Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: We have recently demonstrated that the TNF superfamily member is critical for the pathogenesis of Calcineurin Inhibitor Toxicity (CNT). CNT is a common side effect of treatment with calcineurin inhibitors (Cyclosporine A and Tacrolimus) and responsible for long-term allograft deterioration and non-immunological graft loss in a substantial fraction of kidney transplantation recipients. Although pathognomonic for the disease, arterio- and arteriolohyalinosis (ah/aah) is characteristic for advanced CNT. So far, factors that predict the risk of CNT after kidney transplantation are elusive.
*Methods: By employing GWAS data from the Swiss Transplant Cohort Study, we identified a Single Nucleotide Polymorphism (SNP) within the 3’UTR of TWEAK [rs1128963 (*18G>A)] as an independent predictor for ah/aah lesions. Furthermore, homocygocity for the minor allele was associated with inferior death-censored allograft survival.
*Results: The 3’UTR of genes is important for post-transcriptional regulation and mRNA stability. By employing in silico analysis we identified a AU-rich sequence within the 3’UTR of TWEAK with potential regulatory acitivity. Similar regulation via AU-rich sequences has been demonstrated and extensively studied for other pro-inflammatory genes, including TNFa and GM-CSF. In in vitro experiments using reporter assays, we demonstrate that the 3’UTR critically influences mRNA stability and subsequent protein translation of the TWEAK gene.
*Conclusions: In summary, we demonstrate that a common single nucleotide polymorphism within the 3’UTR of TWEAK is predictive for ah/aah-lesions in renal allografts and associated with death-censored allograft survival. The 3’UTR of TWEAK critically influences mRNA stability and mRNA half-life. Current experiments focus on the precise activity of the SNP alleles on TWEAK mRNA regulation in vitro and on quantification of TWEAK mRNA stability ex vivo as a diagnostic test.
To cite this abstract in AMA style:Karolin A, Thottan D, Zinsli J, Rudloff S, Huynh-Do U, Banz V, Berney T, Pascual M, Müller T, d’Amico P, Binet I, Sidler D. A Single Nucleotide Polymorphism of Tweak Predicts Arterio- and Arteriolohyalinosis in Kidney Transplants and is Associated with Allograft Survival [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/a-single-nucleotide-polymorphism-of-tweak-predicts-arterio-and-arteriolohyalinosis-in-kidney-transplants-and-is-associated-with-allograft-survival/. Accessed December 5, 2020.
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