Association of the RET Intronic Variant rs2435357 on Hirschsprung's Disease Susceptibility: A Systematic Review and Meta-Analysis

Background: Hirschsprung disease (HSCR) is a congenital life-threatening intestinal disorder characterized by the absence of nerves in the myenteric and submucosal plexuses in the distal bowel. There are several studies on the association of rs2435357 polymorphism in the proto-oncogene RET gene and HSCR susceptibility. However, some of the results remain controversial. Therefore, we conducted this updated meta-analysis to estimate the association of this polymorphism and HSCR risk. Methods: We searched PubMed, Scopus, Web of Science and Google Scholar according to PRISMA guidelines to assess the association of RET rs2435357 with HSCR up to Jan 2024. We included case-control/cohort studies to perform meta-analysis conducted using genotype models. Odd ratios (ORs) with 95%CI were utilized to determine the susceptibility to HSCR. Q-test and I2 were used to evaluate heterogeneity, and Egger's/ Begg's tests were used to assess publication bias. Results: Overall, 89 eligible studies meeting the inclusion criteria were retrieved with 2690 cases and 5408 controls from online databases. Finally, 17 studies were used for meta-analysis. RET rs2435357 showed a statistically significant association with HSCR under allelic model (OR = 4.50, 95%CI: 3.78-5.36, P<0.05), additive model (OR=2.02, 95%CI: 1.54-2.63, P<0.05), recessive model (OR=4.39, 95%CI: 3.33-5.78, P<0.05) and dominant model (OR=8.66, 95%CI: 6.96-10.76, P<0.05). Conclusion: The polymorphism rs2435357 in RET gene provides substantial susceptibility in all inheritance models and to HSCR. However, more research is needed to clarify its specific role in prognosis and the interaction with other genetic and environmental factors affecting HSCR.