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

研究成果: Article

15 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)2752-2763
ページ数12
ジャーナルBlood
126
発行部数25
DOI
出版物ステータスPublished - 17-12-2015

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Transplantation (surgical)
Stem Cell Transplantation
Graft vs Host Disease
Stem cells
Grafts
Genes
Alleles
Genome
Genome-Wide Association Study
Polymorphism
Single Nucleotide Polymorphism
Transplants
Nucleotides
Minor Histocompatibility Antigens
HLA-A Antigens
HLA-B Antigens
Bone
Bone Marrow
Molecules

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

これを引用

Sato-Otsubo, A., Nannya, Y., Kashiwase, K., Onizuka, M., Azuma, F., Akatsuka, Y., ... 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
Sato-Otsubo, Aiko ; Nannya, Yasuhito ; Kashiwase, Koichi ; Onizuka, Makoto ; Azuma, Fumihiro ; Akatsuka, Yoshiki ; Ogino, Yasuko ; Satake, Masahiro ; Sanada, Masashi ; Chiba, Shigeru ; Saji, Hiroh ; Inoko, Hidetoshi ; Kennedy, Giulia C. ; Yamamoto, Ken ; Morishima, Satoko ; Morishima, Yasuo ; Kodera, Yoshihisa ; Sasazuki, Takehiko ; Ogawa, Seishi. / Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation. :: Blood. 2015 ; 巻 126, 番号 25. pp. 2752-2763.
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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.",
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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, GC, 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, 巻. 126, 番号 25, pp. 2752-2763. https://doi.org/10.1182/blood-2015-03-630707

Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation. / Sato-Otsubo, Aiko; Nannya, Yasuhito; Kashiwase, Koichi; Onizuka, Makoto; Azuma, Fumihiro; Akatsuka, Yoshiki; Ogino, Yasuko; Satake, Masahiro; Sanada, Masashi; Chiba, Shigeru; Saji, Hiroh; Inoko, Hidetoshi; Kennedy, Giulia C.; Yamamoto, Ken; Morishima, Satoko; Morishima, Yasuo; Kodera, Yoshihisa; Sasazuki, Takehiko; Ogawa, Seishi.

:: Blood, 巻 126, 番号 25, 17.12.2015, p. 2752-2763.

研究成果: Article

TY - JOUR

T1 - Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation

AU - Sato-Otsubo, Aiko

AU - Nannya, Yasuhito

AU - Kashiwase, Koichi

AU - Onizuka, Makoto

AU - Azuma, Fumihiro

AU - Akatsuka, Yoshiki

AU - Ogino, Yasuko

AU - Satake, Masahiro

AU - Sanada, Masashi

AU - Chiba, Shigeru

AU - Saji, Hiroh

AU - Inoko, Hidetoshi

AU - Kennedy, Giulia C.

AU - Yamamoto, Ken

AU - Morishima, Satoko

AU - Morishima, Yasuo

AU - Kodera, Yoshihisa

AU - Sasazuki, Takehiko

AU - Ogawa, Seishi

PY - 2015/12/17

Y1 - 2015/12/17

N2 - 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.

AB - 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.

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Sato-Otsubo A, Nannya Y, Kashiwase K, Onizuka M, Azuma F, Akatsuka Y その他. Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation. Blood. 2015 12 17;126(25):2752-2763. https://doi.org/10.1182/blood-2015-03-630707