Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation

Aiko Sato-Otsubo, Yasuhito Nannya, Koichi Kashiwase, Makoto Onizuka, Fumihiro Azuma, Yoshiki Akatsuka, Yasuko Ogino, Masahiro Satake, Masashi Sanada, Shigeru Chiba, Hiroh Saji, Hidetoshi Inoko, Giulia C. Kennedy, Ken Yamamoto, Satoko Morishima, Yasuo Morishima, Yoshihisa Kodera, Takehiko Sasazuki, Seishi Ogawa

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 (minorHantigens), 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.

Original languageEnglish
Pages (from-to)2752-2763
Number of pages12
JournalBlood
Volume126
Issue number25
DOIs
Publication statusPublished - 17-12-2015

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Sato-Otsubo, A., Nannya, Y., Kashiwase, K., Onizuka, M., Azuma, F., Akatsuka, Y., Ogino, Y., Satake, M., Sanada, M., Chiba, S., Saji, H., Inoko, H., Kennedy, G. C., Yamamoto, K., Morishima, S., Morishima, Y., Kodera, Y., Sasazuki, T., & Ogawa, S. (2015). Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation. Blood, 126(25), 2752-2763. https://doi.org/10.1182/blood-2015-03-630707