Functional Association between a Genetic Variant in the IL-17 Receptor Gene and Chronic Rejection after Lung Transplantation

Abstract

PurposeChronic rejection is the major cause of morbidity and mortality after lung transplantation (LTx). IL-17 producing cells, inducers of airway neutrophilia, have a prominent role in chronic rejection. We investigated the relationship between genetic variants in the IL-17 receptor (IL-17R) gene and the outcome (chronic rejection and death) after LTx; furthermore the functionality (airway neutrophilia) and the impact of azithromycin treatment in patients with this SNP were examined.Methods and MaterialsRecipient DNA from blood or explant lung tissue was evaluated for the IL-17R (rs879574) polymorphism by iPLEX technology on a MassARRAY and paralleled with clinical patient data.ResultsIL-17R SNP (rs879574) was successfully determined in 497 out of 568 LTx recipients, of which 124 had the A-allele (AA+AT, 24.9%) and 373 had the TT-genotype (75.1%). Independent of age, gender, LTx type, underlying disease, time of LTx and the use of azithromycin, carriers of the AA+AT variant had an increased risk for chronic rejection (CR, hazard rate: 1.47 CI: [1.069-2.028]; p=0.003), but not for mortality (hazard rate: 1.00 CI: [0.708-1.411]; p=0.14). [figure 1] The prevalence of acute rejection was significantly higher in the risk genotype (p=0.001). The genotype at risk was functionally associated with a higher % BAL neutrophilia at day 90, 180 and 360 post-LTx (p=0.023). Interestingly, azithromycin therapy was significantly more added as treatment in patients at risk (p=0.047).ConclusionsThe presence of the A-allele of an IL-17R SNP was associated with acute and chronic rejection and a functional association with airway neutrophilia.Therefore, pretransplant determination of this SNP may improve treatment and standard care. Chronic rejection is the major cause of morbidity and mortality after lung transplantation (LTx). IL-17 producing cells, inducers of airway neutrophilia, have a prominent role in chronic rejection. We investigated the relationship between genetic variants in the IL-17 receptor (IL-17R) gene and the outcome (chronic rejection and death) after LTx; furthermore the functionality (airway neutrophilia) and the impact of azithromycin treatment in patients with this SNP were examined. Recipient DNA from blood or explant lung tissue was evaluated for the IL-17R (rs879574) polymorphism by iPLEX technology on a MassARRAY and paralleled with clinical patient data. IL-17R SNP (rs879574) was successfully determined in 497 out of 568 LTx recipients, of which 124 had the A-allele (AA+AT, 24.9%) and 373 had the TT-genotype (75.1%). Independent of age, gender, LTx type, underlying disease, time of LTx and the use of azithromycin, carriers of the AA+AT variant had an increased risk for chronic rejection (CR, hazard rate: 1.47 CI: [1.069-2.028]; p=0.003), but not for mortality (hazard rate: 1.00 CI: [0.708-1.411]; p=0.14). [figure 1] The prevalence of acute rejection was significantly higher in the risk genotype (p=0.001). The genotype at risk was functionally associated with a higher % BAL neutrophilia at day 90, 180 and 360 post-LTx (p=0.023). Interestingly, azithromycin therapy was significantly more added as treatment in patients at risk (p=0.047). The presence of the A-allele of an IL-17R SNP was associated with acute and chronic rejection and a functional association with airway neutrophilia.Therefore, pretransplant determination of this SNP may improve treatment and standard care.