Causal associations between gastroesophageal reflux disease and essential hypertension: A bidirectional Mendelian randomization study

BACKGROUND Clinical studies have reported that patients with gastroesophageal reflux disease(GERD)have a higher prevalence of hypertension.AIM To performed a bidirectional Mendelian randomization(MR)analysis to investi-gate the causal link between GERD and essential hypertension.METHODS Eligible single nucleotide polymorphisms(SNPs)were selected,and weighted median,inverse variance weighted(IVW)as well as MR egger(MR-Egger)re-gression were used to examine the potential causal association between GERD and hypertension.The MR-Pleiotropy RESidual Sum and Outlier analysis was used to detect and attempt to reduce horizontal pleiotropy by removing outliers SNPs.The MR-Egger intercept test,Cochran’s Q test and“leave-one-out”sen-sitivity analysis were performed to evaluate the horizontal pleiotropy,heterogen-eities,and stability of single instrumental variable.RESULTS IVW analysis exhibited an increased risk of hypertension(OR=1.46,95%CI:1.33-1.59,P=2.14E-16)in GERD patients.And the same result was obtained in replication practice(OR=1.002,95%CI:1.0008-1.003,P=0.000498).Meanwhile,the IVW analysis showed an increased risk of systolic blood pressure(β=0.78,95%CI:0.11-1.44,P=0.021)and hypertensive heart disease(OR=1.68,95%CI:1.36-2.08,P=0.0000016)in GERD patients.Moreover,we found an decreased risk of Barrett's esophagus(OR=0.91,95%CI:0.83-0.99,P=0.043)in essential hypertension patients.CONCLUSION We found that GERD would increase the risk of essential hypertension,which provided a novel prevent and therapeutic perspectives of essential hypertension.

Blood cell counts and nonalcoholic fatty liver disease: Evidence from Mendelian randomization analysis

BACKGROUND Previous research has highlighted correlations between blood cell counts and chronic liver disease.Nonetheless,the causal relationships remain unknown.AIM To evaluate the causal effect of blood cell traits on liver enzymes and nonalcoholic fatty liver disease(NAFLD)risk.METHODS Independent genetic variants strongly associated with blood cell traits were extracted from a genome-wide association study(GWAS)conducted by the Blood Cell Consortium.Summary-level data for liver enzymes were obtained from the United Kingdom Biobank.NAFLD data were obtained from a GWAS meta-analysis(8434 cases and 770180 controls,discovery dataset)and the Fingen GWAS(2275 cases and 372727 controls,replication dataset).This analysis was conducted using the inverse-variance weighted method,followed by various sensitivity analyses.RESULTS One SD increase in the genetically predicted haemoglobin concentration(HGB)was associated with aβof 0.0078(95%CI:0.0059-0.0096),0.0108(95%CI:0.0080-0.0136),0.0361(95%CI:0.0156-0.0567),and 0.0083(95%CI:00046-0.0121)for alkaline phosphatase(ALP),alanine aminotransferase(ALT),aspartate aminotransferase,and gammaglutamyl transferase,respectively.Genetically predicted haematocrit was associated with ALP(β=0.0078,95%CI:0.0052-0.0104)and ALT(β=0.0057,95%CI:0.0039-0.0075).Genetically determined HGB and the reticulocyte fraction of red blood cells increased the risk of NAFLD[odds ratio(OR)=1.199,95%CI:1.087-1.322]and(OR=1.157,95%CI:1.071-1.250).The results of the sensitivity analyses remained significant.CONCLUSION Novel causal blood cell traits related to liver enzymes and NAFLD development were revealed through Mendelian randomization analysis,which may facilitate the diagnosis and prevention of NAFLD.

Mendelian Randomization Study of Causal Relationship between Inflammatory Factors and Vascular Dementia and Chinese Herbal Medicines Screening for Prevention and Treatment

