Genetic variants in major histocompatibility complex-linked genes associate with pediatric liver transplant rejection.
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.
Sindhi
Rakesh
R
Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. Rakesh.Sindhi@chp.edu
Higgs
Brandon W
BW
Weeks
Daniel E
DE
Ashokkumar
Chethan
C
Jaffe
Ronald
R
Kim
Cecilia
C
Wilson
Patrick
P
Chien
Nydia
N
Glessner
Joseph
J
Talukdar
Anjan
A
Mazariegos
George
G
Barmada
M Michael
MM
Frackleton
Edward
E
Petro
Nancy
N
Eckert
Andrew
A
Hakonarson
Hakon
H
Ferrell
Robert
R
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
D006681:HLA-D Antigens; C046148:HLA-DO antigens