Identification of HLA-A, HLA-B and HLA-C triple homozygous and double homozygous donors: a path towards synthetic superdonor Advanced Therapeutic Medicinal Products
Naumovas, D.; Rojas-Araya, B.; M. Polanco, C.; Andrade, V.; Cekauskiene, R.; Valatkaite-Rakstiene, B.; Laurinaityte, I.; Jakubauskas, A.; Stoskus, M.; Griskevicius, L.; Nalvarte, I.; Inzunza, J.; Baltriukiene, D.; Arias, J.
Show abstract
Immune matching and rejection pose major hurdles in tissue transplantation. Here, we profile HLA-A, HLA-B, and HLA-C alleles in 3,496 Lithuanian donors genotyped at three-field resolution. The five most frequent alleles constitute 74.6% of HLA-A, 43.2% of HLA-B, and 59.2% of HLA-C, with HLA-A*02:01:01, HLA-B*07:02:01, and HLA-C*07:02:01 being the most common. Lithuanian allele frequencies closely resemble those of populations with pre-Neolithic hunter-gatherer ancestry, such as European-American and British groups. We identified 153 double homozygotes and 51 triple homozygotes for HLA-A, HLA-B, and HLA-C. Compatibility modeling showed triple homozygous profiles match 60.5% of Lithuanians (33.3% for double homozygotes), 13.4% of British population, and 7.4% of European-Americans. CRISPR-Cas9 guide RNA design yielded 54 candidates predicted to disrupt HLA-A or HLA-B, while preserving HLA-C, producing edited profiles matching over 98.1% of Lithuanians, 95.8% of European-Americans, and 95.6% of British population. Finally, we established 16 fibroblast lines from double and triple homozygotes, offering a resource for immune-compatibility studies and regenerative medicine applications.
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