education and GDM.METHODS Mendelian randomization(MR)was conducted using data from genome-wide association studies of European populations.We initially performed a two-sample MR analysis using data on genetic variants associated with the duration of education as instruments,and subsequently adopted a two-step MR approach using metabolic and lifestyle factors as mediators to examine the mechanisms underlying the relationship between the level of maternal education and risk of developing GDM.In addition,we calculated the proportions of total causal effects mediated by identified metabolic and lifestyle factors.RESULTS A genetically predicted higher educational attainment was found to be associated with a lower risk of developing GDM(OR:0.71,95%CI:0.60-0.84).Among the metabolic factors assessed,four emerged as potential mediators of the education-GDM association,which,ranked by mediated proportions,were as follows:Waist-to-hip-ratio(31.56%,95%CI:12.38%-50.70%),body mass index(19.20%,95%CI:12.03%-26.42%),high-density lipoprotein cholesterol(12.81%,95%CI:8.65%-17.05%),and apolipoprotein A-1(7.70%,95%CI:4.32%-11.05%).These findings proved to be robust to sensitivity analyses.CONCLUSION Our findings indicate a causal relationship between lower levels of maternal education and the risk of developing GDM can be partly explained by adverse metabolic profiles.

Causal relationship between feelings and cognitive decline:An univariable and multivariable Mendelian randomization study

BACKGROUND While the impact of depression on cognition is well-documented,the relationship between feelings and cognition has received limited attention.AIM To explore the potential association between feelings and cognition with a twosample Mendelian randomization(MR)analysis.METHODS Our analysis utilized genome-wide association data on various feelings(fed-up feelings,n=453071;worrier/anxious feelings,n=450765;guilty feelings,n=45-0704;nervous feelings,n=450700;sensitivity/hurt feelings,n=449419;miserableness,n=454982;loneliness/isolation,n=455364;happiness,n=152348)in the European population and their impact on cognitive functions(intelligence,n=269867).Conducting a univariable MR(UVMR)analysis to assess the relationship between feelings and cognition.In this analysis,we applied the inverse variance weighting(IVW),weighted median,and MR Egger methods.Additionally,we performed sensitivity analysis(leave-one-out analysis),assessed heterogeneity(using MR-PRESSO and Cochran’s Q test),and conducted multiple validity test(employing MR-Egger regression).Subsequently,a multivariable MR(MVMR)analysis was employed to examine the impact of feelings on cognition.IVW served as the primary method in the multivariable analysis,complemented by median-based and MR-Egger methods.RESULTS In this study,UVMR indicated that sensitivity/hurt feelings may have a negative causal effect on cognition(OR=0.63,95%CI:0.43-0.92,P=0.017).After adjustment of other feelings using MVMR,a direct adverse causal effect on cognition was observed(OR_(MVMR)=0.39,95%CI:0.17-0.90,P_(MVMR)=0.027).While a potential increased risk of cognitive decline was observed for fed-up feelings in the UVMR analysis(ORUVMR=0.64,95%CI:0.42-0.97,PUVMR=0.037),this effect disappeared after adjusting for other feelings(OR_(MVMR)=1.42,95%CI:0.43-4.74,P_(MVMR)=0.569).These findings were generally consistent across MV-IVW,median-based,and MR-Egger analyses.MR-Egger regression revealed pleiotropy in the impact of worrier/anxious feelings on cognition,presenting a challenge in identifying the effect.Notably,this study did not demonstrate any significant impact of guilty feelings,nervous feelings,miserableness,or loneliness/isolation on cognition.Due to a limited number of instrumental variables for happiness,this study was unable to analyze the relationship between happiness and cognition.CONCLUSION This MR study finds that sensitivity/hurt feelings are associated with cognitive decline,while the link between worrier/anxious feelings and cognition remains inconclusive.Insufficient evidence supports direct associations between happiness,guilty feelings,nervous feelings,miserableness,loneliness/isolation,and cognition.

