Association of ADD3 Gene Polymorphisms with Biliary Atresia: Systematic Review and Meta-Analysis

Abstract

Background: Biliary atresia (BA) is a serious disease of the pediatric hepatobiliary system that progresses rapidly. The protein encoded by the ADD3 gene plays a key role in cytoskeletal organization, cell migration, and intercellular connectivity and may be involved in the pathogenesis of BA. Objectives: This study aims to evaluate whether ADD3 variants contribute to the pathogenesis and clinical severity of BA, rather than to its diagnostic use. Methods: A comprehensive search was conducted in PubMed, Embase, the Cochrane Library, CNKI, and the Wanfang database, and studies on the correlation between ADD3 gene polymorphism and BA were collected from database inception until October 31, 2024. After rigorous screening, nine case-control studies were eventually included, involving a total of 2,004 BA children and 15,464 controls. The data were extracted according to the pre-established criteria, including the basic characteristics of the study objects, gene polymorphism loci, genotype distribution, and other information. A meta-analysis was performed using RevMan 5.4 software to calculate the pooled risk ratio (RR) and its 95% confidence interval (CI) to assess the possible strength of association between genetic polymorphisms and BA. All statistical processes were reviewed by qualified biostatisticians. Results: Meta-analysis showed that the rs17095355 locus of the ADD3 gene was found in the allele model (A vs a comparison). Among the 2,004 BA cases, the T allele frequency of rs17095355 was 30.1% compared with 42.4% in 15,464 controls (P < 0.01). Meta-analysis of the allele model showed RR = 0.714 (95%CI: 0.659 - 0.773) for the C versus T comparison. However, the moderate overlap in allele frequencies between cases and controls suggests that this polymorphism contributes to disease susceptibility rather than serving as a diagnostic marker. For rs10509906, a significant association was found (P < 0.01, RR = 1.291, 95%CI: 1.071 - 1.557). Clinical outcome data were limited; three studies reported γ-GT levels but lacked standardized reporting to assess genotype-phenotype correlations. In genotype models (AA vs Aa vs aa comparison), the GG genotype was associated with an increased risk of BA (P < 0.01), RR = 0.298 (95% CI: 0.262 - 0.339). The rs10509906 locus of the ADD3 gene had a significantly positive correlation with the increased risk of BA (P < 0.01), RR = 1.291 (95%CI: 1.071 - 1.557). Conclusions: The rs17095355 polymorphism of ADD3 shows a significant association with BA susceptibility, with a lower frequency of the T allele observed in BA cases. However, due to the overlap in allele distributions between cases and controls, this polymorphism is not suitable as a diagnostic marker. Additionally, the rs10509906 locus of the ADD3 gene demonstrates a positive significant correlation with an increased risk of BA, suggesting that multiple variants within the ADD3 gene may contribute to disease susceptibility. Given the limited data on clinical outcomes, further longitudinal studies are required to determine the impact of these genetic variants on the phenotype, severity, and prognosis of BA.