Causal effects of genetic birth weight and gestational age on adult esophageal diseases: Mendelian randomization study

Abstract

BACKGROUND

Few studies have investigated the association between gestational age, birth weight, and esophageal cancer risk; however, causality remains debated. We aimed to establish causal links between genetic gestational age and birth weight traits and gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE), and esophageal adenocarcinoma (EA). Additionally, we explored if known risk factors mediate these links.

AIM

To analyze of the relationship between gestational age, birth weight and GERD, BE, and EA.

METHODS

Genetic data on gestational age and birth weight (n = 84689 and 143677) from the Early Growth Genetics Consortium and outcomes for GERD (n = 467253), BE (n = 56429), and EA (n = 21271) from genome-wide association study served as instrumental variables. Mendelian randomization (MR) and mediation analyses were conducted using MR-Egger, weighted median, and inverse variance weighted methods. Robustness was ensured through heterogeneity, pleiotropy tests, and sensitivity analyses.

RESULTS

Birth weight was negatively correlated with GERD and BE risk [odds ratio (OR) = 0.78; 95% confidence interval (CI): 0.69-0.8] and (OR = 0.75; 95%CI: 0.60-0.9), respectively, with no significant association with EA. No causal link was found between gestational age and outcomes. Birth weight was positively correlated with five risk factors: Educational attainment (OR = 1.15; 95%CI: 1.01-1.31), body mass index (OR = 1.06; 95%CI: 1.02-1.1), height (OR = 1.12; 95%CI: 1.06-1.19), weight (OR = 1.13; 95%CI: 1.10-1.1), and alcoholic drinks per week (OR = 1.03; 95%CI: 1.00-1.06). Mediation analysis showed educational attainment and height mediated the birth weight-BE link by 13.99% and 5.46%.

CONCLUSION

Our study supports the protective role of genetically predicted birth weight against GERD, BE, and EA, independent of gestational age and partially mediated by educational attainment and height.

Keywords: Birth weight; Barrett’s esophagus; Esophageal adenocarcinoma; Gestational age; Gastroesophageal reflux disease; Preterm birth

Core Tip: Our study demonstrates that low birth weight, rather than prematurity, is associated with increased risk of gastroesophageal reflux disease (GERD) and Barrett’s esophagus (BE) in adulthood, with no association found for esophageal adenocarcinoma. Furthermore, this relationship is influenced by the mediating effects of educational attainment and height. Attention to educational attainment and height during the growth process of low-birth-weight individuals is necessary to reduce the incidence of GERD and BE.