Journal
BLOOD
Volume 126, Issue 25, Pages 2752-2763Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-03-630707
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Funding
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency
- Ministry of Health, Labor, and Welfare, Japan [H23-Immunology-010]
- Ministry of Education, Culture, Sports, Science, and Technology, Japan [3224-22133002, 22133003, 22133009, 22133011]
- Practical Research Project for Allergic Disease and Immunology (Research on Technology of Medical Transplantation) - Japan Agency for Medical Research and Development
- Grants-in-Aid for Scientific Research [15K05577, 22133003, 26461455, 22133009, 22133011] Funding Source: KAKEN
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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 X 10(-9)) and grade III-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 X 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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