title: Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation.
abstract: Acute graft-versus-host disease (aGVHD) represents one of the major complications in allogeneic stem cell transplantation and is primarily caused by genetic disparity between the donor and recipient. In HLA-matched transplants, the disparity is thought to be determined by loci encoding minor histocompatibility antigens (minor H antigens), which are presented by specific HLA molecules. We performed a genome-wide association study (GWAS) to identify minor H antigen loci associated with aGVHD. A total of 500 568 single nucleotide polymorphisms (SNPs) were genotyped for donors and recipients from 1589 unrelated bone marrow transplants matched for HLA-A, -B, -C, -DRB1, and -DQB1, followed by the imputation of unobserved SNPs. We interrogated SNPs whose disparity between the donor and recipient was significantly associated with aGVHD development. Without assuming HLA unrestriction, we successfully captured a known association between HLA-DPB1 disparity (P = 4.50 × 10(-9)) and grade II-IV aGVHD development, providing proof of concept for the GWAS design aimed at discovering genetic disparity associated with aGVHD. In HLA-restricted analyses, whereby association tests were confined to major subgroups sharing common HLA alleles to identify putative minor H antigen loci, we identified 3 novel loci significantly associated with grade III-IV aGVHD. Among these, rs17473423 (P = 1.20 × 10(-11)) at 12p12.1 within the KRAS locus showed the most significant association in the subgroup, sharing HLA-DQB1*06:01. Our result suggested that a GWAS can be successfully applied to identify allele mismatch associated with aGVHD development, contributing to the understanding of the genetic basis of aGVHD.
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Bunkyō-ku, Tokyo, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan;
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nannya
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan;
authors.forename: Makoto
authors.initials: M
authors.lastname: Onizuka
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan;
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Azuma
authors.affiliation: Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan; Aichi Cancer Center Research Institute, Nagoya, Japan;
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Akatsuka
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Bunkyō-ku, Tokyo, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan;
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Ogino
authors.affiliation: Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Satake
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Bunkyō-ku, Tokyo, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan;
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.affiliation: HLA Foundation Laboratory, Kyoto, Japan;
authors.forename: Hiroh
authors.initials: H
authors.lastname: Saji
authors.affiliation: Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan;
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.affiliation: Affymetrix, Santa Clara, California;
authors.forename: Giulia C
authors.initials: GC
authors.lastname: Kennedy
authors.affiliation: Medical Institute of Bioregulation, Kyusyu University, Fukuoka, Japan;
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan;
authors.forename: Satoko
authors.initials: S
authors.lastname: Morishima
authors.affiliation: Aichi Cancer Center Research Institute, Nagoya, Japan;
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
authors.affiliation: Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University, Nagoya, Japan; and.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kodera
authors.affiliation: Institute for Advanced Study, Kyusyu University, Fukuoka, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Bunkyō-ku, Tokyo, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006086:Graft vs Host Disease / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D015778:Minor Histocompatibility Antigens