Socioeconomic traits and the risk of Barrett's esophagus and gastroesophageal reflux disease: A Mendelian randomization study

Abstract

Background: Previous observational studies have shown that the prevalence of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) is associated with socioeconomic status. However, due to the methodological limitations of traditional observational studies, it is challenging to definitively establish causality.

Aim: To explore the causal relationship between the prevalence of these conditions and socioeconomic status using Mendelian randomization (MR).

Methods: We initially screened single nucleotide polymorphisms (SNPs) to serve as proxies for eight socioeconomic status phenotypes for univariate MR analysis. The inverse variance weighted (IVW) method was used as the primary analytical method to estimate the causal relationship between the eight socioeconomic status phenotypes and the risk of GERD and BE. We then collected combinations of SNPs as composite proxies for the eight socioeconomic phenotypes to perform multivariate MR (MVMR) analyses based on the IVW MVMR model. Furthermore, a two-step MR mediation analysis was used to examine the potential mediation of the associations by body mass index, major depressive disorder (MDD), smoking, alcohol consumption, and sleep duration.

Results: The study identified three socioeconomic statuses that had a significant impact on GERD. These included household income [odds ratio (OR): 0.46; 95% confidence interval (95%CI): 0.31-0.70], education attainment (OR: 0.23; 95%CI: 0.18-0.29), and the Townsend Deprivation Index at recruitment (OR: 1.57; 95%CI: 1.04-2.37). These factors were found to independently and predominantly influence the genetic causal effect of GERD. Furthermore, the mediating effect of educational attainment on GERD was found to be mediated by MDD (proportion mediated: 10.83%). Similarly, the effect of educational attainment on BE was mediated by MDD (proportion mediated: 10.58%) and the number of cigarettes smoked per day (proportion mediated: 3.50%). Additionally, the mediating effect of household income on GERD was observed to be mediated by sleep duration (proportion mediated: 9.75%).

Conclusion: This MR study shed light on the link between socioeconomic status and GERD or BE, providing insights for the prevention of esophageal cancer and precancerous lesions.

Keywords: Barrett’s esophagus; Gastroesophageal reflux disease; Multivariate Mendelian randomization; Socioeconomic status; Two-step Mendelian randomization.

Figure 1

Overview of the Mendelian randomization rationale, design, and procedures. GSCAN: Genome-wide association study and Sequencing Consortium of Alcohol and Nicotine Use; GWAS: Genome-wide association study; IVW: Inverse variance weighted; LD: Linkage disequilibrium; MDD: Major depressive disorder; MR: Mendelian randomization; MRC-IEU: The Medical Research Council Integrative Epidemiology Unit; PGC: Psychiatric Genomics Consortium; SNP: Single nucleotide polymorphism; UVMR: Univariate Mendelian randomization.

Figure 2

Forest plots of univariate Mendelian randomization analysis. A: Univariate Mendelian randomization analysis for genetically causal associations of socioeconomic traits with gastroesophageal reflux disease and Barrett’s esophagus risk; B: Forrest plot for causal associations of socioeconomic traits with gastroesophageal reflux diseases and Barrett’s esophagus risk based on inverse variance weighted multivariate Mendelian randomization; C: Mendelian randomization estimates of socioeconomic traits on modifiable risk factors; D: Mendelian randomization estimates of modifiable risk factors on Barrett’s esophagus and gastroesophageal reflux disease. 95%CI: 95% confidence interval; IVW: Inverse variance weighted; SNPs: Single nucleotide polymorphisms.

Figure 3

Mediation effects by multiple mediators on Barrett’s esophagus and gastroesophageal reflux disease. A: Mediation analysis between education attainment and gastroesophageal reflux disease (GERD). The proportion of the effect of educational attainment on GERD was mediated by major depressive disorder (MDD; proportion mediated: 10.83%); B: Mediation analysis between education attainment and Barrett’s esophagus (BE). The effect of educational attainment on BE was mediated by MDD (proportion mediated: 10.58%) and cigarettes smoked per day (proportion mediated: 3.50%); C: Mediation analysis between household income and GERD. Household income had a 9.75% mediating effect on GERD through sleep duration. βa: The effect of socioeconomic status on the risk of modifiable risk factors; βb: The effect of modifiable risk factors on the risk of Barrett’s esophagus and gastroesophageal reflux disease after adjusting socioeconomic status traits. MDD: Major depressive disorder; GRED: Gastroesophageal reflux disease.