IMMUNOBIOLOGY - GENETICS AND GENOMICS

S.M. Iacob¹, V.R. Cicinnati², A. Dechene², C.G. Klein³, G.C. Sotiropoulos³, A. Radtke⁴, I. Popescu⁵, M. Lindemann⁶, A. Paul³, G. Gerken², S. Beckebaum^3
1Dept. Of General, Visceral And Transplantation Surgery And Dept. Of Gastroenterology And Hepatology, University Hospital Essen, Essen/GERMANY, ²Dept. Of Gastroenterology And Hepatology, University Hospital Essen, Essen/GERMANY, ³Dept. Of General, Visceral And Transplantation Surgery, University Hospital Essen, Essen/GERMANY, ⁴Dept. Of General And Thoracic Surgery, University Hospital Schleswig Holstein, Campus Kiel, Kiel/GERMANY, ⁵, Fundeni Clinical Institute of Digestive Diseases and Liver Transplantation, Bucharest/ROMANIA, ⁶Institute For Transfusion Medicine, University Hospital Essen, Essen/GERMANY

Body: Background: Ischemic type biliary lesions (ITBL) and anastomotic strictures (AS) are major complications following liver transplantation (LT), leading to reduced graft and patient survival. Genetic polymorphisms in chemokine receptors which mediate leukocyte trafficking have been reported to be associated with ITBL. For late AS, others than surgical factors should be incriminated. Genetic polymorphisms of ATP-binding cassette (ABC) transporters which determine serum cholesterol level and cholesterol efflux into bile contribute to production of lithogenic bile. Aim: To investigate the role of chemokine receptors and ABC transporters for development of biliary lesions after LT. Material and Methods: We genotyped 3 chemokine receptors (CCR2, CCR5 and CX3CR1) and ABC transporter G8 (ABCG8) in 165 LT recipients (42 with ITBL, 36 with AS, 87 controls) by PCR or PCR-restriction fragment length polymorphism assay. Serum concentration of chemokines CCL3 and CCL5 as ligands of CCR5 and CX3CL1 as ligand of CX3CR1 were measured by enzyme linked immunosorbent assays. Results: A 32-base pair deletion in the CCR5 gene (CCR5Δ32) was present in 33.3% of patients with ITBL compared to 14.9% in controls (p=0.01). The following genotypes of CX3CR1 were found: G745A (wild type 44.2%, heterozygous 43.6%, homozygous mutant 12.1%) and C839T (72.1%, 24.8%, 3%). The risk of AS in the carriers of the 745A allele was significantly increased compared to controls (p=0.02). CCL3, CCL5, CX3CL1 serum concentrations did not differ between ITBL and control patients, as well as between AS and control group. Analysis of ABCG8 exons 8 and 13 for single nucleotide polymorphisms (SNPs) revealed the following results: C1199A (wild type 69.1%, heterozygous 29.7%, homozygous mutant 1.2%) and C1895T (46.1%, 44.2%, and 9.7%). 16.7% of patients with ITBL had the T1895T genotype compared to 5.7% (p=0.04) in controls. Patients homozygous for either SNPs of ABCG8 had a significantly higher risk to develop both ITBL and AS. Conclusions: CCR5Δ32 hetero/homozygosity and ABCG8 T1895T mutations have shown to be risk factors for occurrence of ITBL. CX3CR1 745A allele carriers had increased risk of AS. These findings may have translational relevance for predicting the risk of occurrence of biliary lesions after LT.

Disclosure: All authors have declared no conflicts of interest.