Effect of Genetic and Nongenetic Factors on the Clinical Response to Mineralocorticoid Receptor Antagonist Therapy in Egyptians with Heart Failure

Sarhan, Neven; Shahin, Mohamed H.; Rouby, Nihal M. El; Elwakeel, Lamia; Solayman, Mohamed Hassan M.; Langaee, Taimour; Khorshid, Hazem; Schaalan, Mona F.; Sabri, Nagwa A.; Cavallari, Larisa H.

doi:10.1111/cts.12702

Cited by 10 publications

(12 citation statements)

References 38 publications

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“…Our finding on the frequency of genetic polymorphisms in Egyptian pancreatic and NSCL cancer patients reported herein does not match that of Africans, Latin Americans, Asians, or Europeans ( Table S3 ). This supports previous reported data related to Egyptians and non-Egyptians ( 40 – 43 ). Indeed, previous studies also revealed such a discrepancy among Asian and non-Asian ethnicity regarding the TNF-308 G/A polymorphisms in hepatocellular carcinoma risk ( 12 ).…”

Section: Discussionsupporting

confidence: 93%

Impact of TNF-α Gene Polymorphisms on Pancreatic and Non-Small Cell Lung Cancer-Induced Cachexia in Adult Egyptian Patients: A Focus on Pathogenic Trajectories

et al. 2021

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BackgroundCachexia is a frequent syndrome in pancreatic and non-small cell lung (NSCL) cancer patients. The storm of cancer-induced inflammatory cytokines, in particular TNF-α, is a crucial pathogenic mechanism. Among the molecular alterations accused of cancer-induced cachexia, TNF-α 308 G/A (rs1800629) and −1031T/C (rs1799964) are single-nucleotide polymorphisms (SNPs) within the gene encoding this pro-inflammatory cytokine. Recent studies have demonstrated the crucial role of non-coding microRNAs (miRNAs) in pathogenesis of different diseases including cachexia. Moreover, the mechanistic cytokine signaling pathway of miR-155, as a TNF-α regulator, supports the involvement of SOCS1, TAB2, and Foxp3, which are direct targets of TNF-α gene.AimA case–control study (NCT04131478) was conducted primarily to determine the incidence of TNF-α 308 G/A (rs1800629) and −1031T/C (rs1799964) gene polymorphisms in adult Egyptian patients with local/advanced or metastatic pancreatic or NSCL cancer and investigate both as cachexia risk factors. The association of gene polymorphism with cachexia severity and the expression of miR-155 in cachectic patients were analyzed. A mechanistic investigation of the cytokine signaling pathway, involving SOCS1, TAB2, and Foxp3, was also performed.ResultsIn both pancreatic and NSCL cancer cohorts, the mutant TNF-α variant of 308 G/A was positively associated with cachexia; on the contrary, that of 1031T/C was negatively associated with cachexia in the NSCL cancer patients. MiR-155 was higher in cachexia and in alignment with its severity in the cachectic group as compared with the non-cachectic group in both the pancreatic and NSCL cancer patients. Though TAB2 did not change to any significant extent in cachectic patients, the levels of SOCS1 and Foxp3 were significantly lower in the cachectic group as compared with the non-cachectic group.ConclusionCarriers of the A allele 308 G/A gene and high miR-155 are at greater risk of cachexia in both the pancreatic and NSCL cancer patients; however, the mutant variant of 1031T/C gene is protective against cachexia in the NSCL cancer patients. Finally, high levels of miR-155 in the cachectic group lead to negative feedback inhibition of both SOCS1 and Foxp3 in both the pancreatic and NSCL cancer patients.

