Functional nonsynonymous single nucleotide polymorphisms from the TGF-β protein interaction network

2007 ◽  
Vol 29 (2) ◽  
pp. 109-117 ◽  
Author(s):  
Sevtap Savas ◽  
Ian W. Taylor ◽  
Jeff L. Wrana ◽  
Hilmi Ozcelik
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Protein Interactions ◽  
Transforming Growth Factor ◽  
Conservation Status ◽  
Genetic Variations ◽  
Phosphorylation Sites ◽  
Nucleotide Polymorphisms ◽  
Protein Protein Interactions ◽  
Single Nucleotide ◽  
Putative Protein

Protein complexes mediated by protein-protein interactions are essential for many cellular functions. Transforming growth factor (TGF)-β signaling involves a cascade of protein-protein interactions and malfunctioning of this pathway has been implicated in human diseases. Using an in silico approach, we analyzed the naturally occurring human genetic variations from the proteins involved in the TGF-β signaling (10 TGF-β proteins and 242 other proteins interacting with them) to identify the ones that have potential biological consequences. All proteins were searched in the dbSNP database for the presence of nonsynonymous single nucleotide polymorphisms (nsSNPs). A total of 118 validated nsSNPs from 63 proteins were retrieved and analyzed in terms of 1) evolutionary conservation status, 2) being located in a functional protein domain or motif, and 3) altering putative protein motif or phosphorylation sites. Our results indicated the presence of 31 nsSNPs that occurred at evolutionarily conserved residues, 37 nsSNPs were located in protein domains, motifs, or repeats, and 46 nsSNPs were predicted to either create or abolish putative protein motifs or phosphorylation sites. We undertook this study to analyze the human genetic variations that can affect the protein function and the TGF-β signaling. The nsSNPs reported in here can be characterized by experimental approaches to elucidate their exact biological roles and whether they are related to human disease.

Abstract 15318: Association of Single-Nucleotide Polymorphisms with Left Atrial Scar in Patients with Atrial Fibrillation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sanghamitra Mohanty ◽  
Amelia W Hall ◽  
Prasant Mohanty ◽  
Chintan Trivedi ◽  
Luigi Di Biase ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Left Atrial ◽  
Transforming Growth Factor ◽  
Univariate Analysis ◽  
Scar Formation ◽  
Taqman Assay ◽  
Inverse Association ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Caveolin 1

Introduction: Earlier studies have demonstrated that some AF patients develop spontaneous atrial scarring that leads to genesis and perpetuation of the arrhythmia. However, it is still unclear why it happens in some and not in others. Therefore, we hypothesized that the atrial scar phenotype is associated with certain specific genetic variants and examined the relationship between AF-related single-nucleotide polymorphisms (SNP) and left atrial scar. Methods: Four hundred AF patients (67% male, 62±12 year, left atrial size 45.3±7 mm, 64% non-paroxysmal) undergoing catheter ablation were prospectively enrolled at our center. DNA extraction and genotyping for 16 AF-associated SNPS identified by GWAS study were performed from the collected blood samples using Qiagen QiaAMP 96 well blood kit and TaqMan assay respectively. Three hundred seventy-two DNA samples were available for genotyping. The Hardy-Weinberg equilibrium was assessed using Chi-square analyses. Multivariable logistic model was utilized to identify predictors of LA scar after adjusting for age, gender, LA size, hypertension and diabetes mellitus and odds ratio (OR) and 95% confidence intervals were computed. Results: Of all 16 SNPs, rs3807989 showed a strong inverse association with LA scar at univariate analysis (0.54 [0.348-0.89] p= 0.014) in the overall population. After adjustment for covariates, the association became highly significant indicating a 50% reduction in scar risk (OR 0.50 (0.30-0.83) p=0.007). When stratified by type of AF, rs3807989 genotype predicted a substantially stronger 69% risk-reduction in the non-PAF population (OR 0.31 (0.15-0.62) p=0.0009). Conclusion: The SNP, rs3807989 on chromosome 7p31, was demonstrated to be associated with reduced risk of left atrial scar formation in AF patients. This genetic variant is located in close proximity to the caveolin-1 gene which is known to have an anti-fibrotic role by inhibiting transforming growth factor-β1, a key mediator in the fibrosis process. Therefore, it can be postulated that by some unknown mechanism the candidate chromosomal variant potentially upregulates caveolin-1 function resulting in attenuation of fibrosis and scar formation.

scholarly journals IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2184
Author(s):  
Doreen M. Floss ◽  
Jens M. Moll ◽  
Jürgen Scheller
Keyword(s):  
Protein Interactions ◽  
Intracellular Signaling ◽  
Signaling Cascades ◽  
Structural Knowledge ◽  
Nucleotide Polymorphisms ◽  
Protein Protein Interactions ◽  
Single Nucleotide ◽  
Mediated Effects ◽  
Protein Functions ◽  
Close Relatives

