NR3C1 Glucocorticoid Receptor Gene Polymorphisms Are Associated with Membranous and IgA Nephropathies

Pac, Michał; Krata, Natalia; Moszczuk, Barbara; Wyczalkowska-Tomasik, Aleksandra; Kaleta, Beata; Foroncewicz, Bartosz; Rudnicki, Witold R.; Pączek, Leszek; Mucha, Krzysztof

doi:10.3390/cells10113186

Cited by 7 publications

(7 citation statements)

References 42 publications

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“…Missense variants can also affect the structure of the protein by affecting the interaction, stability, and solubility of the protein. To evaluate the effect of a missense mutation on protein structure and function, the SNPs are mapped into the protein structure and validated through in silico [ 27 , 28 , 29 ]. The human gene of TNF-α , NR3C1 , and CYP3A5 contains a total of 1119 missense mutations in the NCBI dbSNP database.…”

Section: Resultsmentioning

confidence: 99%

Functional and Structural Impact of Deleterious Missense Single Nucleotide Polymorphisms in the NR3C1, CYP3A5, and TNF-α Genes: An In Silico Analysis

et al. 2022

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Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 (CYP3A5) play a key role in glucocorticoid resistance susceptibility in humans. Possible causative mutations could be used as therapeutic targets and diagnostic markers for glucocorticoid resistance. This study evaluated the missense SNPs of TNF-α, NR3C1, and CYP3A5 to predict their impact on amino acid changes, protein interaction, and functional stability. The protein sequence of dbSNP was obtained and used online in silico method to screen deleterious mutants for the in silico analysis. In the coding regions of TNF-α, NR3C1, and CYP3A5, 14 deleterious mutations were discovered. The protein functional and stability changes in the amino acid between native and mutant energy were identified by analyzing the changes in the hydrogen bonding of these mutants from native, which were all measured using Swiss PDB and PyMOL. F446S and R439K had the highest root-mean-square deviation (RMSD) values among the 14 deleterious mutants. Additionally, the conserved region of amino acid protein interaction was analyzed. This study could aid in the discovery of new detrimental mutations in TNF-α, NR3C1, and CYP3A5, as well as the development of long-term therapy for corticosteroid resistance in several inflammatory diseases. However, more research into the deleterious mutations of the TNF-α, NR3C1, and CYP3A5 genes is needed to determine their role in corticosteroid resistance.

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Section: Resultsmentioning

confidence: 99%

Functional and Structural Impact of Deleterious Missense Single Nucleotide Polymorphisms in the NR3C1, CYP3A5, and TNF-α Genes: An In Silico Analysis

et al. 2022

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“…Genomics can also be used for phenotype-genotype correlation in kidney biopsies of patients with glomerular diseases. In a small Polish study, it was suggested that NR3C1 single nucleotide polymorphisms are associated with the clinical manifestations of IgAN and score in Oxford classification (Pac et al 2021 ).…”

Section: Omicsmentioning

confidence: 99%

“…In a small Polish study, it was suggested that NR3C1 single nucleotide polymorphisms are associated with the clinical manifestations of IgAN and score in Oxford classification (Pac et al 2021).…”

Section: Genomicsmentioning

confidence: 99%

Omics are Getting Us Closer to Understanding IgA Nephropathy

Mucha

Pac

Pączek

2023

Arch. Immunol. Ther. Exp.

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During the last decade, thanks to omics technologies, new light has been shed on the pathogenesis of many diseases. Genomics, epigenomics, transcriptomics, and proteomics have helped to provide a better understanding of the origin and heterogeneity of several diseases. However, the risk factors for most autoimmune diseases remain unknown. The successes and pitfalls of omics have also been observed in nephrology, including immunoglobulin A nephropathy (IgAN), the most common form of glomerulonephritis and a principal cause of end-stage renal disease worldwide. Unfortunately, the immense progress in basic research has not yet been followed by the satisfactory development of a targeted treatment. Although, most omics studies describe changes in the immune system, there is still insufficient data to apply their results in the constantly evolving multi-hit pathogenesis model and thus do to provide a complete picture of the disease. Here, we describe recent findings regarding the pathophysiology of IgAN and link omics studies with immune system dysregulation. This review provides insights into specific IgAN markers, which may lead to the identification of potential targets for personalised treatment in the future.

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“…GCs can modulate inflammatory gene expression through several distinct mechanisms. Many single nucleotide polymorphisms (SNPs) of the NR3C1 gene have already been found to be directly or indirectly related (through GC action or GC resistance) to different mental disorders, especially the stress-related ones and autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and membranous nephropathy [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Recent bioinformatics studies have suggested that there are several polymorphisms in the NR3C1 gene, as well as in other genes such as TNF, CYP3A5 and FKBP5 , that have deleterious potential to cause GC resistance [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

NR3C1 rs6198 Variant May Be Involved in the Relationship of Graves’ Disease with Stressful Events

et al. 2023

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Although stressful events are known to trigger Graves’ disease (GD), the mechanisms involved in this process are not well understood. The NR3C1 gene, encoding for the glucocorticoid receptor (GR), presents single nucleotide polymorphisms (SNPs) that are associated with stress-related diseases. To investigate the relationship between NR3C1 SNPs, GD susceptibility, and clinical features, we studied 792 individuals, including 384 patients, among which 209 presented with Graves’ orbitopathy (GO), and 408 paired healthy controls. Stressful life events were evaluated in a subset of 59 patients and 66 controls using the IES-R self-report questionnaire. SNPs rs104893913, rs104893909, and rs104893911 appeared at low frequencies and presented similar profiles in patients and controls. However, variant forms of rs6198 were rarer in GD patients, suggesting a protective effect. Stressful events were more common in patients than controls, and were reported to have clearly occurred immediately before the onset of GD symptoms in 23 cases. However, no association was found between these events and rs6198 genotypes or GD/GO characteristics. We suggest that the NR3C1 rs6198 polymorphism may be an important protective factor against GD, but its relationship with stressful events needs further investigation.

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NR3C1 Glucocorticoid Receptor Gene Polymorphisms Are Associated with Membranous and IgA Nephropathies

Cited by 7 publications

References 42 publications

Functional and Structural Impact of Deleterious Missense Single Nucleotide Polymorphisms in the NR3C1, CYP3A5, and TNF-α Genes: An In Silico Analysis

Functional and Structural Impact of Deleterious Missense Single Nucleotide Polymorphisms in the NR3C1, CYP3A5, and TNF-α Genes: An In Silico Analysis

Omics are Getting Us Closer to Understanding IgA Nephropathy

NR3C1 rs6198 Variant May Be Involved in the Relationship of Graves’ Disease with Stressful Events

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