title: Single-nucleotide polymorphisms, acute rejection, and severity of tubulitis in kidney transplantation, accounting for center-to-center variation.
abstract: BACKGROUND
  Acute rejection (AR) is associated with worse renal allograft outcomes. Therefore, this study investigated single-nucleotide polymorphisms (SNPs) to identify genetic variants associated with AR, accounting for center variation, in a multicenter, prospective, observation study.
  
  
  METHODS
  We enrolled patients from six transplant centers, five in the United States and one in Canada. A total of 2724 SNPs were genotyped. We accounted for center variation in AR rates by stratifying by transplant center and using novel knowledge discovery methods.
  
  
  RESULTS
  There was significant center variation in AR rates across the six transplant sites (P<0.0001). Accounting for this difference and clinical factors independently associated with AR, we identified 15 novel SNPs associated with AR with stratification by transplant center (P<0.05). We also identified 15 novel SNPs associated with severity of tubulitis scores, after adjusting for transplant center and other clinical factors independently associated with severity of tubulitis (P<0.05). There was some overlap with one SNP associated with AR and also associated with severity of tubulitis, among the top 15 SNPs.
  
  
  CONCLUSIONS
  Center-to-center variation is a major challenge to genomic studies focused on AR. The SNPs associated with AR and severity of tubulitis in this study will need to be validated in independent cohort of kidney transplant recipients.
authors.affiliation: Department of Nephrology, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN, USA. isran001@umn.edu
authors.forename: Ajay
authors.initials: A
authors.lastname: Israni
authors.forename: Robert
authors.initials: R
authors.lastname: Leduc
authors.forename: John
authors.initials: J
authors.lastname: Holmes
authors.forename: Pamala A
authors.initials: PA
authors.lastname: Jacobson
authors.forename: Vishal
authors.initials: V
authors.lastname: Lamba
authors.forename: Weihua
authors.initials: W
authors.lastname: Guan
authors.forename: David
authors.initials: D
authors.lastname: Schladt
authors.forename: Jinbo
authors.initials: J
authors.lastname: Chen
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Matas
authors.forename: William S
authors.initials: WS
authors.lastname: Oetting
mesh_terms: D000328:Adult; D002170:Canada; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000601:surgery; D016030:Kidney Transplantation / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012720:Severity of Illness Index; D013997:Time Factors; D014481:United States