Collagen formation assessed by PRO-C3 is an heritable trait and is associated with liver fibrosis assessed by MRE

Abstract

Background

PRO-C3 (N-terminal pro-peptide of type III collagen) is a biomarker of liver fibrosis in nonalcoholic-fatty-liver-disease (NAFLD). This study examines the association between PRO-C3 concentration and liver fibrosis assessed by magnetic resonance (MR) elastography (MRE)-measured stiffness (MRE-stiffness) and the heritability of PRO-C3 concentration in a cohort of twins and families with and without NAFLD. We performed a cross-sectional analysis of a well-characterized prospective cohort of 306 participants including 44 probands with NAFLD-cirrhosis and their 72 first-degree-relatives, 24 probands with NAFLD without advanced fibrosis and their 24 first-degree-relatives and 72 non-NAFLD controls and their 72 first-degree-relatives. Liver steatosis was assessed by MR imaging proton density fat fraction (MRI-PDFF) and liver fibrosis by MRE-stiffness. Serum PRO-C3 was assessed by competitive ELISA. We assessed the familial correlation of PRO-C3 concentration, shared gene effects between PRO-C3 concentration and liver steatosis and fibrosis, and association between PRO-C3 concentration and genetic variants in PNPLA3, TM6SF2, MBOAT and CGKR.

In multivariable-adjusted models including age, sex, body mass index and ethnicity, serum PRO-C3 correlated strongly with liver fibrosis (r ²=0.50, p<0.001), and demonstrated robust heritability [ h ² :0.36, 95%confidence-interval (CI):0.07–0.59, p=0.016]. PRO-C3 concentration and steatosis had a strong genetic correlation [ r _G :0.62,95%CI:0.236–1.001, p=0.002] whereas PRO-C3 concentration and fibrosis had a strong environmental correlation [ r _E :0.55,95%CI:0.317–0.717, p<0.001]. PRO-C3 concentrations were higher in carriers of TM6SF2rs58542926-T-allele versus non-carriers: 15.7 (±10.5) versus 10.8 (±5.7) ng/L, (p=0.047).

Conclusion

Serum PRO-C3 correlates with MRE-assessed fibrosis, is heritable, shares genetic correlation with liver steatosis and shares environmental correlation with liver fibrosis. PRO-C3 concentration appears to be linked to both fibrosis and steatosis and increased in carriers of TM6SF2rs58542926 risk allele.