Hypertension and NAFLD risk:Insights from the NHANES 2017-2018 and Mendelian randomization analyses

Background:Hypertension and non-alcoholic fatty liver disease(NAFLD)share several pathophysiologic risk factors,and the exact relationship between the two remains unclear.Our study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey(NHANES)2017-2018 and Mendelian randomization(MR)analyses.Methods:Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017-2018.Subsequently,a two-sample MR study was performed using the genome-wide association study(GWAS)summary statistics to identify the causal association between hypertension,systolic blood pressure(SBP),diastolic blood pressure(DBP),and NAFLD.The primary inverse variance weighted(IVW)and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD.Sensitivity analyses were adopted to confirm the robustness of the results.Results:A total of 3144 participants were enrolled for our observational study in NHANES.Weighted multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk(odds ratio[OR]=1.677;95%confidence interval[CI],1.159-2.423).SBP≥130 mmHg and DBP≥80 mmHg were also significantly positively correlated with NAFLD.Moreover,hypertension was independently connected with liver steatosis(β=7.836[95%CI,2.334-13.338]).The results of MR analysis also supported a causal association between hypertension(OR=7.203[95%CI,2.297-22.587])and NAFLD.Similar results were observed for the causal exploration between SBP(OR=1.024[95%CI,1.003-1.046]),DBP(OR=1.047[95%CI,1.005-1.090]),and NAFLD.The sensitive analysis further confirmed the robustness and reliability of these findings(all P>0.05).Conclusion:Hypertension was associated with an increased risk of NAFLD.

Assessment of causal association between thyroid function and lipid metabolism:a Mendelian randomization study

Background:Thyroid dysfunction is associated with cardiovascular diseases.However,the role of thyroid function in lipid metabolism remains partly unknown.The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization(MR).Methods:The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial.A two-sample MR was performed to assess the causal association,using summary statistics from the Atrial Fibrillation Genetics Consortium(n=537,409)and the Global Lipids Genetics Consortium(n=188,577).The clinical measures of thyroid function include thyrotropin(TSH),free triiodothyronine(FT3)and free thyroxine(FT4)levels,FT3:FT4 ratio and concentration of thyroid peroxidase antibodies(TPOAb).The serum lipid metabolism traits include total cholesterol(TC)and triglycerides,high-density lipoprotein,and low-density lipoprotein(LDL)levels.The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism.Results:The results demonstrated that increased TSH levels were significantly associated with higher TC(β=0.052,P=0.002)and LDL(β=0.041,P=0.018)levels.In addition,the FT3:FT4 ratio was significantly associated with TC(β=0.240,P=0.033)and LDL(β=0.025,P=0.027)levels.However,no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids.Conclusion:Taken together,the results of the present study suggest an association between thyroid function and serum lipid metabolism,highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.

Genetic evidence suggesting the predicted causality between osteoarthritis and cardiovascular diseases

Background:Epidemiological studies have shown a close association between osteoarthritis(OA)and cardiovascular disease(CVD),but reliable evidence needs to be provided.We performed a two-sample Mendelian randomization(MR)study to examine the potential causal effect between OA and CVD.Methods:Exposures were self-reported OA,knee osteoarthritis(KOA),and hip osteoarthritis(HOA).The outcomes were 12 CVDs,including heart failure,atrial fibrillation,coronary artery disease,pulmonary embolism,stroke and its subtypes,myocardial infarction,coronary heart disease,and primary hypertension.All outcomes were obtained from published genomewide association studies.The inverse-variance weighted method was used as the primary MR analysis.Heterogeneity tests and sensitivity analyses were conducted to validate the accuracy of the MR results.Results:Self-reported OA increased the incidence of small vessel stroke(odds ratio[OR]=1.25,95%confidence interval[CI]:1.02–1.52,p=0.03)and primary hypertension(1.01[1.00–1.02],p<0.01).HOA increased the incidence of stroke(1.06[1.01–1.11],p=0.02)and two subtypes(cardioembolic stroke:1.12[1.02–1.23],p=0.02;ischemic stroke:1.06[1.01–1.11],p=0.03).Patients with KOA had an increased risk of heart failure(1.10[1.04–1.16],p<0.01),atrial fibrillation(1.08[1.02–1.13],p<0.01),small vessel stroke(1.21[1.06–1.39],p=0.01),and primary hypertension(1.01[1.01–1.02],p<0.01).Conclusions:Patients with OA have an increased risk of several CVDs.The causality of this relationship may have clinical implications for improving the quality of prevention and treatment.