Association Between Promoter Polymorphisms in CD46 and CD59 in Kidney Donors and Transplant Outcome

Abstract

Complement regulating proteins, including CD46, CD55, and CD59, protect cells against self-damage. Because of their expression on the donor endothelium, they are hypothesized to be involved in accommodation. Polymorphisms in their promoter regions may affect their expression. The aim of this study was to investigate if donor polymorphisms in complement regulating proteins influence kidney transplant outcomes. We included 306 kidney transplantations between 2005 and 2010. Five polymorphisms in the promoters of CD46, CD55, and CD59 were genotyped. A CD59 promoter polymorphism (rs147788946) in donors was associated with a lower 1-year rejection-free survival [adjusted hazard ratio (aHR) 2.18, 95% CI 1.12–4.24] and a trend toward impaired 5-year graft survival (p = 0.08). Patients receiving a kidney with at least one G allele for the CD46 promoter polymorphism rs2796267 (A/G) showed a lower rejection-free survival, though this became borderline significant after adjustment for potential confounders (aHR 1.87, 95% CI 0.96–3.65). A second CD46 promoter polymorphism (rs2796268, A/G), was also associated with a lower freedom from acute rejection in the presence of at least one G allele (aHR 1.95, 95% CI 1.03–3.68). Finally, the combined presence of both favorable genotypes of rs2796267 and rs147788946 had an additional protective effect both on acute rejection (p = 0.006) and graft survival (p = 0.03). These findings could help to identify patients who could benefit from intensified immunosuppressive therapy or novel complement inhibitory therapeutics.

Human kidney clonal proliferation disclose lineage-restricted precursor characteristics

“…Interestingly, Elevation of CD genes related to immune response and exosomal communication was noted in EL clones. The former included CD46 associated with compliment pathway retardation 50 and CD274, linked with inhibition of T cell function, all three were shown to decrease kidney allograft rejection 51,52 . CD9, an exosome-complex gene was also elevated in EL clones.…”

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

“…Multiple single nucleotide polymorphisms (SNPs) have been identified in association with allograft renal function 105 although disputed on further study 106 . Donor polymorphisms have also been identified associated with allograft survival 107,108 . There have also been associations with protection against allograft loss and NF‐κB1 .…”

Complement and Transplantation

“…As donor-expressed complement regulatory proteins could confer protection from DSA 61 , investigators have hypothesized that donor SNPs within regulators could also be used to assess post-transplant risk. Indeed, a donor CD59 promoter polymorphism (rs147788946) is associated with an increased rate of early acute rejection in renal allografts 62 and a higher incidence of chronic rejection among lung transplant recipients 63 . Going forward, sufficiently powered validation studies will be crucial in ultimately determining whether treatment strategies should be individualized based on expression of the various SNPs.…”