BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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: P Loiseau; H Espérou; M Busson; R Sghiri; R Tamouza; M Hilarius; C Raffoux; A Devergie; P Ribaud; G Socié; E Gluckman; D Charron Journal: Bone Marrow Transplant Date: 2002-10 Impact factor: 5.483
Authors: Minnie Sarwal; Mei-Sze Chua; Neeraja Kambham; Szu-Chuan Hsieh; Thomas Satterwhite; Marilyn Masek; Oscar Salvatierra Journal: N Engl J Med Date: 2003-07-10 Impact factor: 91.245
Authors: T K Toby; M Abecassis; K Kim; P M Thomas; R T Fellers; R D LeDuc; N L Kelleher; J Demetris; J Levitsky Journal: Am J Transplant Date: 2017-06-27 Impact factor: 8.086
Authors: M Ningappa; C Ashokkumar; B W Higgs; Q Sun; R Jaffe; G Mazariegos; D Li; D E Weeks; S Subramaniam; R Ferrell; H Hakonarson; R Sindhi Journal: Am J Transplant Date: 2015-12-11 Impact factor: 8.086
Authors: Ravi Starzl; Gerald Brandacher; W P Andrew Lee; Jaime Carbonell; Wensheng Zhang; Jonas Schnider; Vijay Gorantla; Stefan Schneeberger; Xin Xiao Zheng Journal: Clin Dev Immunol Date: 2013-02-13
Authors: Kevin Y Urayama; Anand P Chokkalingam; Catherine Metayer; Helen Hansen; Suzanne May; Patricia Ramsay; Joseph L Wiemels; John K Wiencke; Elizabeth Trachtenberg; Pamela Thompson; Yasushi Ishida; Paul Brennan; Kent W Jolly; Amanda M Termuhlen; Malcolm Taylor; Lisa F Barcellos; Patricia A Buffler Journal: PLoS One Date: 2013-08-22 Impact factor: 3.240