Gene expression signature for biliary atresia and a role for interleukin-8 in pathogenesis of experimental disease.
Biliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental BA. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice.


CONCLUSIONS
The hepatic expression of IL8 and LAMC2 has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA.
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Kazuhiko
K
Bessho
Reena
R
Mourya
Pranavkumar
P
Shivakumar
Stephanie
S
Walters
John C
JC
Magee
Marepalli
M
Rao
Anil G
AG
Jegga
Jorge A
JA
Bezerra
D000818:Animals; D000831:Animals, Newborn; D001656:Biliary Atresia / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002779:Cholestasis / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D003937:Diagnosis, Differential; D004195:Disease Models, Animal; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016209:Interleukin-8 / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D007797:Laminin / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011446:Prospective Studies; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000276:immunology; D012680:Sensitivity and Specificity
D015415:Biomarkers; C508606:CXCL8 protein, human; D016209:Interleukin-8; C400567:LAMC2 protein, human; C498522:Lamc2 protein, mouse; D007797:Laminin; D023063:Receptors, Interleukin-8B