NIV Congres

Background Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, resulting in fibrotic strictures frequently necessitating orthotopic liver transplantation (OLT), often accompanied by ulcerative colitis (UC) Matrix metalloproteinases (MMPs) play a role in many fibrotic diseases due to their involvement in connective tissue remodeling related to cancer, inflammatory diseases and complications after OLT. We previously found the MMP-2 or -9 genotype not to be indicative for PSC in 314 OLT patients.

Aim of the present study was to assess MMP-2 and MMP-9 gene polymorphisms within a group of PSC patients in relation to disease severity as evaluated by death or need for OLT.

Methods For this study, 132 PSC patients were included from two liver transplantation centers. Follow-up was from initial onset of PSC until OLT, death or end of follow-up. From these patients genomic DNA was extracted routinely from peripheral blood and/or tissue samples. MMP-2 (-1306 C/T) and MMP-9 (-1562 C/T) gene promoter polymorphisms were analyzed using high-resolution DNA melting analysis (HRMA) or by PCR followed by restriction length polymorphisms (RFLP) respectively. Demographical and clinicopathological variables such as OLT, time of OLT, age, gender, type of IBD and survival were analyzed.

Results Of the PSC patients 88 (66.7%) were male. Sixty (45.5%) PSC patients underwent OLT with a mean follow-up from PSC onset to OLT of 7.2 years (range 0.4 – 21 years). Mean age at OLT was 46 years (range 18.3 – 67.7 years). Twenty-years cumulative incidence of death or OLT in the CT/TT group was 92.7% compared to 53.0% in the wild-type group (CC) (p=0.02) and reached 93.2% when MMP-2 CT/TT genotype was accompanied by ulcerative colitis (UC) compared to 51.2% with UC and wild-type MMP-2 (p<0.01). Age at onset of PSC (aHR=1.03; 95% CI 1.01-1.05) and MMP-2 CT/TT genotype were independent risk factors for OLT or death (aHR=1.97; 95% CI 1.20 - 3.23), both p<0.01). In contrast, no significant association was found between MMP-9 genotype and the risk of OLT in PSC patients.

Conclusion MMP-2 CT/TT genotype in PSC is a significant independent risk factor for disease severity as reflected by patient mortality or need for OLT and identifies, therefore, this polymorphism as a disease modifying gene.