A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT

Martín-Antonio, Beatriz; Álvarez-Laderas, Isabel; Cardesa, Rocio; Márquez-Malaver, Francisco J.; Báez, Alicia; Carmona, María Teresa Padilla; Falantes, José; Suárez‐Lledó, María; Fernández‐Avilés, Francesc; Martı́nez, Carmen; Rovira, Montserrat; Espigado, Ildefonso; Urbano-Ispizúa, Álvaro

doi:10.1038/bmt.2011.253

Cited by 7 publications

(7 citation statements)

References 24 publications

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“…It has also been noted to have seven splice isoforms (Ensembl, GRCh38.p10), which in addition to tissue-specific enhancer and repressor can provide additional mechanisms for differential regulation of various downstream pathways. Consistent with our findings, three distinct TonEBP signals have been associated with various phenotypes, such as: (1) rs7193778 with uric acid and CRP, 33,34 rs33063 with pulse pressure, 21,35 and rs9980 with plasma osmolality, 35 which are all in strong LD with each other and rs244416 from our analysis (associated with IL-1b and DBP); (2) rs12599391 with age at menarche 36 and rs6499244 with allogeneic hematopoietic stem cell transplantation outcomes, 37 which are in LD with each other but not with any of our identified SNP's; and (3) rs17297207 with DN, 30 which is in LD with our monocyte count-associated SNP (rs118095741). Lastly, in an interesting human case of TonEBP haplo-insufficiency, disturbances in both innate and adaptive immunity leading to intestinal autoimmunity 38 were noted, again supporting our findings.…”

Section: Discussionsupporting

confidence: 88%

Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury

Choi

Lim

Salimi

et al. 2018

JASN

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Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury.

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Section: Discussionsupporting

confidence: 88%

Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury

Choi

Lim

Salimi

et al. 2018

JASN

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“…False-positive report probability (FPRP) was calculated to address the robustness of the findings for individual SNPs that were most significantly (P < 0.01) associated with risk for SCC in miners (20). Prior probability was assigned to different SNPs based on their predicted functional potential assessed by searching the Functional SNP Prediction module of SNPinfo Web Server (21) and their association with disease phenotypes and/or functional readouts in the published work by others (22)(23)(24)(25)(26)(27)(28). Associations with FPRP ≤ 0.15 are considered noteworthy.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau

Leng¹,

Picchi²,

Liu³

et al. 2013

Carcinogenesis

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Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2 × 10(-5)) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.

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“…The study showed that rs20551 in EP300 was associated with different expression in genes involved in innate immunity and the cell cycle. Patients with the AA gene variant had lower interleukin-2 production, higher expression of genes involved in innate immunity and the cell cycle, and lower expression of p53 [ 27 ]. However, none of the rs20551 genetic variants has been previously reported in association studies with lymphoma prognosis, including DLBCL.…”

Section: Discussionmentioning

confidence: 99%

EP300 single nucleotide polymorphism rs20551 correlates with prolonged overall survival in diffuse large B cell lymphoma patients treated with R-CHOP

et al. 2017

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BackgroundRituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is used as standard frontline regimen for diffuse large B-cell lymphoma (DLBCL). The landscape of somatic mutations in DLBCL revealed that inactivation of EP300 plays an important role in lymphomagenesis. A common EP300 single nucleotide polymorphism (SNP) rs20551 results in the substitution of valine for isoleucine at codon 997 close to the Bromodomain. However, the association between SNP rs20551 and clinical prognosis in DLBCL patients treated with R-CHOP is unknown.MethodsIn this study we analyzed the EP300 SNP rs20551 and prognosis of 226 DLBCL patients who treated with R-CHOP or R-CHOP-like regimes from 2002 to 2013. Determination of the EP300 SNP rs20551 from genomic DNA was obtained by Sanger chain termination sequencing.ResultIn this study, the frequency of the A and G allele of the EP300 SNP rs20551 in 226 patients were 92.5 and 7.5%, respectively. We did not observe obvious correlation between patients’ disease features and the EP300 SNP rs20551. But the patients with genotype AA had a higher 5-year overall survival rate than those with genotype GA (77.0% vs. 64.7%, p = 0.045). Furthermore, multivariate Cox regression analysis showed that the GA genotype of EP300 SNP rs20551 was an independent poor prognostic factor for DLBCL patients treated with Rituximab-chemotherapy (p = 0.009, HR 2.956, 95% CI 1.315–6.645).ConclusionThis study suggests that EP300 SNP rs20551 might be a useful biomarker to predict the long-term outcome of R-CHOP in DLBCL patients.

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A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT

Cited by 7 publications

References 24 publications

Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury

Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury

Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau

EP300 single nucleotide polymorphism rs20551 correlates with prolonged overall survival in diffuse large B cell lymphoma patients treated with R-CHOP

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