Analysis Of The Correlation Between GERD And Essential Hypertension:an Observational And Mendelian Randomization Study

BackgroundHypertension is one of the most common chronic cardiovascular diseases worldwide.In 2015,the overall prevalence of hypertension in adults worldwide was approximately 30%45%.As the aging population,changes in people’s lifestyles,and quality of life evolves,the number of people with hypertension is expected to approach 1.5 billion worldwide by 2025.Long-term hypertension damages target organs such as the heart,brain,blood vessels,kidneys,and retina,which is the greatest single risk factor for the morbidity and mortality burden worldwide.Hypertension’s close association with cardiovascular disease and its overall prevalence worldwide make prevention and control of hypertension an important global public health strategy to reduce premature mortality.Hypertension is classified into essential hypertension(EH)and secondary hypertension based on whether a clear cause can be found,with essential hypertension accounting for 90%-95%of cases.So far,the treatment for essential hypertension is mainly long-term blood pressure control,which cannot completely cure the disease;therefore,it is clinically important to study the pathogenic mechanisms.Gastroesophageal Reflux Disease(GERD)is one of the most widespread chronic gastrointestinal disorders with the main clinical manifestations of acid reflux and heartburn.In recent years,the potential role of GERD in the development of essential hypertension has attracted attention.Growing numbers of observational studies have shown that GERD may increase the risk of essential hypertension.However,to date,conclusions from epidemiological studies regarding the role of GERD in essential hypertension have not been entirely consistent.The discordance of these findings may be attributed to the small sample size of these studies,different methods used to measure GERD(e.g.,gastroscopy or questionnaires),inadequate adjustment for confounders,population heterogeneity,and short follow-up periods,among others.Moreover,all these pieces of evidence were derived from traditional observational studies which are prone to selection bias and reverse causality,i.e.,the correlation should not simply be equated with causation.Therefore,whether GERD is a cause of primary hypertension or a downstream effect deserves further exploration.In clinical research,the "gold standard" for establishing association and causality between medically relevant exposures and outcomes is Randomized Controlled Trial(RCT).However,RCTs are expensive,prolonged,and not always ethical.When RCTs are not feasible or ethical,observational studies are an effective way to study the causal relationship between exposure and health-related outcomes due to the large sample size,high feasibility,and closer proximity to the real world.Nevertheless,the exposure-outcome link described from observational studies does not directly reflect causality and may produce spurious results owing to confounding factors,reverse causality,or selection bias.Since large-scale and longterm RCTs may not be practicable and ethical,in addition to residual confounders and reverse causality are unavoidable in observational studies,Mendelian Randomization(MR)has emerged as an alternative method.MR employs single nucleotide polymorphisms(SNPs)as instrumental variables(IVs)to "randomize",participants to infer the causal relationship between exposure and outcome.Because alleles are randomly assigned at gamete formation and conception,independent of environmental factors,and genotypes are fixed before the onset of disease,causal estimates of MR are minimally influenced by reverse causality or confounding factors.ObjectiveFirst,we performed an observational analysis using the National Readmission Database(NRD),a massive database,to elucidate the association between GERD and essential hypertension;then,we performed a bidirectional two-sample Mendelian randomization study using a Genome-Wide Association Study(GWAS)summary statistic with a large sample size to determine the causal nature and direction of the association between these two diseases.Methods1.Observational studyWe selected 14,422,183 participants in the 2018 NRD and collected information on their age,gender,alcohol consumption status,smoking status,and the prevalence of primary hypertension,obesity,and hyperlipidemia.We divided the study population into GERD and non-GERD groups and compared the general characteristics of participants in both groups using univariate logistic regression analysis followed by multivariate logistic regression analysis to explore whether GERD was associated with the risk of developing hypertension.2.Mendelian randomization studyWe downloaded data from the publicly available large GWAS of GERD and essential hypertension for this study.First,a forward MR study was conducted with GERD as the exposure and essential hypertension as the outcome.The instrumental variables were rigorously screened and the effects of SNPs for exposure and outcome were reconciled.Next,the basic analysis approach,namely inverse-variance weighted(IVW),was used to assess the positive causality.In addition,four other MR methods were used namely mendelian randomization-egger regression(MR-Egger),weighted median(WME),simple mode,and weighted mode to test the reliability and stability of the results.Then,we performed a series of sensitivity analyses to address the multi-effectiveness in causal estimation.Finally,a reverse two-sample MR study was performed to validate the causal direction between these two diseases,considering essential hypertension as the exposure and GERD as the outcome.Results1.Observational study(1)The prevalence of essential hypertension was higher in the GERD group compared with the non-GERD group,and the difference was statistically significant(P<0.001).(2)Univariate binary logistic regression analysis showed that GERD was positively associated with the risk of developing essential hypertension in the total population(OR=1.43;P<0.001),and the results remained significant after performing gender subgroup analysis.(3)Multivariate logistic regression analysis showed that GERD was positively associated with the risk of essential hypertension in the total population after adjusting for confounders such as age,sex,alcohol consumption status,smoking status,obesity,and hyperlipidemia(OR=1.26;P<0.001).The results remained significant after performing a gender subgroup analysis.The above findings suggest that GERD is an independent risk factor for essential hypertension.2.Mendelian randomization study(1)The forward two-sample MR study enrolled 65 instrumental variable SNPs after a rigorous screening process.The primary analysis method,the IVW method,showed that genetically predicted GERD can increase the risk of developing essential hypertension(OR=1.52;95%CI=1.39-1.67;P=3.51 × 10-18<0.05).The remaining four MR analysis methods all yielded more consistent conclusions.(2)The reverse two-sample MR study ultimately integrated 33 instrumental variable SNPs.The main analysis of the IVW method showed no significant causal relationship between genetically predicted essential hypertension and the risk of GERD(OR=1.03;95%CI=0.97-1.09;P=0.33>0.05).The remaining four MR analysis methods all yielded relatively uniform conclusions.The above findings suggest that genetically predicted GERD can increase the risk of developing essential hypertension without a reverse causal association,Conclusion1.GERD is one of the independent risk factors for essential hypertension.2.Genetically predicted GERD can increase the risk of developing essential hypertension,while conversely,no causal association was found between essential hypertension and GERD.