Objective: This study aims to examine the causal relationship between inflammatory factors and the probability of developing vascular dementia (VD) using Mendelian Randomization (MR) and Chinese herbal medicine prediction method, and to screen potential Chinese herbal medicines for the prevention and treatment of VD. Methods: Single nucleotide polymorphisms (SNPs) that exhibit a strong association with vascular dementia (VD) were identified as instrumental variables from the summary statistics of genome-wide association studies (GWAS). The primary analytical method employed was inverse variance weighting (IVW), while auxiliary analyses included the MR-Egger method, weighted median method, simple model, and weighted model. A two-way Mendelian randomization analysis was conducted to assess the causal relationship between inflammatory factors and the risk of VD, thereby identifying the key inflammatory factors involved. The MR-Egger intercept test and Cochran’s Q test were employed to assess the horizontal polymorphism and heterogeneity of instrumental variables. A sensitivity analysis was conducted by excluding one method at a time. Ultimately, based on key inflammatory factors, predictions for the prevention and treatment using traditional Chinese medicine were made, along with the screening of homologous herbal remedies. Results: Based on the results of the forward MR, the probability of developing VD was elevated when the inflammatory factors CXCL10 and CXCL5 were expressed at higher levels, whereas the probability of developing VD decreased as the expression levels of IL-13 and IL-20RA increased. These findings were supported by the assessment of pleiotropy, heterogeneity, and sensitivity. The results of the reverse MR analysis showed that there was no causal relationship between VD, as an exposure dataset, and these four inflammatory factors. According to the key inflammatory factors, 37 Chinese herbal medicines such as Siraitia grosvenorii were selected. Their characteristics including four natures, five flavors, channel tropism and treatment efficiency were cold, warm, neutral, pungent, sweet, bitter, lung meridian, spleen meridian, liver meridian, kidney meridian and clearing heat. Among them, Siraitia grosvenorii, Poria with hostwood, Perilla frutescens, and Radix Platycodi were all medicine and food homologous Chinese herbal medicines. Conclusions: The increase of CXCL10 and CXCL5 expression levels can increase the risk of VD, and the increase of IL-13 and IL-20 RA expression levels can reduce the risk of VD. Siraitia grosvenorii and other Chinese herbal medicines might be potential sources of therapeutic drugs for the treatment of VD. Medicine and food homologous Chinese herbal medicines, such as Siraitia grosvenorii, Poria with hostwood, Perilla frutescens, and Radix Platycodi, may help the elderly population with corresponding Traditional Chinese Medicine (TCM) constitutions to prevent VD.

Lack of a causal relationship between tea intake and sleep disorders: a two-sample Mendelian randomization study

Background:The relationship between tea intake(TI)and sleep disorders(SDs)has been a topic of interest for some time,but there remains a lack of data showing a causal relationship.We aimed to use a two-sample Mendelian randomization study to determine whether there is a causal link between TI and SDs.Methods:We collected data regarding TI,with a focus on green tea intake(GTI),herbal tea intake(HTI),and rooibos tea intake(RTI);and data regarding SDs and insomnia from genome-wide association studies.We analyzed these data using an inverse variance-weighted two-sample Mendelian randomization study,by means of the TwoSampleMR package in R4.2.3 software.Results:We found no genetic causal relationships of TI,GTI,HTI,or RTI with insomnia.The odds ratios(ORs)for these relationships were as follows:TI:OR=0.61,95%confidence interval(CI):0.29–1.28;GTI:OR=1.04,95%CI:0.95–1.14;HTI:OR=0.98,95%CI:0.82–1.17;and RTI:OR=1.04,95%CI:0.99–1.09.In addition,there were no genetic causal relationships of TI,GTI,HTI,or RTI with SDs.The OR values for these relationships were as follows:TI:OR=0.6,95%CI:0.34–1.06;GTI:OR=1,95%CI:0.93–1.07;HTI:OR=0.89,95%CI:0.66–1.2;and RTI:OR=1.02,95%CI:0.98–1.06.Conclusion:We found no causal relationships of TI with SDs or insomnia,irrespective of the type of tea consumed.However,additional Mendelian randomization studies are required to further explore the relationships of the timing and quantity of tea consumption with SDs and insomnia.

Genetic causal relationship between tea intake and cerebral aneurysm: a two-sample Mendelian Randomization Study

Background:Prior research has established a strong link between cerebral aneurysm(CA)occurrence and inflammation.Tea intake(TI)has been found to have anti-inflammatory properties through multiple mechanisms,potentially lowering CA incidence.This study aims to employ Mendelian Randomization(MR)methodology to explore the genetic causality between TI and CA.Methods:We collected Genome-wide association study(GWAS)data for CA,TI,Green tea intake(GTI),Herbal tea intake(HTI),and Rooibos tea intake(RTI).The MR analysis employed the TwoSampleMR package and utilized the inverse variance-weighted(IVW)method.Results:The findings suggest no genetic causal relationship between TI and CA(IVW:OR=1.10,95%CI:0.59–2.05,P=0.772).Similarly,there is no genetic causal association between GTI and CA(IVW:OR=1.07,95%CI:0.91–1.26,P=0.388),HTI and CA(IVW:OR=1.00,95%CI:0.89–1.13,P=0.943),or RTI and CA(IVW:OR=1.02,95%CI:0.96–1.09,P=0.472).Conclusion:There is no genetic causal relationship between TI and CA,and the different types of tea do not change this result.Further MR analysis is needed to investigate whether there is a potential genetic causal association between the quantity of TI and CA.