Cytokines of the IL-12 family show structural similarities but have distinct functions in the immune system. Prominent members of this cytokine family are the pro-inflammatory cytokines IL-12 and IL-23. These two cytokines share cytokine subunits and receptor chains but have different functions in autoimmune diseases, cancer and infections. Accordingly, structural knowledge about receptor complex formation is essential for the development of new therapeutic strategies preventing and/or inhibiting cytokine:receptor interaction. In addition, intracellular signaling cascades can be targeted to inhibit cytokine-mediated effects. Single nucleotide polymorphisms can lead to alteration in the amino acid sequence and thereby influencing protein functions or protein–protein interactions. To understand the biology of IL-12 and IL-23 and to establish efficient targeting strategies structural knowledge about cytokines and respective receptors is crucial. A highly efficient therapy might be a combination of different drugs targeting extracellular cytokine:receptor assembly and intracellular signaling pathways.

scholarly journals Single Nucleotide Polymorphisms in PEMT and MTHFR Genes are Associated with Omega 3 and 6 Fatty Acid Levels in the Red Blood Cells of Children with Obesity

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2600 ◽  
Author(s):  
Vlad Serafim ◽  
Adela Chirita-Emandi ◽  
Nicoleta Andreescu ◽  
Diana-Andreea Tiugan ◽  
Paul Tutac ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Methylenetetrahydrofolate Reductase ◽  
Genetic Variations ◽  
Nucleotide Polymorphisms ◽  
Dietary Intakes ◽  
Omega 3 ◽  
Single Nucleotide ◽  
Pufa Composition

Polyunsaturated fatty acids (PUFAs) play important roles in health and disease. PUFA levels are influenced by nutrition and genetic factors. The relationship between PUFA composition in red blood cells (RBCs) and genetic variations involved in PUFA metabolism has not been investigated in children with obesity. This study evaluated the association between several genetic variations and PUFA levels in RBCs in children with obesity. One hundred ninety-six children with obesity (101 females, 95 males) were evaluated using anthropometric measurements, dietary intakes, plasma and RBC PUFA quantification, blood biochemistry, and 55 single nucleotide polymorphisms within 14 genes. phosphatidylethanolamine N-methyltransferase (PEMT) rs1109859 and methylenetetrahydrofolate reductase gene (MTHFR) rs4846052 genotypes were associated with PUFA levels in RBCs. PUFA intake did not influence the RBC eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels. Higher RBC DHA and EPA levels were observed for PEMT rs1109859 GG and GA genotypes versus the AA genotype. Higher levels of RBC DHA, EPA, arachidonic acid (ARA), and linoleic acid (LA) and were observed for MTHFR rs4846052 TT genotype versus TC and CC genotypes. Genetic variations in PEMT rs1109859 and MTHFR rs4846052 were associated with different PUFA levels in RBC membranes and are estimators for PUFA species in RBCs. Further research is needed to establish whether these genotype-specific alterations are specific to overweight children.

Single Nucleotide Polymorphisms in Promoter Region of Tgf-β 1 Gene Distinguish African Americans from Caucasians: A Possible Genetic Basis for Racial Differences in Epidemiology of Hypertension and End Stage Renal Disease.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 717-717
Author(s):  
Ruchuang Ding ◽  
Baogui Li ◽  
Mohini Gulhati ◽  
Yun Zhang ◽  
Geraldine Helseth ◽  
...  
Keyword(s):  
African Americans ◽  
Single Nucleotide Polymorphisms ◽  
Renal Disease ◽  
Racial Differences ◽  
End Stage Renal Disease ◽  
Transforming Growth Factor ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Stage Renal Disease ◽  
End Stage

P135 Transforming growth factor-beta 1 (TGF-β 1 ) excess is a candidate risk factor for hypertension and hypertensive complications including LVH, vascular remodeling and end stage renal disease (ESRD). We reported that hyperexpression of TGF-β 1 protein is more prevalent in African Americans (AA) compared with Caucasians (C), particularly AA with hypertension and/or ESRD. Single nucleotide polymorphisms (SNPs) have been reported in the TGF-β 1 gene, and there is evidence for heritable control of TGF-β 1 protein levels. In this study we tested the hypothesis that TGF-β 1 SNPs distinguish AA from C. We determined the frequencies of all 6 known biallelic TGF-β 1 DNA polymorphisms in 793 subjects (AA=342 [normal: 77, hypertension: 66, ESRD: 199], C=451 [normal: 142, hypertension: 81, ESRD: 228]). SNPs as well as cis/trans combination of alleles (haplotypes) were identified by designing and using allele specific primers in an amplification refractory mutation system PCR . Our data demonstrate that SNPs at -800bp and -509bp and the haplotype frequencies (GC, GT, AC, AT) are significantly different between AA and C (Table). In conclusion, genetically determined differences in TGF-β 1 production may explain TGF-β 1 excess in AA as well as provide a molecular basis for the excess burden of hypertension and hypertensive complications in AA.

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