Genetic variation in interleukin-17 receptor A is functionally associated with chronic rejection after lung transplantation

Chronic rejection is the major cause of morbidity and mortality after lung transplantation.IL-17 producing cells, inducers of airway neutrophilia, play a prominent role in chronic rejection.We investigated the association between genetic variants in the IL-17/IL-23 pathway and outcome after lung transplantation.Six genetic variants in IL-17 and IL-23 receptor genes were genotyped in 497 lung transplant patients.Associations with chronic rejection, mortality, airway and systemic inflammatory parameters were assessed.The rs879574A, genetic variant in the IL-17A receptor gene, was associated with chronic rejection.In particular, carriers of the rs879574 at-risk A-allele exhibited increased susceptibility to chronic rejection with multivariable-adjusted hazard ratio of 1.47 (CI=1.07-2.03;p=0.004), but no association was found with mortality (CI=0.71-1.41;p=0.14).Also the prevalence of acute rejection was higher in the at-risk population (p=0.001).Interestingly, rs879574A was associated with airway neutrophilia (p=0.020),suggesting that this variant may functionally affect the IL-17A receptor gene and thereby contribute to chronic rejection after lung transplantation.We conclude that rs879574A is associated with chronic rejection after lung transplantation, and is functionally associated with airway neutrophilia.Pre-transplant determination of this genetic variant may improve treatment and follow-up of our patients, aiming to reduce acute and chronic rejection.