Genome-wide association-studies (GWAS) can be used to establish allele mismatch in acute-graft-versus-host disease (aGVHD), a major complication of allogeneic stem cell transplantation, according to an article published in Blood.1

Disparities within minor histocompatibility antigens (minor H antigens) are known to contribute to the development of aGVHD. Investigators genotyped 500,568 single nucleotide polymorphisms (SNPs) from 1,589 unrelated donor and recipient bone marrow transplants matched for human leukocyte antigen (HLA) A, B, C, DRB1, and DQB1.

By examining SNPs where disparities between donor and recipient were significantly associated with aGVHD development, investigators found an established association of an HLA-DBP1 disparity with grade 2-4 aGVHD (P=4.50 x 10-9). This provided proof of concept that GWAS is capable of discovering genetic variances associated with aGVHD.

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When performing an HLA-restricted analyses, where testing was limited to major HLA subgroups to identify known minor H antigen loci, three novel loci were significantly associated with grade 3-4 aGVHD. Of the three, rs17473423 (P=1.2 x 10-11) at 12p12.1 within the KRAS locus displayed the most significant association in the HLA DQB1*06:01 subgroup.

These findings contribute to understanding the genetics associated with aGVHD.

Reference

  1. Sato-Otsubo A, Yasuhito N, Kashiwase K, et al. Genome-wide surveillance of mismatched alleles for graft versus host disease in stem cell transplantation [published online ahead of print October 2, 2015]. Blood. doi: 10.1182/blood-2015-03-630707.

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Hematologic Cancers