Corey, Kathleen E, Pitts, Rebecca, Lai, Michelle, Loureiro, Joe, Masia, Ricard, Osganian, Stephanie A, Gustafson, Jenna L, Hutter, Matthew M, Gee, Denise W, Meireles, Ozanan R, Witkowski, Elan R, Richards, Shola, Jacob, Jaison, Finkel, Nancy, Ngo, Debby, Wang, Thomas J, Gerszten, Robert E, Ukomadu, Chinweike and Jennings, Lori (2021) ADAMTSL2 protein and a soluble biomarker signature identify significant and advanced fibrosis in adults with NAFLD. Journal of hepatology. ISSN 1600-0641

Abstract

Abstract
Aims and background: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and inform treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD.

Methods: We used aptamer-based proteomics to measure 4783 proteins in two cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modelling-logistic regression assessed the candidate proteins to classify fibrosis.

Results: From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n=62) and B (n=98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n=71) and D (n=84). The protein A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) accurately distinguished NAFL/NASH with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4 with an AUROC of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3) with an AUROC of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROC 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROC 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and Fibrosis-4 score.

Conclusion: The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis with superior performance to standard of care fibrosis scores.

Lay summary: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in blood which may identify fibrosis without the need for a liver biopsy.

Item Type:	Article
Keywords:	proteomics ADAMTSL2 non-alcoholic fatty liver disease non-alcoholic steatohepatitis fibrosis biomarker
Date Deposited:	02 Nov 2021 00:45
Last Modified:	02 Nov 2021 00:45
URI:	https://oak.novartis.com/id/eprint/45312