Abstract
Biliary atresia (BA) is a multifactorial pathogenic disease with possible genetic components. As a member of membrane skeletal proteins in the liver and bile ducts, a haplotype composed by five single nucleotide polymorphisms (SNPs) on adducin 3 (ADD3) has been identified as associated with BA. However, limited study was designed to further elaborate the mutual relationship amongst those replicated SNPs to disease. We selected three susceptibility SNPs in ADD3 and conducted a replication study using 510 BA cases and 1473 controls to evaluate the individual function of the SNPs and further stratified the potential roles with disease and its subclinical features. Two SNPs in ADD3 were replicated as associated with BA (1.60E-04 ≤ P≤1.70E-04, 1.33 ≤ odds ratio (OR) ≤ 1.58 for rs17095355, 2.10E-04 ≤ P≤5.30E-04, 1.26 ≤ OR ≤ 1.57 for rs2501577). Though we failed to replicate the individual association of rs10509906 to disease, the intragenic epistatic effect between rs10509906 and rs2501577 was suggested as exhibiting susceptibility to BA, further cross-validated by multifactor dimensionality reduction (MDR) (P=0.068, OR = 1.37), which may explain extra hidden heritability of ADD3 to BA. Furthermore, through subclinical stratification, we also observed the association of risk to disease mainly came from the female patients.
Highlights
Biliary atresia (BA) is a multifactorial pathogenic disease exclusively seen in infants
Three previously identified single nucleotide polymorphism (SNP) in adducin 3 (ADD3) were selected for replication using 510 patients and 1473 controls from South Chinese population
X-prolyl aminopeptidase P (XPNPEP1) is found in liver epithelial cells which is important in bile acid excretion
Summary
Biliary atresia (BA) is a multifactorial pathogenic disease exclusively seen in infants It is characterized by exacerbating jaundice and acholic stools caused by progressive intra- and extrahepatic bile duct fibrosis. Cheng et al [8] revealed five single nucleotide polymorphisms (SNPs) in the intergenic region between X-prolyl aminopeptidase P (XPNPEP1) and adducin 3 (ADD3) as associated with BA, including rs17095355, rs10509906, rs2501577, rs6584970, and rs708605. They found the risk haplotype may modulate the ADD3 expression level which varies in different status of the disease. Whether the haplotype association acquired according to the linkage equilibrium or potential intragenic effect was not clear
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