Donor genetic variants in interleukin-6 and interleukin-6 receptor associate with biopsy-proven rejection following kidney transplantation

Felix Poppelaars,Jeffrey Damman,Siawosh K Eskandari,Marc A Seelen,Mariana Gaya Da Costa

doi:10.1038/s41598-021-95714-z

Abstract

Rejection after kidney transplantation remains an important cause of allograft failure that markedly impacts morbidity. Cytokines are a major player in rejection, and we, therefore, explored the impact of interleukin-6 (IL6) and IL-6 receptor (IL6R) gene polymorphisms on the occurrence of rejection after renal transplantation. We performed an observational cohort study analyzing both donor and recipient DNA in 1271 renal transplant‐pairs from the University Medical Center Groningen in The Netherlands and associated single nucleotide polymorphisms (SNPs) with biopsy-proven rejection after kidney transplantation. The C-allele of the IL6R SNP (Asp358Ala; rs2228145 A > C, formerly rs8192284) in donor kidneys conferred a reduced risk of rejection following renal transplantation (HR 0.78 per C-allele; 95%-CI 0.67–0.90; P = 0.001). On the other hand, the C-allele of the IL6 SNP (at position-174 in the promoter; rs1800795 G > C) in donor kidneys was associated with an increased risk of rejection for male organ donors (HR per C-allele 1.31; 95%-CI 1.08–1.58; P = 0.0006), but not female organ donors (P = 0.33). In contrast, neither the IL6 nor IL6R SNP in the recipient showed an association with renal transplant rejection. In conclusion, donor IL6 and IL6R genotypes but not recipient genotypes represent an independent prognostic marker for biopsy-proven renal allograft rejection.

Highlights

Rejection after kidney transplantation remains an important cause of allograft failure that greatly impacts morbidity[18,19,20]
Use of novel therapies to reduce allosensitization is vital, but new drug development for kidney transplantation is limited[21], necessitating the repurposing of existing anti-inflammatory drugs approved for other indications
The main finding of our study is a significant association between a common functional IL6 and interleukin 6 (IL-6) receptor (IL6R) polymorphisms in the donor and the risk of biopsy-proven rejection following kidney transplantation

Summary

Introduction

Rejection after kidney transplantation remains an important cause of allograft failure that markedly impacts morbidity. We performed an observational cohort study analyzing both donor and recipient DNA in 1271 renal transplant‐pairs from the University Medical Center Groningen in The Netherlands and associated single nucleotide polymorphisms (SNPs) with biopsy-proven rejection after kidney transplantation. The C-allele of the IL6R SNP (Asp358Ala; rs2228145 A > C, formerly rs8192284) in donor kidneys conferred a reduced risk of rejection following renal transplantation (HR 0.78 per C-allele; 95%-CI 0.67–0.90; P = 0.001). Neither the IL6 nor IL6R SNP in the recipient showed an association with renal transplant rejection. Donor IL6 and IL6R genotypes but not recipient genotypes represent an independent prognostic marker for biopsy-proven renal allograft rejection. Aberrant IL-6 activity is implicated in diseases including systemic inflammatory response syndrome, chronic immune disorders such as crescentic glomerulonephritis, transplant rejection, and graft-versus-host disease, rheumatic diseases including rheumatoid arthritis and juvenile idiopathic arthritis, and lymphoproliferative conditions like Castleman’s d isease[4,8,9]

Methods

Results

Conclusion