Two promoter polymorphisms in the genes encoding for complement regulating proteins CD46 and CD59 in kidney donors are associated with biopsy proven acute rejection

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L.A. Michielsen, A.D van Zuilen, T. Kardol-Hoefnagel, M.C. Verhaar, H.G. Otten

Chair(s): Prof. dr. L.B. Hilbrands & dr. H.M. Kwakkel-van Erp

Wednesday 8 march 2017

18:42 - 18:54h at Willem Pijperzaal

Categories: Parallel - Klinisch

Parallel session: Parallelsessie VI - Klinisch 1 - HLA-antilichamen en immunomodulatie

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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 transcription. In lung transplantation, an insertion in the CD59 promoter in donors was associated with bronchiolitis obliterans syndrome. The aim of this study was to investigate if donor polymorphisms in complement regulating proteins influence kidney transplant outcomes.

We have included 317 kidney transplantations between 2005 and 2010. Five frequent polymorphisms in the promoters of CD46 (rs2796267 and rs2796268), CD55 (rs150046210 and rs283715831) and CD59 (rs147788946) were genotyped. Log-rank analyses were used to compare survival curves.

The absence of an insertion in the CD59 promoter (rs147788946) of donors was associated with a lower freedom from biopsy proven acute rejection or acute borderline rejection (BPAR) within the first year (p=0.04). Although the 5-year graft survival curve suggests an impaired graft survival, mainly early posttransplantation, this was not significant (p=0.13). Furthermore, for a single nucleotide polymorphism (SNP) in the CD46 promoter (rs2796267, A/G) we found that the presence of at least one G allele resulted in a lower freedom from BPAR within the first year (p=0.03). There was no correlation with 5-year graft survival (p=0.73). Next, we compared the presence of both protective genotypes in donors (n=24) to the presence of both risk genotypes (n=145). The results indicated an even more distinct difference in freedom from BPAR within the first year between both groups (p=0.007). Moreover, the presence of both protective genotypes was also correlated with an improved 5-year graft survival (p=0.04). Finally, a second SNP in the CD46 promoter (rs2796268, A/G) showed a trend towards a lower freedom from BPAR in the presence of at least one G allele (p=0.08). CD55 promoter SNPs did not significantly correlate with transplant outcomes.

These results suggest that two promoter polymorphisms in CD46 (rs2796267) and CD59 (rs147788946) in kidney donors correlate with a lower freedom from BPAR within the first year. Although numbers are relatively low, the combined presence of both protective genotypes appeared to have an additional preservative effect on freedom from BPAR and 5-year graft survival.