Whole genome histocompatibility

Whole genome histocompatibility in hematopoietic stem cell and solid organ transplantations

We aim at identification of novel genetic and immunological factors that influence susceptibility to rejection, graft-versus-host disease (GvHD) and relapse, the major, even life-threating complications of transplantations. 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 and liver diseases and has been shown to be cost effective and improving the quality of patient life.

Complications of transplantations can be assumed to be a multifactorial trait in which both environmental and genetic factors of both recipient and donor are important.

In our genome studies, we use three mutually non-exclusive genetic models for histocompatibility risks:

  1. Genome or protein level compatibility between donor and recipient. For example, matching of HLA alleles, or the role of gene deletions;
  2. Immunologically high versus low responder genotypes. Gene variation that regulates individual’s tendency to alloimmune response or immunological tolerance, e.g. certain cytokine IL-10 gene variants regulate the overall level of immune response and are related to GvHD risk;
  3. Pharmacogenetic response for immunosuppression or conditioning. Complication may manifest when patient’s pharmacogenetic profile leads to decreased response to immunosuppressive drugs.

Any protein sequence level difference between donated tissue or cells and recipient can lead to alloimmune response. As an extreme example of protein differences, we have reported (McCarroll SA et al. 2009) that mismatching for common gene deletions predisposed to GvHD in a large collaborative study.

We now are developing bioinformatic tools that would estimate the personalised, genomic level histocompatibility by integrating all genome and clinical data available from transplantations. We have collected large national and international cohorts including genome data from both recipient and donor and detailed clinical data. We currently have results from over 1000 stem cell transplantations and ~ 1000 kidney and 800 liver transplantations. We are a member of cGvHD Eurograft COST consortium.

We perform:

  1. Standard GWAS and candidate gene analyses (see, e.g. Koskela S et al. 2018; and, Hyvärinen K et al. 2017.)
  2. GWAS analyses combined to gene expression data (see e.g. Hyvärinen K et al. 2020)
  3. Whole genome level matching analyses between donor-recipient pairs (McCarroll SA et al. 2009; and, Ritari J et al. 2019)
  4. Machine learning prediction modellings (see e.g. Ritari J et al. 2019).

Related to the general subject of histocompatibility is our collaborative project with Professor Jukka Kekäläinen of the University of Eastern Finland. In this project we study histocompatibility genetics in human gametes. The results show that, interestingly, fertilisation efficacy depends on similarity of HLA alleles between the male and female, indicating a common mechanism for recognition of allogeneic cells.

Our key publications:

Partanen J et al. Review of Genetic Variation as a Predictive Biomarker for Chronic Graft-Versus-Host-Disease After Allogeneic Stem Cell Transplantation. Front Immunol. 2020;11:575492. PMID: 33193367

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;11:19.PMID: 32117222

Clancy J et al. Increased MHC Matching by C4 Gene Compatibility in Unrelated Donor Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2019;25(5):891-898. PMID: 30592985

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;10:1625. PMID: 31379830

Ritari J et al. Genomic prediction of relapse in recipients of allogeneic haematopoietic stem cell transplantation. Leukemia. 2019;33(1):240-248.PMID: 30089915

Hyvärinen K et al. Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease. Sci Rep. 2017;7(1):15666.PMID: 29142307

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;5:405. PMID: 25202311

Spierings E et al. Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19(8):1244-1253. PMID: 23756210

Jokiniemi A et al. Post-copulatory genetic matchmaking: HLA-dependent effects of cervical mucus on human sperm function. Proc Biol Sci. 2020;287(1933):20201682.PMID: 32811307

Team and key collaborators
FRC Blood Service team
Jukka Partanen, PI (see: http://www.researcherid.com/rid/B-7207-2014)
Kati Hyvärinen
Jarmo Ritari
Jouni Lauronen
Satu Koskela

Students:
Salla Markkinen (kidney transplantation genomics)
Julia Nihtilä (stem cell transplantation genomics)
Silja Tammi (imputation)
Jonna Clancy (biobank genetics)
Maria Semenova (liver transplantation genomics)

Alumns:
Tiira Johansson (HLA expression), dissertation 2022

Collaborators:
Helsinki University Central Hospital, Helsinki, Finland: Dr Urpu Salmenniemi, allogeneic stem cell transplantation; Dr Ilkka Helanterä, kidney transplantation; and Dr Fredrik Åberg, liver transplantation.
Turku University Hospital, Turku, Finland: Dr Maija Itälä-Remes, allogeneic stem cell transplantation.
Newcastle University, Newcastle, UK: Dr Rachel Crossland, allogeneic stem cell transplantation.
Polish Academy of Sciences, Wroclaw, Poland: Dr Katarzyna Bogunia-Kubik, allogeneic stem cell transplantation.
University of Eastern Finland, Joensuu, Finland: Dr Jukka Kekäläinen, human gamete studies.