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

Mei-Rong Bai,Wei Cai,Ying Zhou,Huan-Lei Song,Wei-Bo Niu,Xun Chu,Wenjie Wu,Yan-Jiao Lu,Yi-Ming Gong,Xian-Xian Yu,Bei-Lin Gu,Zhi-Liang Wei,Wen-Wen Yu

doi:10.18632/aging.103067

Abstract

Biliary atresia (BA) is an idiopathic neonatal cholestatic disease. Recent genome-wide association study (GWAS) revealed that common variation of ADD3, GPC1, ARF6, and EFEMP1 gene was associated with BA susceptibility. We aimed to evaluate the association of these genes with BA in Chinese population. Twenty single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 340 BA patients and 1,665 controls. Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP (PAllele = 3.23×10-6). Meta-analysis of published data and current data indicated that rs17095355 was associated with BA susceptibility in Asians and Caucasians. Three associated SNPs were expression quantitative trait loci (eQTL) for ADD3. Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1. Haplotype harboring these two SNPs almost reached the study-wide significance (P = 0.0035). No association for ARF6 and EFEMP1 was found with BA risk in the current population. Our study validated associations of ADD3 and GPC1 SNPs with BA risk in Chinese population and provided evidence of epistatic contributions of genetic factors to BA susceptibility.

Highlights

Biliary atresia (BA) is a devastating inflammatory and fibro-obliterative disease of the infant biliary tree involving extra- and intrahepatic bile ducts which invariably leads, if left untreated, to cholestasis and hepatic fibrosis even progresses to liver cirrhosis and eventually liver failure [1]
The genotypes of the remaining 18 single nucleotide polymorphism (SNP) were conformed to Hardy-Weinsberg equilibrium (HWE) (P > 0.05) and the minor allele frequencies (MAFs) were all above 0.01
Our results validated that three ADD3 variants, and two GPC1 variants were associated with BA susceptibility in Chinese population

Summary

Introduction

Biliary atresia (BA) is a devastating inflammatory and fibro-obliterative disease of the infant biliary tree involving extra- and intrahepatic bile ducts which invariably leads, if left untreated, to cholestasis and hepatic fibrosis even progresses to liver cirrhosis and eventually liver failure [1]. The most effective treatment of choice is palliative surgery (Kasai operation) and the majority of patients would still need liver transplantation later in life due to the progressive intrahepatic bile ducts injury [2]. It is likely to be a multifactorial disease, in that environmental and genetic interaction underlies its pathogenesis. It was found that the disease could be inherited in a dominant or recessive www.aging-us.com pattern but more probably was a polygenic condition with incomplete penetrance, genetic heterogeneity and variable clinical manifestations [3, 8]. Recent genome-wide association studies (GWASs) revealed that variants in adducing-3 (ADD3), glypican-1 (GPC1), adenosine diphosphate-ribosylation factor-6 (ARF6) and epidermal growth factor-containing fibulinlike extracellular matrix protein 1 (EFEMP1) were associated with BA susceptibility [9, 10, 12, 16]

Objectives

Methods

Results

Conclusion