Rapid Identification of Clinical Relevant Minor Histocompatibility Antigens via Genome-Wide Zygosity-Genotype Correlation Analysis

• Published in: Clinical cancer research 2009-12, Vol.15 (23), p.7137-7143
• Main Authors: SPAAPEN, Robbert M, DE KORT, Ron A. L, VAN DEN OUDENALDER, Kelly, VAN ELK, Maureen, BLOEM, Andries C, LOKHORST, Henk M, MUTIS, Tuna
• Format: Article
• Language: English
• Subjects: Alleles; Antineoplastic agents; Arginine - chemistry; Biological and medical sciences; CD4; CD4-Positive T-Lymphocytes - metabolism; Genome; Genotype; Graft vs Host Disease; Graft vs Tumor Effect; Humans; identification; Medical sciences; Membrane Transport Proteins - genetics; minor histocompatibility antigen; Minor Histocompatibility Antigens - analysis; Models, Genetic; Multiple Myeloma - metabolism; Peptides - chemistry; Pharmacology. Drug treatments; Phenotype; Polymorphism, Single Nucleotide; Reduced Folate Carrier Protein; SLC19A1; T cells; zygosity-genotype correlation analysis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-09-1914

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. (Clin Cancer Res 2009;15(23):7137–43)