This is a proposal to identify genetic susceptibility factors for biliary atresia (BA). BA is a devastating pediatric disease associated with medical complications related to a rapidly developing biliary cirrhosis that accounts for 50% of all pediatric liver transplantations. The etiology of BA is unknown, although it is proposed to be multi-factorial, with potential infectious, environmental, inflammatory and genetic causes. In the proposed study, we will test the hypothesis that there is an underlying genetic susceptibility to BA. We will identify susceptibility genes for BA using a large, well-characterized cohort of patients that has been identified through an NIDDK sponsored research consortium. We will conduct a genome-wide association study, testing for association of genetic variation (both single nucleotide polymorphisms and copy number variants) to identify genes or genomic regions associated with BA disease susceptibility. We will perform exome sequencing of a family with two affected and one unaffected sibling, and three additional unrelated BA patients. We will follow up on regions and genes identified, via next generation sequencing to identify causal variants. This proposal will build upon the resources of a large multi-center consortium and our own cutting-edge genomic and bioinformatic facilities. We anticipate that our studies will contribute new knowledge about the biologic pathogenesis of BA and will lead to the development of rationale therapeutics and diagnostics.

Public Health Relevance

Biliary Atresia (BA) is an idiopathic pediatric liver disease lacking effective therapies and accounting for half of all pediatric liver transplantations. We propose a study to identify genetic factors contributing to susceptibility to BA that builds upon the resources of a large multi-center consortium and our own cutting-edge genomic and bioinformatic facilities. We anticipate that our studies will contribute new knowledge about the biologic pathogenesis of BA and will lead to the development of rationale therapeutics and diagnostics.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK090045-04
Application #
8731200
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Karp, Robert W
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tsai, Ellen A; Grochowski, Christopher M; Loomes, Kathleen M et al. (2014) Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia. Hum Genet 133:235-43
Cui, Shuang; Leyva-Vega, Melissa; Tsai, Ellen A et al. (2013) Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene. Gastroenterology 144:1107-1115.e3