Whole genome histocompatibility

We aim at identification of novel genetic and immunological factors that influence susceptibility to rejection, graft-versus-host disease, and relapse – the major, potentially life-threating complications following transplantations. These complications cannot be reliably predicted using current recipient-donor matching protocols, and they result in considerable human suffering and suboptimal use of healthcare resources.

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 (Partanen et al 2024; Helanterä et al 2024), 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 transplantation (McCarroll et al 2009). We have found similar results in kidney (Markkinen et al. 2022) and liver (Semenova et al 2025) 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 study (Spierings et al 2013). An integral component of this research line is understanding how the predicted miHA peptides bind to HLA molecules (Ritari et al 2019), 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 (Collins et al 2024; 2025a;2025b). We also have evaluated several candidate genetic variants in our transplantation cohorts. Notable examples include variants regulating thymopoiesis (Nihtilä et al 2024) and genetic variation influencing the function of natural killer (NK) cells (Nihtilä et al 2024; 2025; Impola et al 2014). 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 data (Hyvärinen et al 2020) have yield promising results This work is now being advanced within a research project funded by the Sigrid Juselius Foundation.

Key publications

Collins, K. E. et al. Donor genetic burden for cerebrovascular risk and kidney transplant outcome. J. Nephrol. 2024 Jul;37(6):1643-1652. doi: 10.1007/s40620-024-01973-0.

Collins, K. E. et al. Donor and Recipient Polygenic Risk Scores Influence Kidney Transplant Function. Transplant. Int. 2025a Mar 4;38:14171. doi: 10.3389/ti.2025.14171.

Collins, K. E. et al. Polygenic risk scores for eGFR are associated with age at kidney failure. J. Nephrol. 2025b Apr;38(3):969-978. doi: 10.1007/s40620-025-02207-7.

Helanterä, I. et al. Novel Aspects of Immunogenetics and Post-Transplant Events in Kidney Transplantation. Transpl Int. 2024 Dec 5;37:13317. doi: 10.3389/ti.2024.13317.

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. 2020 Feb 3;11:19. doi: 10.3389/fimmu.2020.00019.

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. 2014 Aug 25;5:405. doi: 10.3389/fimmu.2014.00405.

Markkinen, S. et al. Mismatches in Gene Deletions and Kidney-related Proteins as Candidates for Histocompatibility Factors in Kidney Transplantation. Kidney Int. Rep. 2022 Sep 6;7(11):2484-2494. doi: 10.1016/j.ekir.2022.08.032.

McCarroll, S. A. et al. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nat. Genet. 2009 Dec;41(12):1341-4. doi: 10.1038/ng.490.

Nihtilä, J. et al. Donor genetic determinant of thymopoiesis, rs2204985, and stem cell transplantation outcome in a multipopulation cohort. Hum. Immunol. 2024a May;85(3):110791. doi: 10.1016/j.humimm.2024.

Nihtilä, J. et al. Effect of NK cell receptor genetic variation on allogeneic stem cell transplantation outcome and in vitro NK cell cytotoxicity. Sci. Rep. 2024b Nov 6;14(1):26988. doi: 10.1038/s41598-024-78619-5.

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. 2025 Dec;31(12):954.e1-954.e4. doi: 10.1016/j.jtct.2025.08.023.

Partanen, J. et al. Potilaan ja luovuttajan välinen kudossopivuus elinten ja kantasolujen siirroissa. Duodecim 2024;140(18):1517-24. https://www.duodecimlehti.fi/duo18424

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. 2019 Jul 16;10:1625. doi: 10.3389/fimmu.2019.01625.

Semenova, M. et al. The Impact of Genome-wide Histocompatibility on Liver Transplantation Outcomes. Transplantation 2026 Jan 1;110(1):e175-e184. doi: 10.1097/TP.0000000000005475.

Spierings, E. et al. Multicenter Analyses Demonstrate Significant Clinical Effects of Minor Histocompatibility Antigens on GvHD and GvL after HLA-Matched Related and Unrelated. Biol. Blood. Marrow. Transplant. 2013 Aug;19(8):1244-53. doi: 10.1016/j.bbmt.2013.06.001.

Last modified: 09.06.2026