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Caveolin-1 rs4730751 single-nucleotide polymorphism may not influence kidney transplant allograft survival.

ABSTRACT: Caveolin-1 is a protein (encoded by the CAV1 gene) supposedly harboring a protective effect against fibrosis. CAV1 rs4730751 single nucleotide polymorphism (SNP) AA genotype was initially associated with lower graft survival compared to non-AA. However, subsequent studies could not find the same effect. CAV1 rs4730751 SNP was investigated on 918 kidney donors. Multivariate Cox-model analyses were performed to evaluate risk factors for graft loss. Longitudinal changes on long-term estimated glomerular filtration rate (eGFRs) were evaluated with a linear mixed model. Histopathological findings from protocolled biopsies after 3 months post transplantation were also analyzed. Donor CAV1 rs4730751 genotyping proportions were 7.1% for AA, 41.6% for AC and 51.3% for CC. The AA genotype, compared to non-AA, was not associated with lower graft survival censored or not for death (multivariate analysis: HR?=?1.23 [0.74-2.05] and HR?=?1.27 [0.84-1.92]). Linear mixed model on long-term eGFRs revealed also no significant difference according to the genotype, yet we observed a trend. AA genotype was also not associated with a higher degree of fibrosis index on protocolled kidney biopsies at 3 months. To conclude, donor CAV1 rs4730751 SNP may impact on kidney transplantation outcomes, but this study could not confirm this hypothesis.

SUBMITTER: Maanaoui M

PROVIDER: S-EPMC6820546 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Caveolin-1 rs4730751 single-nucleotide polymorphism may not influence kidney transplant allograft survival.

Maanaoui Mehdi M Lenain Rémi R Hamroun Aghilès A Van der Hauwaert Cynthia C Lopez Benjamin B Gibier Jean-Baptiste JB Frimat Marie M Savary Grégoire G Hennart Benjamin B Larrue Romain R Pottier Nicolas N Broly Franck F Provôt François F Hazzan Marc M Glowacki François F Cauffiez Christelle C

Scientific reports 20191029 1

Caveolin-1 is a protein (encoded by the CAV1 gene) supposedly harboring a protective effect against fibrosis. CAV1 rs4730751 single nucleotide polymorphism (SNP) AA genotype was initially associated with lower graft survival compared to non-AA. However, subsequent studies could not find the same effect. CAV1 rs4730751 SNP was investigated on 918 kidney donors. Multivariate Cox-model analyses were performed to evaluate risk factors for graft loss. Longitudinal changes on long-term estimated glome ...[more]

PMID: 31664124

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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.

Project description:BACKGROUND Interstitial fibrosis and tubular atrophy (IF/TA) have been recognized as crucial factors contributing to graft loss resulting from chronic renal allograft injuries. Recent studies have indicated a significant association between the progression of organ fibrosis and single nucleotide polymorphisms (SNPs) found on certain genes. Our research sought to understand these potential associations and detect the potential impact of SNPs on ubiquitin-related genes related to allograft fibrosis in kidney transplant recipients. MATERIAL AND METHODS There were 200 patients enrolled in this study, from which samples were extracted for total DNA. Targeted next-generation sequencing was used to detect SNPs on 9 genes (FBXL21, PIAS1/2, SUMO1/2/3/4, UBE2D1, and UBE2I). Minor allele frequency (MAF) and Hardy-Weinberg equilibrium (HWE) tests were used and followed by linkage disequilibrium analysis. General linear models (GLM) were used to identify significant confounding factors. Finally, multiple inheritance models and haplotype analyses were conducted to explore associations between SNPs and the degree of the severity of renal allograft fibrosis. RESULTS In total, 144 SNPs were identified in targeted sequencing. After filtering based on results from MAF and HWE tests, 15 tagger SNPs were selected for further analyses of associations. GLMs indicated that the administration of sirolimus significantly contributed to the degree of severity of allograft fibrosis (P=0.011). After adjusting for confounding factors and applying a Bonferroni correction, multiple inheritance model analyses indicated that the recessive model of rs644731 of the PIAS2 gene was significantly correlated with the occurrence of IF/TA (P=0.01). Furthermore, single-locus based analysis of rs644731 did not indicate that it had a positive influence on IF/TA in a degree-dependent manner. Finally, linkage disequilibrium analysis revealed 3 haplotypes all lacking significant correlation with respect to the IF/TA experimental cohort. CONCLUSIONS We are the first to reveal that mutations of rs644731 in the PIAS2 gene were significantly correlated with the progression of IF/TA in kidney transplant recipients.

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Caveolin-1 rs4730751 single-nucleotide polymorphism may not influence kidney transplant allograft survival.

Publications

Caveolin-1 rs4730751 single-nucleotide polymorphism may not influence kidney transplant allograft survival.

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