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.

The authors have declared no competing interest.

This project was supported by Mission-driven Implementation of Science and Innovation Program 02-002-P-0001 to D.B. and J.A., funded by the Economic Revitalization and Resilience Enhancement Plan "New Generation Lithuania".

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval. This study is part of the ethical approval 2023/6-1524-984 - Highly-immune compatible iPS cells as source for Regenerative Medicine and Cell Therapy-oriented applications - from the Vilnius Regional Biomedical Research Ethics Committee to Vilnius University and 2023/4-1507-968 - Analysis of the Distribution of Human Leukocyte Antigen (HLA Encoding Genes - HLA) Alleles and Haplotypes in the Group of the Lithuanian Unrelated Bone Marrow Donor Registry - to Vilnius University Hospital Santaros Klinikos. Written consents were obtained from the participants of the study.

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All data is made available through public repositories.