Z Gastroenterol 2012; 50 - K045
DOI: 10.1055/s-0032-1323980

A frequent PNPLA3 variant predicts disease course in PSC patients with dominant bile duct strictures

K Friedrich 1, C Rupp 1, JR Hov 2, KH Weiss 1, P Sauer 1, P Schemmer 3, W Stremmel 1, TH Karlsen 2, D Gotthardt 1
  • 1Universitätsklinik Heidelberg, Innere Medizin IV, Heidelberg, Germany
  • 2Rikshospitalet, Oslo University Hospital, Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo, Norway
  • 3Universitätsklinik Heidelberg, Chirurgische Klinik, Heidelberg, Germany

Background and aims: Primary sclerosing cholangitis (PSC) is caused by chronic inflammation of the bile ducts and can progress to end-stage liver disease. The rs738409 variant (I148M) of the PNPLA3 gene is associated with alcoholic and non-alcoholic liver disease and we evaluated its impact on the disease course of PSC.

Methods: I148M polymorphism was screened in 121 PSC patients in a long-term prospective study cohort and in 83 PSC patients who had undergone endoscopic retrograde cholangiography (ERC) at our institute. In addition, we screened a Norwegian cohort of PSC patients for the I148M variant. Kaplan-Meier analysis was used defining liver transplantation (OLT) or death as events. Expression analysis was performed in biliary tract samples from humans and mice.

Results: In the prospective study cohort actuarial survival free of OLT was significantly reduced (p=0.011) in I148M carriers (mean 13.9±1yrs; 95% CI: 11.80–16.02) compared to non-carriers (mean 19.3±1yrs; 95% CI: 17.32–21.43). In the Norwegian study cohort there was no impact of the I148M variant on actuarial survival free of liver transplantation. Subgroup analysis in the prospective study cohort revealed that patients with a DS showed markedly reduced actuarial survival free of OLT (p=0.004) from the time-point of first dilatation when carrying the I148M variant (mean 9.6±0.9yrs; 95% CI: 7.77–11.53) compared to WT patients (mean 16.2±1.2yrs; 95% CI: 13.72–18.69). Evaluation of all 204 PSC patients that had received ERC at our institute showed that I148M carriers were at significantly higher risk of developing dominant stenosis (61.0% vs. 74.4%; p=0.045). PNPLA3 expression could be detected in tissue from the biliary tract.

Conclusions: The I148M variant of the PNPLA3 gene is a risk factor for PSC patients with dominant bile duct stenosis. This might lead to novel diagnostic and therapeutic approaches in PSC. Genetic testing for the common PNPLA3 variant might become routine practice.