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Cell Mol Gastroenterol Hepatol. 2016 May 26;2(5):663-675.e2. doi: 10.1016/j.jcmgh.2016.05.013. eCollection 2016 Sep.

THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome.

Author information

1
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
2
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Department of Neurology, University of Michigan, Ann Arbor, Michigan.
4
Department of Neurology, University of Michigan, Ann Arbor, Michigan; Department of Physiology, University of Michigan, Ann Arbor, Michigan; VA Ann Arbor Healthcare System, Ann Arbor, Michigan.
5
Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan.
6
Department of Physiology, Department of Small Animal Clinical Sciences, Colleges of Natural Science, Osteopathic Medicine, and Veterinary Medicine, Michigan State University, East Lansing, Michigan; Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
7
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
8
Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada.
9
Division of Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Molecular Medicine, University La Sapienza, Rome, Italy.

Abstract

BACKGROUND & AIMS:

Alagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder.

METHODS:

We performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus.

RESULTS:

We identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased microvessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1-NOTCH2 interactions.

CONCLUSIONS:

Based on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1-NOTCH2 signaling in patients harboring a JAG1 mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille syndrome.

KEYWORDS:

ALGS, Alagille syndrome; BSA, bovine serum albumin; CK19, cytokeratin 19; ChiLDReN, Childhood Liver Disease Research Network; Cholestasis; GFP, green fluorescent protein; GWAS, genome-wide association study; Gene Modifier; Genome-Wide Association Study; JAG1; NOTCH2; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism; THBS2, thrombospondin 2; cDNA, complementary DNA; ddPCR, droplet digital polymerase chain reaction

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