Bootcongres

Background Non-anastomotic biliary strictures (NAS) are the second cause for graft loss after liver transplantation. Because of the clinical similarities that are seen between transplant recipients with NAS and patients suffering from Primary Sclerosing Cholangitis (PSC), it is thought that both conditions share a similar pathophysiology. Recently, GWAS analyses identified the polymorphism rs601338 (G>A) in the Fucosyltransferase-2 (FUT2) gene as a risk factor for PSC. Homozygosity for rs601338 (AA) leads to a truncated, dysfunctional FUT2 enzyme, affecting epithelial glycocalyx integrity and leading to absence of ABH antigens (FUT2 non-secretor status) in body fluids. The aim of this study was to investigate whether FUT2 rs601338 genotype is a risk factor for NAS after liver transplantation. Methods Genotyping was performed in n=258 donors and n=343 recipients, by qPCR on DNA isolated from blood or spleen cells that were collected from consecutive transplantations. Secretor (GA or GG) and non-secretor (AA) status of donors, recipients or paired donors and recipients were compared between recipients who developed NAS and recipients who did not. A sub-analysis on a cohort of transplanted PSC patients (n=67) was performed.  Results In the entire study cohort, 21,5% of the donors and recipients were non-secretor (AA) for FUT2. Cox-regression analysis showed no association between NAS and FUT2 genotype in donors. FUT2 AA-genotype in PSC recipients, however, showed an increased incidence of NAS after LT in patients compared to PSC patients with either GA or GG genotype (P=0.006, HR:5.1), while this association with FUT2 genotype was not found in non-PSC recipients. Analysis of paired donors and recipients disclosed that a FUT2 mismatch, namely the combination of FUT2-secretor donors with FUT2-non-secretor recipients, gives the highest risk for development of NAS (P=0.038). This suggests that, in PSC patients undergoing liver transplantation, an aggravated immune response could be triggered by implanting a liver graft with functional FUT2 proteins into a recipient with dysfunctional FUT2. Further studies are needed to confirm our findings. 

Conclusion FUT2 genotype in PSC patients strongly influences the risk to develop NAS after liver transplantation. This is potentially related to an aggravated immune response induced by FUT2 mismatching between donors and recipients.