No genetic causal relationship between tea intake and diabetes:a two-sample Mendelian randomization study

Background:Previous studies have suggested a potential risk-reducing effect of tea intake(TI)on diabetes.However,the specific impacts of TI on different types of diabetes and its underlying mechanisms remain unclear.To further explore this topic,we conducted a comprehensive investigation to assess the causal relationship between TI and various types of diabetes,as well as its effects on blood glucose(Glu)and glycated hemoglobin(HbA1).Methods:We collected genome-wide association study data for TI,diabetes,type 1 diabetes(T1D),type 2 diabetes(T2D),Glu,HbA1,green tea intake,herbal tea intake,and Rooibos tea intake from the IEU database.Subsequently,we performed two-sample Mendelian randomization analysis using the TwoSampleMR package.Results:Our analysis revealed no evidence of a causal relationship between TI and the incidence of diabetes,T1D,blood Glu,HbA1c,or T2D.Similarly,no genetic causal relationship was found between green tea intake and diabetes,T1D,T2D,Glu,or HbA1c.The same applied to herbal tea intake and Rooibos tea intake,as there was no genetic causal link with diabetes,T1D,T2D,Glu,or HbA1c.Conclusion:Based on our findings,there is no indication of a causal relationship between TI and the incidence of all types of diabetes,regardless of the specific tea type.However,to comprehensively understand the potential effects of TI on diabetes incidence,including the quantity and timing of intake,further evaluation through additional Mendelian randomization studies is warranted.

Causal relationship between inflammatory bowel disease and gingivitis or periodontal disease:A two-sample Mendelian randomized analysis

Background:Observational studies have shown that inflammatory bowel disease(IBD),such as ulcerative colitis(UC)and Crohn disease(CD),is associated with gingivitis and periodontal disease(GP).This study aims to investigate whether there is a causal relationship between IBD and GP.Methods:This study assessed the causal relationship between IBD and GP through a two-sample Mendelian randomization(MR)study.The required data were obtained through the IEU OpenGWAS project.Instrumental variable screening and the MR and sensitivity analyses were performed using the“TwoSampleMR”R package.Results:IBD,UC,and CD may have a causal effect on GP(IBD,inverse variance weighting[IVW]OR=1.05,95%CI=1.00–1.10,P=0.03;UC,IVWOR=1.05,95%CI=1.00–1.11,P=0.03;CD,weighted median OR=1.06,95%CI=1.00–1.13,P=0.04;simple mode OR=1.15,95%CI=1.02–1.31,P=0.03).Scatterplots,forest plots,and funnel plots showed a significant relationship between IBD and GP and confirmed the robustness of the model.In sensitivity testing,no horizontal pleiotropy or heterogeneity was found in this study.Conclusions:This study found a possible causal relationship between IBD(UC and CD)and GP,which deserves to be considered in clinical practice.

Causal Relationship Between Gut Microbiota and Liver Cirrhosis:16S rRNA Sequencing and Mendelian Randomization Analyses

Background and Aims:Accumulating evidence highlights the association between the gut microbiota and liver cirrhosis.However,the role of the gut microbiota in liver cirrhosis remains unclear.Methods:We first assessed the differences in the composition of the bacterial community between CCl4-induced liver cirrhosis and control mice using 16S rRNA sequencing.We then performed a two-sample Mendelian randomization(MR)analysis to reveal the underlying causal relationship between the gut microbiota and liver cirrhosis.Causal relationships were analyzed using primary inverse variance weighting(IVW)and other supplemental MR methods.Furthermore,fecal samples from liver cirrhosis patients and healthy controls were collected to validate the results of the MR analysis.Results:Analysis of 16S rRNA sequencing indicated significant differences in gut microbiota composition between the cirrhosis and control groups.IVW analyses suggested that Alphaproteobacteria,Bacillales,NB1n,Rhodospirillales,Dorea,Lachnospiraceae,and Rhodospirillaceae were positively correlated with the risk of liver cirrhosis,whereas Butyricicoccus,Hungatella,Marvinbryantia,and Lactobacillaceae displayed the opposite effects.However,the weighted median and MR-PRESSO estimates further showed that only Butyricicoccus and Marvinbryantia presented stable negative associations with liver cirrhosis.No significant heterogeneity or horizontal pleiotropy was observed in the sensitivity analysis.Furthermore,the result of 16S rRNA sequencing also showed that healthy controls had a higher relative abundance of Butyricicoccus and Marvinbryantia than liver cirrhosis patients.Conclusions:Our study provides new causal evidence for the link between gut microbiota and liver cirrhosis,which may contribute to the discovery of novel strategies to prevent liver cirrhosis.

