Genome-wide search for higher order epistasis as modifiers of treatment effects on bone mineral density in childhood cancer survivors
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001002645 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Background: Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA. Methods: Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2,138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability. Results: For EAA-Horvath, a genome-wide significant association was mapped to SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge. Conclusions: We identified novel genetic variants in SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate identification of survivors at higher risk in developing accelerated aging, and potentially inform drug targets for future intervention strategies among vulnerable survivors.
2022-03-09 | GSE197675 | GEO
Project description:Background: Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA. Methods: Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2,138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability. Results: For EAA-Horvath, a genome-wide significant association was mapped to SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge. Conclusions: We identified novel genetic variants in SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate identification of survivors at higher risk in developing accelerated aging, and potentially inform drug targets for future intervention strategies among vulnerable survivors.
2022-03-09 | GSE197674 | GEO
Project description:Background: Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA. Methods: Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2,138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability. Results: For EAA-Horvath, a genome-wide significant association was mapped to SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge. Conclusions: We identified novel genetic variants in SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate identification of survivors at higher risk in developing accelerated aging, and potentially inform drug targets for future intervention strategies among vulnerable survivors.
2022-03-09 | GSE197676 | GEO
Project description:Ovarian cancer is the seventh-most common cancer and the eight-most common cause of death from cancer in woman. Some women with ovarian cancer survive a long time (> 10yrs). We want to know if there’s a genetic difference between these long survivors and the broader population of interest. Affymetrix SNP arrays were performed according to the manufacturer's directions on sample DNA.
2015-10-07 | GSE73822 | GEO
Project description:Millions of sepsis survivors annually face long-term neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered in sepsis, and their use affects neuropsychiatric outcomes, but the mechanisms are unknown. We used the cecal ligation and puncture method to induce acute infection in mice and test the hypothesis that corticosteroid treatment during illness has long-term effects on hippocampal function. Functional phenotyping and hippocampal RNA-sequencing were performed in the same survivor mice to identify underlying mechanisms of behavioral and neuroendocrine outcomes. Long-term CLP survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal (HPA) axis activity, and persistent systemic and neuro-inflammation. The relationship between gene expression and behavior suggested a protective role for inflammation and oxidative metabolism after CLP. Corticosterone treatment during illness had distinct effects on hippocampal function in survivors, including object memory impairment. The long-term behavioral effects of corticosterone treatment were associated with persistent downregulation of activity-dependent gene expression in the hippocampus. The results suggest that corticosteroid treatment for sepsis influences hippocampal function in survivors via long-lasting changes to basal hippocampal activity. Neural activity, inflammation, and oxidative metabolism should be explored as future treatment targets to modify neuropsychiatric outcomes in sepsis survivors.
2023-07-31 | GSE225868 | GEO
Project description:Cancer-related fatigue is one of the most frequent complaints among breast cancer survivors, with a major negative impact on general life. However, the etiology behind this syndrome is still unraveled. Gene expression analysis was performed on whole blood samples from breast cancer survivors classified as either fatigued or non-fatigued at two consecutive time points. The analysis identified several gene sets concerning plasma and B cell pathways as different between the fatigue and non-fatigue groups, suggesting that a deregulation in these pathways might underlie the fatigue syndrome. The fatigue group also showed a higher mean level of leucocytes, lymphocytes and neutrophiles compared with the non-fatigue group, thus further implicating the immune system in the biology behind the fatigue syndrome. Keywords: Blood RNA and late side effects Breast cancer survivors treated with adjuvant radiotherapy at The Norwegian Radium Hospital between 1998 and 2002 were invited to participate in a study assessing late treatment effects in breast cancer survivors. In the present study, gene expression analysis was performed on whole blood samples from breast cancer survivors with and without persistent fatigue, to look for different expression patterns that might shed light on the biology behind cancer-related fatigue.
2009-07-01 | E-GEOD-14786 | biostudies-arrayexpress
Project description:We aimed to characterize the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis. Although health outcomes continued to improve, SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations.
2023-09-06 | GSE216357 | GEO
Project description:There is currently no reliable tool available to measure immune dysfunction in septic patients in the clinical setting. This proof-of-concept study assesses the potential of gene expression profiling of whole blood as a tool to monitor immune dysfunction in critically ill septic patients. Whole blood samples were collected daily for up to 5 days from patients admitted to the intensive care unit with sepsis. RNA isolated from whole blood samples was assayed on Illumina HT-12 gene expression microarrays consisting of 48,804 probes. Microarray analysis identified 3677 genes as differentially expressed across 5 days between septic patients and healthy controls. Of the 3677 genes, biological pathway analysis identified 86 genes significantly down-regulated in the sepsis patients were present in pathways relating to immune response. These 86 genes correspond to known immune pathways implicated in sepsis including lymphocyte depletion, reduced T lymphocyte activation and deficient antigen presentation. Furthermore, expression levels of these genes correlated with clinical severity, with a significantly greater degree of down-regulation found in non-survivors compared to survivors. The results show that whole blood gene-expression analysis can capture systemic immune dysfunctions in septic patients. Our study provides an experimental basis to support further study on the use of a gene expression based assay, to assess immunosuppression and guide immunotherapy in future clinical trials. Daily PAXgene samples for up to 5 days for sepsis survivors (n=26), sepsis nonsurvivors (n=9), and healthy controls (n=18).
2014-02-04 | E-GEOD-54514 | biostudies-arrayexpress
Project description:In this study RNA-Seq was performed in anthracycline- exposed childhood cancer survivors who had cardiomyopathy (cases) matched to those without cardiomyopathy (controls) to understand the pathogenesis of anthrcaycline-related cardiomyopathy
2023-01-31 | GSE218276 | GEO
Project description:Clinical follow-up of Ebola virus disease (EVD) survivors revealed a persistence of clinical symptoms and higher risk of mortality. Long-term analyses of the immune and inflammatory profiles of EVD survivors are currently lacking. Here, we evaluate gene expression profiles in 26 Guinean Ebola virus disease survivors (EBOV_S) and 33 Healthy donnors (HD). We show a persistent increase of several biomarkers of inflammation, immune activation and gut tissue damage in EBOV_S compared to healthy donors living in the same area. Gene expression profiling in blood revealed a significant enrichment in genes associated with antiviral responses in EBOV_S.
2020-05-25 | GSE143549 | GEO