Genomic alterations in biliary atresia suggest region of potential disease susceptibility in 2q37.3

Abstract

Biliary atresia (BA) is a progressive, idiopathic obliteration of the extrahepatic biliary system occurring exclusively in the neonatal period. It is the most common disease leading to liver transplantation in children. The etiology of BA is unknown, although infectious, immune and genetic causes have been suggested. While the recurrence of BA in families is not common, there are more than 30 multiplex families reported and an underlying genetic susceptibility has been hypothesized. We screened a cohort of 35 BA patients for genomic alterations that might confer susceptibility to BA. DNA was genotyped on the Illumina Quad550 platform, which analyzes over 550,000 single nucleotide polymorphisms (SNPs) for genomic deletions and duplications. Areas of increased and decreased copy number were compared to those found in control populations. In order to identify regions that could serve as susceptibility factors for BA, we searched for regions that were found in BA patients, but not in controls. We identified two unrelated BA patients with overlapping heterozygous deletions of 2q37.3. Patient 1 had a 1.76 Mb (280 SNP), heterozygous deletion containing thirty genes. Patient 2 had a 5.87 Mb (1,346 SNP) heterozygous deletion containing fifty-five genes. The overlapping 1.76 Mb deletion on chromosome 2q37.3 from 240,936,900 to 242,692,820 constitutes the critical region and the genes within this region could be candidates for susceptibility to BA.

Evidence From Human and Zebrafish That GPC1 Is a Biliary Atresia Susceptibility Gene

“…Previously, we investigated potentially causative large genomic alterations in 35 patients compared with more than 2000 controls and uncovered overlapping deletions in 2q37.3 in the patients with BA. 19 In the current study, we extended this work to examine association with CNVs in 61 patients and 5088 healthy controls. This analysis uncovered a CNV region on chromosome 2 overlapping the previously identified region as well as additional regions (Supplementary Table 2).…”

“…DNA was prepared from peripheral blood using standard extraction procedures. 19 The patients were genotyped on the Illumina Infinium II HumanHap 550 BeadChip SNP array (San Diego, CA) through the Center for Applied Genomics at CHOP. The Center for Applied Genomics also supplied genotypes of 5088 healthy controls run on the same platform.…”

“…Early findings in these studies were reported previously, in which 35 patients with BA were compared with more than 2000 controls to identify a potential region of interest at 2q37.3. 19 Here we report expansion of these studies that narrow the region to include only one gene, GPC1 . GPC1 encodes glypican 1, one of 6 members of the glypican family of heparan sulfate proteoglycans that are distinct from other proteoglycans in that they attach to the cell membrane by a glycosyl-phosphatidylinositol linkage.…”

Participation of natural killer cells in the pathogenesis of bile duct lesions in biliary atresia

“…Recently, many genetic studies, moreover, have recently reported. For example, genomic study including genome-wide association study identified a susceptibility locus for BA on 10q24.2 and 2q37.3 18 19. Moreover, DNA hypermethylation at the CD11a locus in CD4+ cells, polymorphisms of vascular endothelial growth factor gene, and two microRNAs (miR-29a/29b1) may contribute significantly to BA susceptibility, but polymorphisms of IL-4, IL-18, IFN-γ genes were unlikely 20–25.…”

Management of Biliary Atresia: A Review

“…3,4 The disease is most common in East Asia with a frequency of 1/5,000. 5 Reasons for this high incidence have not been described yet. Some analyses of time and space distribution of BA cases suggested seasonal variation and clustering of cases 6 , but these observations were not confirmed in larger studies.…”