Common Vitamin D Receptor (NR 1I1) gene polymorphisms and 25-OH vitamin D serum levels influence fibrosis progression and hepatic MMP-9 expression in chronic hepatitis C patients

Aims: The vitamin D receptor (VDR) pathway mediates antiinflammatory and antifibrotic effects in hepatic stellate cells. In chronic HCV pts, 25-OH-vitamin D levels are associated with stage of fibrosis and inflammation. We examined if VDR gene polymorphisms (SNP) and low serum vitamin D lead to altered hepatic gene expression and rapid fibrosis progression in HCV pts. Methods: 251 HCV pts received VDR genotyping (Cdx2 rs11568820, bat haplotype: Bsm rs1544410, Apa rs 7975232, Taq rs 731236). Exclusion criteria: HBV/HIV coinfection, alcohol >40g/d, morbid obesity. Hepatic mRNA expression of MMP-9 was quantified in pts with early fibrosis (F0-F2). Associations of VDR SNPs with ALT&GGT, Metavir F-stage, fibrosis progression rate and gene expression were calculated. 25-OH vitamin D serum was quantified in pts. with early fibrosis (F0–2). Results: ALT and GGT are correlated to Apa CC (p=0.034) and the bAt haplotype (p=0.021). 28.3% of Apa CC pts were cirrhotic with a significant association for CC vs. CA vs. AA (p=0.025) and for CC vs. CA/AA (p=0.009, OR 2.67). The CCA (bAt) haplotype was significantly associated with cirrhosis (OR 1.84; p=0.022) too. 21.1% of HCV pts with the bAt haplotype were cirrhotic. Similar was found for fibrosis progression rate (<1.01 vs. >1.01 U/year) in Apa CC (OR 2.32; p=0.042) and the CCA (bAt) haplotype (OR 2.02; p=0.007). Hepatic MMP-9 mRNA was significantly elevated for Apa CC (p=0.038) and in trend for the CCA (bAt) haplotype (p=0.058). We saw a significant association of vitamin D levels with fibrosis stage (p=0.005) and fibrosis progression rate (p=0.013). Conclusions: Specific VDR gene SNP, the bAt haplotype and low serum vitamin D are associated with cirrhosis and fibrosis progression rate in chronic HCV pts. ALT/GGT and MMP-9 expression are increased accordingly reflecting liver injury/inflammation. For the first time a pathomechanistic link between VDR signalling and fibrosis progression in chronic HCV pts is shown.

Fibrosis - Hepatitis C - NR 1I1 - Polymorphisms - VDR - Vitamin D