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


METHODS
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.
Spaapen
Robbert M
RM
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands.
de Kort
Ron A L
RA
van den Oudenalder
Kelly
K
van Elk
Maureen
M
Bloem
Andries C
AC
Lokhorst
Henk M
HM
Mutis
Tuna
T
D000483:Alleles; D001120:Arginine / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016678:Genome; D005838:Genotype; D006086:Graft vs Host Disease; D020350:Graft vs Tumor Effect; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D015778:Minor Histocompatibility Antigens / Q000032:analysis*; D008957:Models, Genetic; D009101:Multiple Myeloma / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D058978:Reduced Folate Carrier Protein
D026901:Membrane Transport Proteins; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D001120:Arginine