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Impact of complement component 3/4/5 single nucleotide polymorphisms on renal transplant recipients with antibody-mediated rejection.

ABSTRACT: Antibody-mediated rejection (ABMR) is an important risk of allograft dysfunction in kidney transplantation. The complement system is considered to be associated with the generation of alloreative antibodies and donor-specific antibodies. However, the association of complement single nucleotide polymorphisms (SNPs) with ABMR still remained unclear. Blood samples of 199 renal transplant recipients containing 68 with ABMR and 131 with stable graft function were collected, and analyzed by next-generation sequencing with an established gene panel. High quality readout was obtained in 18 C3 SNPs, 9 C4 SNPs and 22 C5 SNPs. Concerning C3 gene polymorphisms, after being adjusted with age, sex and immunosuppressive protocols, rs10411506 and rs2230205 were found to be statistically associated with ABMR in dominant model (rs10411506: OR=2.73, 95% CIs: 1.16, 6.68, P=0.028; rs2230205: OR=2.52, 95% CIs: 1.07, 5.92, P=0.034); rs10411506, rs2230205 and rs2230201 were found different in HET model (rs10411506: OR=3.05, 95% CIs: 1.22, 7.64, P=0.017; rs2230205: OR=2.90, 95% CIs: 1.20, 7.00, P=0.018; rs2230201: OR=2.41, 95% CIs: 1.03, 5.64, P=0.042). The linkage analysis showed relatively high linkage disequilibrium among these SNPs. In addition, no significant correlation was found between C4 SNPs, or C5 SNPs, and the development of ABMR. Our study firstly identified the two SNPs (rs10411506 and rs2230205) in C3 gene were statistically correlated with ABMR in kidney transplantation. These findings may have implications for the diagnosis and prevention of ABMR.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5706894 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Impact of complement component 3/4/5 single nucleotide polymorphisms on renal transplant recipients with antibody-mediated rejection.

Wang Zijie Z Yang Haiwei H Guo Miao M Han Zhijian Z Tao Jun J Chen Hao H Ge Yuqiu Y Wang Ke K Tan Ruoyun R Wei Ji-Fu JF Gu Min M

Oncotarget 20171010 55

Antibody-mediated rejection (ABMR) is an important risk of allograft dysfunction in kidney transplantation. The complement system is considered to be associated with the generation of alloreative antibodies and donor-specific antibodies. However, the association of complement single nucleotide polymorphisms (SNPs) with ABMR still remained unclear. Blood samples of 199 renal transplant recipients containing 68 with ABMR and 131 with stable graft function were collected, and analyzed by next-gener ...[more]

PMID: 29212248

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Project description:BackgroundNowadays, renal allograft survival is confined by the development of allograft fibrosis. Previous studies have reported interleukin-33 (IL-33) upregulated significantly in patients with chronic renal allograft dysfunction, and it could induce renal tubular epithelial to mesenchymal transition (EMT), which eventually contributed to renal allograft fibrosis. Our study intended to detect the underlying association between single nucleotide polymorphisms (SNPs) of IL-33 gene and renal allograft fibrosis in kidney transplant recipients.MethodsWe collected blood samples from 200 renal transplant recipients for the identification of SNPs and transplanted kidney tissue samples for identifying differentially expressed genes (DEGs). Intersection of SNP-related genes and DEGs was conducted for further analysis. Relationships between these SNPs and renal allograft fibrosis were evaluated by the inheritance models. Immunohistochemical (IHC) staining and western blotting (WB) were used to detect the expression of IL-33 and the markers of EMT in human kidney tissues obtained from control and chronic renal allograft dysfunction (CAD) patients. In vitro, we detected the progressions of EMT-related markers and the levels of MAPK signaling pathway mediators after transfecting IL-33 mutant plasmids in HK2 cells.ResultsThree intersected genes including IL-33 genes were significantly expressed. IL-33 expression was validated in kidney tissues by IHC and WB. Thirty-nine IL-33-related SNPs were identified in targeted sequencing, in which 26 tagger SNPs were found by linkage disequilibrium analysis for further analysis. General linear models indicated sirolimus administration significantly influenced renal allograft fibrosis (P < 0.05), adjustment of which was conducted in the following analysis. By multiple inheritance model analyses, SNP rs10975519 of IL-33 gene was found closely related to renal allograft fibrosis (P < 0.005). Furthermore, HK2 cells transfected with mutated plasmid of rs10975519 showed stronger mobility and migration ability. Moreover, IL-33 mutant plasmids could promote the IL-33-induced EMT through the sustained activation of p38 MAPK signaling pathway in HK2 cells.ConclusionIn our study, rs10975519 on the IL-33 gene was found to be statistically associated with the development of renal allograft fibrosis in kidney transplant recipients. This process may be related to the IL-33-induced EMT and sustained activation of p38 MAPK signaling pathway.

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Impact of complement component 3/4/5 single nucleotide polymorphisms on renal transplant recipients with antibody-mediated rejection.

Publications

Impact of complement component 3/4/5 single nucleotide polymorphisms on renal transplant recipients with antibody-mediated rejection.

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