Role of PAR1 −506 deletion/insertion polymorphism in primary sclerosing cholangitis

Abstract

AbstractAimPrimary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by inflammation of the intra‐ and extrahepatic bile ducts. Pathogenesis of PSC is still enigmatic but is likely to be multifactorial. Recently, we identified an interleukin‐6 (IL‐6)‐dependent signal transducer and activator of transcription 3 (STAT3) activation in CD4+ TH1 and TH17 cells in PSC. The IL‐6/STAT3 pathway was shown to be regulated by protease‐activated receptor 1 (PAR1) contributing to inflammation. The role of the PAR1 −506 deletion/insertion (Del/Ins) polymorphism in PSC has not yet been investigated.MethodsTwo hundred eighty four PSC patients (200 patients with inflammatory bowel diseases [IBD] and 84 without IBD) and 309 healthy controls were genotyped for PAR1 rs11267092 (−506 Del/Ins −13 bp). Results were correlated with clinical characteristics and transplant‐free survival.ResultsThe frequency of PAR1 –506 Ins allele carriers (Del/Ins and Ins/Ins) was significantly higher in PSC patients (57.0%) compared to healthy controls (39.8%). Furthermore, carriers of PAR1 −506 Ins allele were more likely to have PSC than noncarriers (odds ratio 2.01; 95% confidence interval, 1.45–2.79). Patients with PSC carrying the PAR1 −506 Ins allele showed significantly higher alanine aminotransferase serum levels (p = 0.0357) and a trend toward shorter transplant‐free survival time compared to noncarriers (8.9 ± 6.6 years vs. 10.5 ± 7.1 years; p = 0.076).ConclusionsOur study shows that PAR1 −506 Ins is significantly more frequent in people with PSC. As PAR1 −506 Ins allele carriers tended to have a shorter transplant‐free survival, PAR1 might play a role in the development and course of PSC.