Circulating microRNAs as noninvasive diagnostic biomarkers of liver disease in children with cystic fibrosis
Date
2015
Authors
Cook, N.L.
Pereira, T.N.
Lewindon, P.J.
Shepherd, R.W.
Ramm, G.A.
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Journal article
Citation
Journal of Pediatric Gastroenterology and Nutrition, 2015; 60(2):247-254
Statement of Responsibility
Naomi L. Cook, Tamara N. Pereira, Peter J. Lewindon, Ross W. Shepherd,
and Grant A. Ramm
Conference Name
Abstract
Objectives: Cystic fibrosis liver disease (CFLD), resulting from progressive hepatobiliary fibrosis, causes significant morbidity and mortality in up to 20% of children with cystic fibrosis (CF). Both pathogenesis and early detection of CFLD are elusive. Current diagnostic procedures to detect early CFLD and stage fibrosis severity are inadequate. Recent studies highlight a role for microRNAs (miRNAs) in the pathogenesis of many diseases and have suggested that serum miRNAs could be used as diagnostic biomarkers. Methods: We profiled circulating serum miRNA levels in patients with CFLD (n = 52), patients with CF without liver disease (CFnoLD, n = 30), and non-CF pediatric controls (n = 20). Extracted RNA was subjected to polymerase chain reaction (PCR) array of 84 miRNAs detectable in human serum. Seven candidate miRNAs identified were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), normalizing data to geNorm-determined stable reference genes, miR-19b and miR-93. Results: miR-122 was significantly elevated in patients with CFLD versus patients with CFnoLD and controls (P < 0.0001). miR-25 (P = 0.0011) and miR-21 (P = 0.0133) were elevated in patients with CFnoLD versus patients with CFLD and controls. CFLD was discriminated by both miR-122 (area under the curve [AUC] 0.71, P = 0.002) and miR-25 (AUC 0.65, P = 0.026). Logistic regression combining 3 miRNAs (-122, -25, -21) was greatly predictive of detecting CFLD (AUC 0.78, P < 0.0001). A combination of 6 miRNAs (-122, -21, -25, -210, -148a, -19a) distinguished F0 from F3–F4 fibrosis (AUC 0.73, P = 0.04), and miR-210 combined with miR-22 distinguished F0 fibrosis from any fibrosis, that is, F1–F4 (AUC 0.72, P = 0.02). Conclusions: These data provide the first evidence of changes to circulating miRNA levels in CF, suggesting that serum-based miRNA analysis may complement and extend current CFLD screening strategies with potential to predict early hepatic fibrosis.
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© 2015 by ESPGHAN and NASPGHAN