title: Genetic variants in major histocompatibility complex-linked genes associate with pediatric liver transplant rejection.
abstract: OBJECTIVE
  Limited access to large samples precludes genome-wide association studies of rare but complex traits. To localize candidate genes with family-based genome-wide association, a novel exploratory analysis was first tested on 1774 major histocompatibility complex single nucleotide polymorphisms (SNPs) in 240 DNA samples from 80 children with primary liver transplantation and their biologic parents.
  
  
  METHODS
  Initially, 57 SNPs with large differences (P < .05) in minor allele frequencies were selected when parents of children with early rejection (rejectors) were compared with parents of nonrejectors.
  
  
  RESULTS
  In hypothesis testing of selected SNPs, the gamete competition statistic identified the minor allele G of the SNP rs9296068, near HLA-DOA, as being significantly different (P = .018) between outcome groups in parent-to-child transmission. Subsequent simple association testing confirmed over- and undertransmission of rs9296068 based on the most significant differences between outcome groups, of 1774 SNPs tested (P = .002), and allele (G) frequencies that were greater among rejectors (51.4% vs 36.8%, respectively, P = .015) and lower among nonrejectors (26.8% vs 36.8%, respectively, P = .074) compared with 400 normal control Caucasian children. In early functional validation, rejectors demonstrated significant repression of the first HLA-DOA exon closest to rs9296068. Also, intragraft B lymphocytes, whose antigen-presenting function is selectively inhibited by HLA-DOA were 3-fold more numerous during rejection among rejectors with the risk allele, than those without.
  
  
  CONCLUSIONS
  The minor allele of the SNP rs9296068 is significantly associated with liver transplantation rejection and with enhanced B-lymphocyte participation in rejection, likely because of a dysfunctional HLA-DOA gene product.
authors.affiliation: Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. Rakesh.Sindhi@chp.edu
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sindhi
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weeks
authors.forename: Chethan
authors.initials: C
authors.lastname: Ashokkumar
authors.forename: Ronald
authors.initials: R
authors.lastname: Jaffe
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kim
authors.forename: Patrick
authors.initials: P
authors.lastname: Wilson
authors.forename: Nydia
authors.initials: N
authors.lastname: Chien
authors.forename: Joseph
authors.initials: J
authors.lastname: Glessner
authors.forename: Anjan
authors.initials: A
authors.lastname: Talukdar
authors.forename: George
authors.initials: G
authors.lastname: Mazariegos
authors.forename: M Michael
authors.initials: MM
authors.lastname: Barmada
authors.forename: Edward
authors.initials: E
authors.lastname: Frackleton
authors.forename: Nancy
authors.initials: N
authors.lastname: Petro
authors.forename: Andrew
authors.initials: A
authors.lastname: Eckert
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Robert
authors.initials: R
authors.lastname: Ferrell
mesh_terms: D001402:B-Lymphocytes / Q000473:pathology; D002452:Cell Count; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006681:HLA-D Antigens / Q000235:genetics*; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D010290:Parents; D020641:Polymorphism, Single Nucleotide
chemical_list: D006681:HLA-D Antigens; C046148:HLA-DO antigens