Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA105805 | ENA |
REPOSITORIES: ENA
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Project description:We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome wide association study was performed using 500.568 single nucleotide polymorphisms (SNPs) in two series of homogeneously treated MM patients: one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162 and rs17110453) mapped within the Cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (p=1.07x10-6, p=4.231x10-6, p=6.22x10-6 and p=2.15x10-5, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value=0.02). Genotyping results displayed an overrepresentation of the T allele in cases as compared with controls (48% vs. 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (Odds ratio 12.75, 95% confidence interval 3.7 to 43.5).
2008-09-25 | GSE11948 | GEO
Project description:We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome wide association study was performed using 500.568 single nucleotide polymorphisms (SNPs) in two series of homogeneously treated MM patients: one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162 and rs17110453) mapped within the Cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (p=1.07x10-6, p=4.231x10-6, p=6.22x10-6 and p=2.15x10-5, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value=0.02). Genotyping results displayed an overrepresentation of the T allele in cases as compared with controls (48% vs. 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (Odds ratio 12.75, 95% confidence interval 3.7 to 43.5). We studied 22 cases (MM with ONJ) and 65 controls (MM without ONJ), matched for age, gender and ethnicity (note: all of the cases and controls are Caucasian). All patients were enrolled in the GEM-00 protocol, which consists on polychemotherapy and autologous transplantation. All received BPs therapy, either Pamidronate (16 cases, 57 controls) or Zoledronic Acid (6 cases, 8 controls) planned for 2 years (median 22 months, range 9-24 months). Clinical characteristics were similar between controls and cases. Study protocols were approved by the ethics committee and written informed consent was obtained from all participants. Each patient was genotyped using the Affymetrix GeneChip Mapping 500K set of microarrays (Affymetrix, Santa Clara, CA) according to the manufacturer’s recommendations. Genotypes were determined using the BRLMM algorithm with cases and controls undergoing joint cluster analysis, after ensuring a robust association test through quality filtering tests. Based on stringent quality control criteria a total of 339.972 SNPs were selected for subsequent analyses. Criteria for exclusion were: 1) call rate<90%, 2) minor allele frequency <5% and 3) deviations from Hardy-Weinberg equilibrium with a p<0.00001. Sexual chromosomes were excluded for analysis. To test for allelic associations between SNPs and ONJ, we constructed 2x2 contingency tables and compared using the two-sided Fisher’s exact or Chisquare tests through SPSS software (SPSS 14.0, Inc. Chicago, IL, USA). P-values were corrected (Pc) using the Bonferroni correction. The strength of association was estimated by the odds ratio (OR), and their 95% confidence intervals (CI) were calculated by Cornfield methods. Linkage disequilibrium between SNPs was analyzed using the Arlequin Software (http://anthro.unige.ch/arlequin).
2008-09-25 | E-GEOD-11948 | biostudies-arrayexpress
Project description:BACKGROUND:; Osteonecrosis of the jaw (ONJ) has been reported in patients with a history of aminobisphosphonate use. METHODS:; In order to define ONJ and gain insights into its pathophysiology, clinical, radiographic, biochemical, and microarray profiling studies were conducted in 11 patients with multiple myeloma (MM) and ONJ. RESULTS:; Eleven patients between the ages of 57 and 81 yrs were treated with either pamidronate (n=3), zoledronate (n=4), or both agents sequentially (n=4) for a mean of 38.7 months. Radiographic studies demonstrated radiolucency and sclerosis on plain films. Functional imaging with positron emission tomography (PET) demonstrated a visual increase in glucose metabolism and mineralization at sites of ONJ, using fluorodeoxyglucose (FDG) and sodium fluoride (NaF), respectively. Quantitative regional analysis confirmed an increased standardized uptake value (SUVmax) in areas of ONJ. The target to background ratio of SUVmax was significantly greater for NaF-PET than FDG-PET scans, suggesting that NaF-PET may provide superior image quality for identifying ONJ. Transcriptional profiling of peripheral blood mononuclear cells (PBMCs) using the Affymetrix U133Plus 2.0 gene chip in all 11 MM patients compared with 10 age matched MM controls and 5 healthy volunteers demonstrated that genes involved in osteoblast and osteoclast signaling cascades were significantly downregulated in patients with ONJ, as were proteins confirmed by ELISA. CONCLUSIONS:; ONJ is seen in patients with a history of aminobisphosphonate use. Functional imaging with NaF PET confirms the diagnosis of ONJ. Gene and protein studies are consistent with altered bone remodeling, evidenced by suppression of both bone resorption and formation. Experiment Overall Design: Transcriptional profiling of peripheral blood mononuclear cells (PBMCs) was performed using the Affymetrix U133Plus 2.0 Gene Chip (Affymetrix, Santa Clara, CA, USA) in 11 patients with osteonecrosis of the jaw and multiple myeloma and compared with the profiles of the 10 myeloma patients on bisphosphonate therapy without osteonecrosis of the jaw and 5 healthy volunteers.
2008-06-15 | E-GEOD-7116 | biostudies-arrayexpress
Project description:Clinical, radiographic, and biomarker characterization of multiple myeloma patients with osteonecrosis of the jaw.
| PRJNA98425 | ENA
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:To study pathways associated with ferroptosis sensitivity
2022-06-01 | GSE173905 | GEO
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain.A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development.Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.
| S-EPMC4686780 | biostudies-literature
Project description:PurposeWe investigated the evidence of recent positive selection in the human phototransduction system at single nucleotide polymorphism (SNP) and gene level.MethodsSNP genotyping data from the International HapMap Project for European, Eastern Asian, and African populations was used to discover differences in haplotype length and allele frequency between these populations. Numeric selection metrics were computed for each SNP and aggregated into gene-level metrics to measure evidence of recent positive selection. The level of recent positive selection in phototransduction genes was evaluated and compared to a set of genes shown previously to be under recent selection, and a set of highly conserved genes as positive and negative controls, respectively.ResultsSix of 20 phototransduction genes evaluated had gene-level selection metrics above the 90th percentile: RGS9, GNB1, RHO, PDE6G, GNAT1, and SLC24A1. The selection signal across these genes was found to be of similar magnitude to the positive control genes and much greater than the negative control genes.ConclusionsThere is evidence for selective pressure in the genes involved in retinal phototransduction, and traces of this selective pressure can be demonstrated using SNP-level and gene-level metrics of allelic variation. We hypothesize that the selective pressure on these genes was related to their role in low light vision and retinal adaptation to ambient light changes. Uncovering the underlying genetics of evolutionary adaptations in phototransduction not only allows greater understanding of vision and visual diseases, but also the development of patient-specific diagnostic and intervention strategies.
| S-EPMC3743458 | biostudies-literature