title: Genetic variation in interleukin-17 receptor A is functionally associated with chronic rejection after lung transplantation.
abstract: BACKGROUND
  Chronic rejection is the major cause of morbidity and mortality after lung transplantation. Interleukin (IL)-17-producing cells, inducers of airway neutrophilia, play a prominent role in chronic rejection.
  
  
  METHODS
  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, death, airway and systemic inflammatory parameters were assessed.
  
  
  RESULTS
  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 (95% confidence interval, 1.07-2.03; p = 0.004), but no association was found with death (95% confidence interval, 0.71-1.41; p = 0.14). The prevalence of acute rejection was also 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.
  
  
  CONCLUSIONS
  The rs879574A genetic variant 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.
authors.affiliation: Lung Transplant Unit, Laboratory of Pneumology, Katholieke Universiteit Leuven, University Hospital Gasthuisberg, Leuven.
authors.forename: David
authors.initials: D
authors.lastname: Ruttens
authors.forename: Els
authors.initials: E
authors.lastname: Wauters
authors.forename: Michal
authors.initials: M
authors.lastname: Kiciński
authors.forename: Stijn E
authors.initials: SE
authors.lastname: Verleden
authors.forename: Elly
authors.initials: E
authors.lastname: Vandermeulen
authors.forename: Robin
authors.initials: R
authors.lastname: Vos
authors.forename: Dirk E
authors.initials: DE
authors.lastname: Van Raemdonck
authors.forename: Tim S
authors.initials: TS
authors.lastname: Nawrot
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Geert M
authors.initials: GM
authors.lastname: Verleden
authors.forename: Bart M
authors.initials: BM
authors.lastname: Vanaudenaerde
mesh_terms: D000483:Alleles; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006084:Graft Rejection / Q000453:epidemiology* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D016040:Lung Transplantation / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000473:pathology; D018123:Receptors, Interleukin / Q000235:genetics; D053722:Receptors, Interleukin-17 / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate
chemical_list: C109985:IL17RA protein, human; C515500:IL23R protein, human; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17
keywords: IL-17; chronic rejection; genetics; lung transplantation; neutrophils