Common genetic variants regulating ADD3 gene expression alter biliary atresia risk

Area of Science:

• Genetics
• Pediatric Gastroenterology
• Epidemiology

Background:

• Biliary atresia (BA) is a severe neonatal cholestatic disease with unknown pathogenic mechanisms.
• Previous genome-wide association studies (GWAS) identified the 10q24.2 region, including ADD3 and XPNPEP1 genes, associated with BA in Han Chinese populations.
• Replication studies confirmed this association in Chinese and Thai populations.

Purpose of the Study:

• To comprehensively characterize the genetic architecture of the 10q24.2 region in relation to BA.
• To elucidate the functional link between genetic variants in this region and BA pathogenesis.
• To investigate the epidemiological and evolutionary implications of these genetic findings.

Main Methods:

• Genotyping of 107 single nucleotide polymorphisms (SNPs) in the 10q24.2 region in 339 Han Chinese BA patients and 401 controls.
• Follow-up association studies and Sanger sequencing to analyze risk signals and rare variants.
• Bioinformatics and in vivo genotype-expression studies to assess the impact of SNPs on ADD3 gene expression.

Main Results:

• A significant association was confirmed for a GWAS SNP (rs17095355) with BA (p=6.06×10⁻¹⁰).
• A common risk haplotype comprising 5 tagging-SNPs was identified, significantly associated with BA risk (p=5.32×10⁻¹¹; OR=2.38).
• No deleterious rare variants were found within the risk haplotype. Associated SNPs correlated with ADD3 gene expression (p=0.0030), and positive selection was observed at the ADD3 locus.

Conclusions:

• Common genetic variants in the 10q24.2 region contribute to biliary atresia risk.
• These variants likely exert their effect by regulating ADD3 expression in the liver.
• The findings suggest a role for these common variants in BA epidemiology and shaping general population diversity.