Abstract
In rodents, immune responses to minor histocompatibility antigens are the most important drivers of corneal graft rejection. However, this has not been confirmed in humans or in a large animal model and the genetic loci are poorly characterised, even in mice. The gene sequence data now available for a range of relevant species permits the use of genome-wide association (GWA) techniques to identify minor antigens associated with transplant rejection. We have used this technique in a pre-clinical model of corneal transplantation in semi-inbred NIH minipigs and Babraham swine to search for novel minor histocompatibility loci and to determine whether rodent findings have wider applicability. DNA from a cohort of MHC-matched and MHC-mismatched donors and recipients was analysed for single nucleotide polymorphisms (SNPs). The level of SNP homozygosity for each line was assessed. Genome-wide analysis of the association of SNP disparities with rejection was performed using log-likelihood ratios. Four genomic blocks containing four or more SNPs significantly linked to rejection were identified (on chromosomes 1, 4, 6 and 9), none at the location of the MHC. One block of 36 SNPs spanned a region that exhibits conservation of synteny with the mouse H-3 histocompatibility locus and contains the pig homologue of the mouse Zfp106 gene, which encodes peptide epitopes known to mediate corneal graft rejection. The other three regions are novel minor histocompatibility loci. The results suggest that rejection can be predicted from SNP analysis prior to transplant in this model and that a similar GWA analysis is merited in humans.
Highlights
The accumulation in recent years of increasingly detailed and accurate sequence data for the human genome and for the genomes of mammalian species used in medical and veterinary research has enabled powerful analytical methods to be employed to identify genetic loci accounting for pathological conditions
Genome-wide association (GWA) analysis has revealed at least four independently segregating non-MHC regions of the pig genome containing genetic polymorphisms associated with corneal graft rejection, three of which have not been previously identified
One of these (Chr 1) containing approximately 115 genes, includes homologues of genes in the H-3 region of the mouse which have already been associated with corneal graft rejection (Zfp106 [9]) and skin graft rejection (β-2M [18] respectively)
Summary
The accumulation in recent years of increasingly detailed and accurate sequence data for the human genome and for the genomes of mammalian species used in medical and veterinary research has enabled powerful analytical methods to be employed to identify genetic loci accounting for pathological conditions. Genome-wide association (GWA) studies using variation data collected by the human 1000 Genomes Project is further facilitating the identification of clinically relevant mHags by eliminating the need for time-consuming T-cell epitope identification strategies [4]. The importance of mHags in the immune response to corneas have long been established in rodent models [5, 6], their identities, both genetic and protein, have remained obscure with the exception of the mouse H-3 locus on chromosome 2. Two CD8 T cell epitopes in the Zfp106 protein contribute to corneal graft rejection in the mouse [9], each resulting from a single nucleotide substitution
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