免疫球蛋白G N-糖基化与代谢特征之间的双向因果关联--一项孟德尔随机化研究

既往研究已发现免疫球蛋白G(immunoglobulin G,IgG)N-糖基化与代谢特征之间存在关联,但它们之间是否存在因果关联尚有待研究。本研究使用孟德尔随机化(Mendelian randomization,MR)研究方法整合全基因组关联研究(genome-wide association studies,GWAS)和数量性状基因座(quantitative trait loci,QTL)数据探究IgG N-糖基化与代谢特征之间的双向因果关联。在正向MR分析中,通过整合IgG N-糖基-QTL遗传变异与GWAS数据和代谢特征进行分析,分别发现59个包括影响体质指数(body mass index,BMI)的9个IgG N-糖基(glycan peaks,GP)(GP1和GP6等)和影响空腹血糖(fasting plasma glucose,FPG)的7个IgG N-糖基(GP1和GP5等)以及15个[包括影响BMI的5个IgG N-糖基(GP2和GP11等)和影响FPG的4个IgG N-糖基(GP1和GP10等)]由遗传决定的IgG N-糖基在单样本和两样本MR研究中与代谢特征存在因果关联(全部P<0.05)。相应地,对整合代谢特征-QTL-遗传变异与GWAS结果和IgG N-糖基进行MR分析的结果显示,在单样本和两样本MR研究中,分别发现72个包括影响GP1的1个因果代谢特征[高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)]和影响GP2的5个因果代谢特征[FPG、收缩压(systolic blood pressure,SBP)等]和4个[包括影响GP3的1个因果代谢特征(HDL-C)和影响GP9的1个代谢特征(HDL-C)]由遗传决定的代谢特征与IgG N-糖基之间存在因果关联(全部P<0.05)。值得注意的是,在单样本和两样本的MR分析中均发现了遗传决定的高水平的GP11与BMI水平增高存在因果关联[固定效应模型-Beta(SE):0.106(0.034)和0.010(0.005)]和高水平的HDL-C与GP9水平降低存在因果关联[-0.071(0.022)和-0.306(0.151)],且这一结果在单样本和两样本的meta汇总分析中得到了进一步验证[固定效应模型-Beta(95%置信区间)分别为:0.0109(0.0012,0.0207)和-0.0759(-0.1186,-0.0332)]。综上所述,本研究全面的双向MR分析提供了IgG N-糖基化与代谢特征之间双向因果关联的证据,在一定程度上揭示了IgG N-糖基化与代谢特征之间的生物学机制。

Scrutinizing the causal relationship between schizophrenia and vitamin supplementation:a Mendelian randomization study

Objective: Observational studies have reported malnutrition and vitamin deficiency in patients with schizophrenia (SZ), which can lead to serious metabolic syndromes and decrease anti-psychiatric drug outcomes. Whereas, vitamin intake along with psychiatric medication can enhance the medication outcomes. However, it is still unknown if SZ induces vitamin deficiency. Herein, we conduct the Mendelian randomization analysis to explore the causal relationship between schizophrenia and vitamins supplementation.Methods: We retrieved the genome-wide summary statistical data for schizophrenia from recent SZ GWAS data (43,175 cases and 65,166 controls) and vitamins supplementation GWAS data from Neale’s GWAS datasets (more than 337,000 samples from the European population) and performed a two-sample Mendelian randomization analysis to determine the causal association of SZ with vitamin supplementation, in addition, we conduct the sensitivity analysis to obtain reliable results and remove confounding bias.Results: SZ have causal relationships with vitamins A, B, C, D, and E (SZ/vitamin A: β = 0.002, se= 0.001, 95% confidence interval (CI): 0.001 to 0.004,P= 1.41E-05, heterogeneityP= 0.4486;SZ/vitamin B: β= 0.004, se= 0.001, 95% CI: 0.002-0.005,P= 7.0E-05, heterogeneityP= 0.2217;SZ/vitamin C: β= 0.004, se= 0.001, 95% CI: 0.002-0.007,P= 0.001, heterogeneityP= 0.1349;SZ/vitamin D: β= 0.003, se= 0.001, 95% CI: 0.002-0.005,P= 0.001, heterogeneityP= 0.433;SZ/vitamin E: β= 0.003, se= 0.001, 95% CI: 0.002-0.005,P= 5.0E-05, heterogeneityP= 0.1382).Conclusion: Our findings suggest that vitamin levels and supplementation should be carefully controlled in patients with SZ, which in turn may enhance the therapeutic effects of antipsychotic drug treatments.