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Section: Discussionsupporting

confidence: 93%

Impact of TNF-α Gene Polymorphisms on Pancreatic and Non-Small Cell Lung Cancer-Induced Cachexia in Adult Egyptian Patients: A Focus on Pathogenic Trajectories

et al. 2021

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“…Our finding on the frequency of genetic polymorphisms in Egyptian pancreatic and NSCL cancer patients reported herein does not match that of Africans, Latin Americans, Asians, or Europeans (Table S3). This supports previous reported data related to Egyptians and non-Egyptians (40)(41)(42)(43). Indeed, previous studies also revealed such a discrepancy among Asian and non-Asian ethnicity regarding the TNF-308 G/A polymorphisms in hepatocellular carcinoma risk (12).…”

Section: Discussionsupporting

confidence: 91%

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“…ARA utilization may be improved if clinicians could preemptively identify patients who are likely to benefit from ARA treatment, while sparing those not expected to benefit from ARA‐associated risks. With the recognition of HF as a phenotypically heterogeneous disease and with known variations in drug response, a personalized approach is a potential strategy to optimize spironolactone use and ultimately improve patient outcomes 16–19 …”

Section: Introductionmentioning

confidence: 99%

“…In vitro, the SNP rs1799998 (c.‐344T>C) results in a higher binding affinity of CYP11B2 to the inhibitory steroidogenic transcription factor 1 (SF‐1), 28 contributing to a decreased production of aldosterone 29 . Evidence suggests that these SNPs may be associated with spironolactone effectiveness in heart failure with reduced ejection fraction (HFrEF) patients 18,19 ; however, they have not been studied in an HFpEF population.…”

Section: Introductionmentioning

confidence: 99%

NR3C2 genotype is associated with response to spironolactone in diastolic heart failure patients from the Aldo‐DHF trial

et al. 2021

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Study Objective This study aimed to determine if variants in NR3C2, which codes the target protein of spironolactone, or CYP11B2, which is involved in aldosterone synthesis, were associated with spironolactone response, focused on the primary end point of diastolic function (E/e′), in Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo‐DHF) participants. Design Post‐hoc genetic analysis. Data Source Data and samples were derived from the multi‐center, randomized, double‐blind, placebo‐controlled Aldo‐DHF trial. Patients Aldo‐DHF participants treated with spironolactone (n = 184) or placebo (n = 178) were included. Intervention Participants were genotyped for NR3C2 rs5522, NR3C2 rs2070951 and CYP11B2 rs1799998 via pyrosequencing. Measurements In the placebo and spironolactone arms, separate multivariable linear regression analyses were performed for change in E/e′ with each single nucleotide polymorphism (SNP), adjusted for age, sex, and baseline E/e′. To discern potential mechanisms of a genotype effect, associated SNPs were further examined for their association with change in blood pressure, circulating procollagen type III N‐terminal peptide (PIIINP), and left atrial area. Main Results Carriers of the rs5522 G allele in the placebo arm had a greater increase in E/e′ over the 12‐month course of the trial compared to noncarriers (β = 1.10; 95% confidence interval [CI]: 0.05–2.16; p = 0.04). No corresponding E/e′ worsening by rs5522 genotype was observed in the spironolactone arm. None of the other genotypes were associated with change in E/e′. Compared to noncarriers, rs5522 G carriers also had a greater increase in left atrial area with placebo (β = 0.83; 95% CI: 0.17–1.48; p = 0.01) and a greater reduction in diastolic blood pressure with spironolactone (β = −3.56; 95% CI: −6.73 to −0.39; p = 0.03). Serum PIIINP levels were similar across rs5522 genotypes. Conclusions Our results suggest that spironolactone attenuates progression of diastolic dysfunction associated with the NR3C2 rs5522 G allele. Validation of our findings is needed.

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Effect of Genetic and Nongenetic Factors on the Clinical Response to Mineralocorticoid Receptor Antagonist Therapy in Egyptians with Heart Failure

Cited by 10 publications

References 38 publications

Impact of TNF-α Gene Polymorphisms on Pancreatic and Non-Small Cell Lung Cancer-Induced Cachexia in Adult Egyptian Patients: A Focus on Pathogenic Trajectories

Impact of TNF-α Gene Polymorphisms on Pancreatic and Non-Small Cell Lung Cancer-Induced Cachexia in Adult Egyptian Patients: A Focus on Pathogenic Trajectories

Table_1.docx

NR3C2 genotype is associated with response to spironolactone in diastolic heart failure patients from the Aldo‐DHF trial

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