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An intronic polymorphism of NFATC1 gene shows a risk association with biopsy-proven acute rejection in renal transplant recipients.

ABSTRACT: Background:We aimed to explore the influence of single nucleotide polymorphisms (SNPs) in NFATC1 gene on the occurrence of biopsy-proven acute rejection (BPAR) in renal transplant recipients. Methods:Blood samples from 131 subjects with stable allograft function (STA) and 69 with BPAR episodes were collected and analyzed using target sequencing (TS) with an established panel. Odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated for logistic regression models adjusted for confounding factors. Pathological changes were extracted and the relationship with tagger SNPs was calculated. Moreover, the CCK-8 assay was performed to explore the proliferation of T lymphocytes, and PCR, Western blotting and enzyme-linked immunosorbent assay were applied to identify the effect of mutant on the activation of T cells. Results:High-quality readouts were obtained for 55 NFATC1 SNPs and 14 tagger SNPs were remained for further analysis. After adjusting for clinical confounding factors, the distribution of four NFATC1 SNPs, including rs2290154, rs2304738, rs754093 and rs754096, were statistically significant between STA and BPAR groups. Pathological association analysis indicated one SNP, rs2290154, was significantly related with the Banff score and renal tubulitis. Our in vitro study suggested that NFATC1 rs2290154 mutant could remarkably promote the T cell proliferation, increase the transcription of NFATC1 mRNA and expression of NFATC1 protein, as well as the interleukin-2 (IL-2) secretion. Conclusions:We reported the crucial association of NFATC1 gene with the occurrence of acute rejection (AR) episodes. Moreover, in vitro NFATC1 rs2290154 was significantly involved in the T lymphocytes activation and proliferation through increasing the translation of NFATC1 mRNA and expression of NFATC1 protein, along with the secretion of IL-2.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7154465 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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An intronic polymorphism of <i>NFATC1</i> gene shows a risk association with biopsy-proven acute rejection in renal transplant recipients.

Wang Zijie Z Zhang Hengcheng H Yang Haiwei H Zheng Ming M Guo Miao M Chen Hao H Sun Li L Han Zhijian Z Tao Jun J Ju Xiaobing X Tan Ruoyun R Wei Ji-Fu JF Gu Min M

Annals of translational medicine 20200301 5

<h4>Background</h4>We aimed to explore the influence of single nucleotide polymorphisms (SNPs) in <i>NFATC1</i> gene on the occurrence of biopsy-proven acute rejection (BPAR) in renal transplant recipients.<h4>Methods</h4>Blood samples from 131 subjects with stable allograft function (STA) and 69 with BPAR episodes were collected and analyzed using target sequencing (TS) with an established panel. Odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated for logistic regression mod ...[more]

PMID: 32309358

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Project description:Background and objectivesThe current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes.Design, setting, participants, & measurementsUsing data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models.ResultsOf the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P<0.01), late rejections (occurring >6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94).ConclusionsHLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

Dataset Information

An intronic polymorphism of NFATC1 gene shows a risk association with biopsy-proven acute rejection in renal transplant recipients.

Publications

An intronic polymorphism of <i>NFATC1</i> gene shows a risk association with biopsy-proven acute rejection in renal transplant recipients.

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