The functional polymorphism Ala258Ser in the innate receptor gene ficolin-2 in the donor predicts improved renal transplant outcome

Transplantation. 2012 Sep 15;94(5):478-85. doi: 10.1097/TP.0b013e31825c5967.

Abstract

Background: Innate immunity plays a role in controlling adaptive immune responses.

Methods: We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen-DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set.

Results: Polymorphisms in TLR-3 (rs3775296) in the recipients and in ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1-0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2-1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed ficolin-2. Donor grafts with the ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of ficolin-2 to N-acetylglucosamine.

Conclusions: Presence of the ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Biopsy
  • Exons
  • Gene Expression Regulation
  • Genotype
  • Graft Rejection / blood
  • Graft Rejection / genetics*
  • Graft Rejection / immunology
  • Graft Rejection / metabolism
  • Graft Survival*
  • Humans
  • Immunity, Innate / genetics*
  • Interleukin-1beta / genetics
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Jurkat Cells
  • Kaplan-Meier Estimate
  • Kidney Transplantation* / adverse effects
  • Kidney Transplantation* / immunology
  • Lectins / blood
  • Lectins / genetics*
  • Logistic Models
  • Multivariate Analysis
  • Netherlands
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Proportional Hazards Models
  • Risk Assessment
  • Risk Factors
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Time Factors
  • Tissue Donors*
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • IL6 protein, human
  • Interleukin-1beta
  • Interleukin-6
  • Lectins
  • Tumor Necrosis Factor-alpha
  • ficolin