Whole genome histocompatibility

Hematopoietic stem cell transplantation is the only known curative treatment for severe hematological malignancies, such as leukemia. Solid organ transplantation is an established treatment for end-stage kidney, liver, lung, and heart diseases, and has been shown to be cost-effective and significantly improve the quality of life.

Complications after transplantation can be considered multifactorial traits in which both acquired and genetic factors from the recipient and donor play important roles. As currently discussed in our reviews^16,17, more accurate tools for predicting transplant outcomes than those currently available could enable more personalized treatments and more precise risk assessment.

The key questions in our studies are the following:

1. How strongly is extended genome or protein-level matching between donor and recipient associated with outcomes of transplantation? Any immunogenic protein difference between the transplanted graft and recipient may elicit alloimmune response. As an extreme example of protein differences, we introduced the concept of mismatching for common gene deletions and showed that such mismatches predispose recipients to graft-versus-host-disease after hematopoietic stem cell transplantation¹⁸. We have found similar results in kidney¹⁹ and liver²⁰ transplantations, suggesting that mismatches of common gene deletions may represent a novel category of clinically relevant matching factor. The protein-level differences are generally referred to as minor histocompatibility antigens (miHAs), and their significance in stem cell transplantation matching was recognized early in our collaborative study²¹ An integral component of this research line is understanding how the predicted miHA peptides bind to HLA molecules²² , a fundamental property for alloimmune activation.
2. Can we identify recipient- or donor-specific genetic variants, genotypes, or polygenic risk sums that are associated with outcomes of transplantation? The combined effect of multiple genetic variants, usually called polygenic risk sum/score (PRS), provides a valuable tool for identifying individuals at the extreme ends (high/low) of genetic risk. We have demonstrated the value of PRS in kidney transplantation in large collaborations including more than 6,500 cases^23–25. We also have evaluated several candidate genetic variants in our transplantation cohorts. Notable examples include variants regulating thymopoiesis²⁶ and genetic variation influencing the function of natural killer (NK) cells^27–29. The latter line of research links our studies with the development of therapeutic NK cell products at the Advanced Cell Therapy Centre of the Blood Service.
3. To what extent can immunological or multiomics approaches enhance the prediction of transplantation outcomes? Our preliminary analyses integrating genetic associations with gene expression data³⁰ have yield promising results This work is now being advanced within a research project funded by the Sigrid Juselius Foundation.

Our key publications:

1. Partanen, J. et al. Potilaan ja luovuttajan välinen kudossopivuus elinten ja kantasolujen siirroissa. Duodecim 1517–1524 (2024).
2. Helanterä, I., Markkinen, S., Partanen, J. & Hyvärinen, K. Novel Aspects of Immunogenetics and Post-Transplant Events in Kidney Transplantation. Transplant Int 37, 13317 (2024).
3. McCarroll, S. A. et al. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nat. Genet. 41, (2009).
4. Markkinen, S. et al. Mismatches in Gene Deletions and Kidney-related Proteins as Candidates for Histocompatibility Factors in Kidney Transplantation. Kidney Int. Rep. 7, 2484–2494 (2022).
5. Semenova, M. et al. The Impact of Genome-wide Histocompatibility on Liver Transplantation Outcomes. Transplantation https://doi.org/10.1097/TP.0000000000005475 (2025)
6. Spierings, E. et al. Multicenter Analyses Demonstrate Signi fi cant Clinical Effects of Minor Histocompatibility Antigens on GvHD and GvL after HLA-Matched Related and Unrelated. Biol Blood Marrow Transplant 19, 1244–1253 (2013).
7. Ritari, J. et al. Computational Analysis of HLA-presentation of Non-synonymous Recipient Mismatches Indicates Effect on the Risk of Chronic Graft-vs.-Host Disease after Allogeneic HSCT. Front. Immunol. 10, (2019).
8. Collins, K. E. et al. Donor genetic burden for cerebrovascular risk and kidney transplant outcome. J. Nephrol. 1–10 (2024) doi:10.1007/S40620-024-01973-0/FIGURES/3.
9. Collins, K. E. et al. Donor and Recipient Polygenic Risk Scores Influence Kidney Transplant Function. Transplant Int 38, 14171 (2025).
10. Collins, K. E. et al. Polygenic risk scores for eGFR are associated with age at kidney failure. J. Nephrol. 1–10 (2025) doi:10.1007/S40620-025-02207-7/TABLES/4.
11. Nihtilä, J. et al. Donor genetic determinant of thymopoiesis, rs2204985, and stem cell transplantation outcome in a multipopulation cohort. Hum. Immunol. 85, 110791 (2024).
12. Nihtilä, J. et al. Impact of MICA-129 Mismatch on Hematopoietic Stem Cell Transplantation Outcomes: Evidence from a Large European Cohort and Meta-Analysis. Transplant. Cell. Ther. 31, 954.e1-954.e4 (2025).
13. Nihtilä, J. et al. Effect of NK cell receptor genetic variation on allogeneic stem cell transplantation outcome and in vitro NK cell cytotoxicity. Scientific Reports 2024 14:1 14, 1–12 (2024).
14. Impola, U. et al. Donor haplotype B of NK KIR receptor reduces the relapse risk in HLA-identical sibling hematopoietic stem cell transplantation of AML patients. Front. Immunol. 5, 1–5 (2014).
15. Hyvärinen, K. et al. Meta-analysis of genome-wide association and gene expression studies implicates donor T cell function and cytokine pathways in acute GvHD. Front. Immunol. 11, (2020).