The intragenic epistatic association of ADD3 with biliary atresia in Southern Han Chinese population

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.

Irrelevance of USF2 rs916145 polymorphism with the risk of biliary atresia susceptibility in Southern Chinese children

“…Through a previous GWAS on Han Chinese, Cheng et al [25] discovered the correlation of the 10q24.2 region encompassing ADD3 and XPNPEP1 genes, which was confirmed in Chinese and Thai populations. Our earlier study also revealed the intragenic epistatic association of ADD3 with BA in Southern Han Chinese population [26].…”

Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility

“…We incorporated the published data before 2015, the newly published data and our current data to perform a further meta-analysis. In Asian population, rs17095355 showed consistent significant association with BA [11,18,19,21]. Rs17095355 also showed significant association in European descent, but rs7099604 showed more significant association [20].…”

“…These foundings indicated that ADD3 was the BA susceptibility gene at 10q24.2. The association between rs17095355 of ADD3 and BA was investigated repeatedly in multiple studies from different population [11,[18][19][20][21], and a meta-analysis comprising six case-control studies before 2015 has been conducted [26]. We incorporated the published data before 2015, the newly published data and our current data to perform a further meta-analysis.…”

“…Literature searches and selection yielded 7 involved studies, which comprised 8 case-control studies [9,11,[16][17][18][19]21]. The study of Garcia-Barcelo MM, et al included a GWAS stage and a replication stage in two independent samples [9], which were considered as two case-control studies in our meta-analysis (Table 7).…”

“…A previous GWAS in Chinese population firstly identified a susceptibility locus for BA on 10q24.2 with rs17095355 as the lead single nucleotide polymorphism (SNP), which is located in the intergenic region between the X-prolyl aminopeptidase 1 (XPNPEP1) and ADD3 genes [9]. The association was then validated in Thai, Chinese and European population [11,[17][18][19][20][21]. Further study in model organism revealed that both xpnpep1 and add3a were expressed in the liver of developing zebrafish, only knockdown of add3a produced intrahepatic defects and decreased biliary function by activating Hedgehog signaling [22].…”