Role of chemokine receptor and ATP-binding cassette transporter gene polymorphisms for biliary lesions following liver transplantation

Abstract

Aims: Ischemic type biliary lesions (ITBL) and anastomotic strictures (AS) are major complications following LT, leading to reduced graft and patient survival. Genetic polymorphisms in chemokine (CC) receptors which mediate leucocyte trafficking were reported to be associated with ITBL. For late AS, others than surgical factors should be incriminated. Genetic polymorphisms of ATP-binding cassette (ABC) transporters determine serum cholesterol level and cholesterol efflux into bile and contribute to production of lithogenic bile. Aim: To investigate the role of CC-receptors and ABC transporters for development of biliary lesions after LT. Methods: We genotyped two CC-receptors (CCR5, CX3CR1) and ABCG8 in 165 LT recipients (45 with ITBL, 38 with AS, 82 controls) by PCR or PCR-RFLP. Serum concentration of chemokines CCL3 and CCL5, as ligands of CCR5, were measured by ELISA. Results: A 32-bp deletion in CCR5 gene (CCR5Δ32) was present in 29.5% of patients with ITBL compared to 13.2% without ITBL (p=0.01). CCL3 and CCL5 serum levels tended to be higher in patients with CCR5Δ32 genotype. The following genotypes of CX3CR1 were found: G745A (wild type 44.8%, heterozygous 40.6%, homozygous mutant 11.5%) and C839T (72.1%, 24.8%, 3%). The risk of AS in the carriers of 745A allele was significantly increased compared to controls (p=0.04). 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 (45.5%, 44.8%, 9.7%). 25% of patients with ITBL were hetero/homozygous for both SNPs of ABCG8 compared to 12.4% (p=0.04) in controls. Conclusions: CCR5Δ32 hetero/homozygosity and ABCG8 with concomitant C1895T and C1199A mutations have shown to be risk factors for ITBL occurrence. 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.