A genome-wide association study identifies a susceptibility locus for biliary atresia on 2p16.1 within the gene EFEMP1

Abstract

Biliary atresia (BA) is a rare pediatric cholangiopathy characterized by fibrosclerosing obliteration of the extrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and eventual liver failure. The etiology of BA remains unknown, although environmental, inflammatory, infectious, and genetic risk factors have been proposed. We performed a genome-wide association study (GWAS) in a European-American cohort of 343 isolated BA patients and 1716 controls to identify genetic loci associated with BA. A second GWAS was performed in an independent European-American cohort of 156 patients with BA and other extrahepatic anomalies and 212 controls to confirm the identified candidate BA-associated SNPs. Meta-analysis revealed three genome-wide significant BA-associated SNPs on 2p16.1 (rs10865291, rs6761893, and rs727878; P < 5 ×10−8), located within the fifth intron of the EFEMP1 gene, which encodes a secreted extracellular protein implicated in extracellular matrix remodeling, cell proliferation, and organogenesis. RNA expression analysis showed an increase in EFEMP1 transcripts from human liver specimens isolated from patients with either BA or other cholestatic diseases when compared to normal control liver samples. Immunohistochemistry demonstrated that EFEMP1 is expressed in cholangiocytes and vascular smooth muscle cells in liver specimens from patients with BA and other cholestatic diseases, but it is absent from cholangiocytes in normal control liver samples. Efemp1 transcripts had higher expression in cholangiocytes and portal fibroblasts as compared with other cell types in normal rat liver. The identification of a novel BA-associated locus, and implication of EFEMP1 as a new BA candidate susceptibility gene, could provide new insights to understanding the mechanisms underlying this severe pediatric disorder.

TGF‐β Signaling Plays a Pivotal Role During Developmental Biliary Atresia in Sea Lamprey (Petromyzon marinus)

“…Several genome‐wide studies of single‐nucleotide polymorphisms or copy number variations and cDNA microarray studies in BA patients have associated few susceptible genes with this disease . For example, adducin 3, ADP ribosylation factor 6, ECM‐related genes, endothelial growth factor containing fibulin extracellular matrix protein 1, glypican 1, x‐prolyl aminopeptidase 1, and genes for several transcription factors are associated with both embryonic and perinatal BA.…”

Genome‐wide association studies of structural birth defects: A review and commentary

“…While this condition is relatively rare with an estimated birth prevalence of 0.7–0.9 per 10,000 births (Caton, Druschel, & McNutt, ; Yoon, Bresee, Olney, James, & Khoury, ), biliary atresia is the most common cause of extrahepatic obstructive jaundice in the newborn and the most frequent indication for liver transplantation in children (Sundaram et al, ; Yoon et al, ). Four independent GWAS of biliary atresia among relatively small cohorts of patients (35–499 patients) have identified four novel biliary atresia susceptibility loci (Table ): (a) an intergenic locus on 10q24.2 between ADD3 and XPNPEP1 (Garcia‐Barcelo et al, ); (b) a deletion in 2q37.3 that included AGXT and GPC1 (Cui et al, ); (c) ARF6 (Ningappa et al, ); and (d) EFEMP1 (Chen et al, ).…”

“…: (a) an intergenic locus on 10q24.2 between ADD3 and XPNPEP1 (Garcia-Barcelo et al, 2010); (b) a deletion in 2q37.3 that included AGXT and GPC1(Cui et al, 2013); (c) ARF6(Ningappa et al, 2015); and (d) EFEMP1(Chen et al, 2018).…”

Exome Sequencing in Individuals with Isolated Biliary Atresia

“…Although the etiology of BA is not clear, a genetic component is supported by multiple lines of evidence. These include the presence of familial cases [3][4][5] , case reports of individuals with syndromic BA with likely causal genes identified (including FOXA2 6 , CFC1 7,8 , ZEB2 9 , ZIC3 10 , HNF1B 11 and PKD1L1 12 ), animal models of BA involving the genes Sox17 13 , Foxm1 14 , Invs 15 , Onecut1 16 , and candidate susceptibility genes including ADD3 17 , GPC1 18 , EFEMP1 19 and ARF6 20 identified by genome-wide association studies (GWAS). Genes implicated in syndromic BA function in bile-duct development and the establishment of left-right symmetry.…”

“…A GWAS identified SNPs associated with BA upstream of XPNPEP1 and ADD3 in a Chinese cohort of isolated BA patients 17 , and this association has been confirmed in both a Thai 22 and an European-American cohort 23 . In a study of 499 isolated and syndromic BA patients and 1928 controls, our group identified a GWAS signal within 2p16.1 implicating common variants in the gene EFEMP1 19 . Another genome-wide association study of 63 BA patients and 1907 controls identified two SNPs downstream of the gene ARF6 associated with isolated BA 20 , although we could not replicate this finding in our study.…”