Rapid identification of clinical relevant minor histocompatibility antigens via genome-wide zygosity-genotype correlation analysis.

Abstract

Identification of minor histocompatibility antigens (mHag) with classic methods often requires sophisticated technologies, determination, and patience. We here describe and validate a nonlaborious and convenient genetic approach, based on genome-wide correlations of mHag zygosities with HapMap single-nucleotide polymorphism genotypes, to identify clinical relevant mHags within a reasonable time frame. Using this approach, we sought for the mHag recognized by a HLA-DRB1*1501-restricted T-cell clone, isolated from a multiple myeloma patient during a strong graft-versus-tumor effect associated with acute graft-versus-host disease grade 3. In a period of 3 months, we determined the mHag phenotype of 54 HapMap individuals, deduced the zygosity of 20 individuals, defined the mHag locus by zygosity-genotype correlation analyses, tested the putative mHag peptides from this locus, and finally showed that the mHag is encoded by the arginine (R) allele of a nonsynonymous single-nucleotide polymorphism in the SLC19A1 gene. We conclude that this powerful and convenient strategy offers a broadly accessible platform toward rapid identification of mHags associated with graft-versus-tumor effect and graft-versus-host disease.