Circulating microRNA is a biomarker of biliary atresia

Abstract

Objective: The lack of reliable noninvasive diagnostic biomarkers of biliary atresia (BA) results in delayed diagnosis and worsened patient outcome. Circulating microRNAs (miRNAs) are a new class of noninvasive biomarkers with encouraging diagnostic utility.

Methods: We examined the ability of serum miRNAs to distinguish BA from other forms of neonatal hyperbilirubinemia. BA-specific serum miRNAs were identified using a microfluidic array platform and validated in a larger, independent sample set.

Results: The miR-200b/429 cluster was significantly increased in the sera of patients with BA relative to infants with non-BA cholestatic disorders.

Conclusions: Circulating levels of the miR-200b/429 cluster are elevated in infants with BA and have promising diagnostic clinical performance.

Trial registration: ClinicalTrials.gov NCT00061828.

FIGURE 1

Low-density array (LDA) analysis of serum miRNA in human biliary atresia (BA). A, Dendrogram of unsupervised hierarchical analysis using 104 miRNAs detected in all samples by LDA. B, Scatterplot of relative serum miRNA levels of 9 candidate miRNAs as determined by LDA and individual qRT-PCR. Control sample means are scaled to 1. Open circles, cholestatic control samples; filled circles, BA samples; ρ, Spearman rank correlation coefficient.

FIGURE 2

Validation of circulating miRNAs in biliary atresia (BA). A,B Box-whisker plots of serum levels of miR-200b/429 cluster members (A) and miR-200c/141 and miR-122 (B) in an independent set of cholestatic controls and BA cases (n=24 each). Box, 25% to 75%; whisker, upper and lower adjacent values; line, median; points, outside values. Cholestatic control sample means are scaled to 1. *p < 0.05 vs. cholestatic control. C, Receiver-operating characteristic curve of miR-200a in cholestatic control and BA sera (n=24 each). AUC = area under the curve. D, Box-whisker plot of relative miRNA expression in liver and extrahepatic bile duct (EHBD) tissue of 8-week-old Balb/c mice (n=6). Box, 25% to 75%; whisker, upper and lower adjacent values; line, median; points, outside values. *p < 0.05 vs. liver.