A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA739769 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:A Polygenic Score for Acute Vaso-Occlusive Pain in Pediatric Sickle Cell Disease
| PRJNA739768 | ENA
Project description:Vaso-occlusive episodes (VOE) or acute pain events, involving complex interactions between sickle erythrocytes and other blood cells, are a hallmark symptom of sickle cell disease (SCD). In this study, we analyzed changes in peripheral blood transcriptomes between steady state and VOE in individuals with SCD. We followed a cohort of 174 individuals with SCD with or without chronic pain and collected peripheral blood at clinic visits (steady state) and during hospitalizations (VOE). We performed RNA-Seq profiling of CD45+ leukocytes and CD71+ erythroid cells. Pathways linked to complement activation, coagulation, and IL6-JAK-STAT3 signaling were enriched at VOE in the CD45+ cells. Contrastingly, the CD71+ cells showed an enrichment of pathways related to the cell cycle such as mTORC1 signaling and the G2M checkpoint. Expression of four genes—FAM20A, IL1B, MS4A4A, and SERPINB2—were elevated during VOE compared to steady state in a majority of patients.
2025-11-26 | GSE291257 | GEO
Project description:Individuals with monogenic disorders can experience variable phenotypes that are influenced by genetic variation. To investigate this in sickle cell disease (SCD), we performed whole-genome sequencing (WGS) of 722 individuals with hemoglobin HbSS or HbSβ0-thalassemia from Baylor College of Medicine and from the St. Jude Children's Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study. We developed pipelines to identify genetic variants that modulate sickle hemoglobin polymerization in red blood cells and combined these with pain-associated variants to build a polygenic score (PGS) for acute vaso-occlusive pain (VOP). Overall, we interrogated the α-thalassemia deletion -α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the β-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10-14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10-13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.
| S-EPMC8341359 | biostudies-literature
Project description:Developing a translational polygenic score of biological sensitivity to context
| PRJNA633782 | ENA
Project description:We sequenced mRNA from the dorsal root ganglion (DRG) of transgenic mouse models of sickle cell disease (SCD) and their transgenic controls. Each genotype (strains) were divided into two age groups and each age groups were subjected to two treatment conditions (each simulating acute and chronic pain respectively). Each of these 8 groups had 6 male mice (except one group had 7 mice) resulting into a total of 49 samples. The goal of mRNA sequencing of these samples is to identify genetic signatures associated with transition from acute to chronic pain in SCD.
2017-04-05 | GSE86418 | GEO
Project description:This study builds the first translational model of biological sensitivity to context. In order to determine gene expression patterns that underlie environmental responsivity, we conduct RNA sequencing of ventral dentate gyrus in C57BL6/J mice exposed to two distinctly divergent contexts: environmental enrichment or chronic social defeat stress. Differential expression analysis revealed 18 genes that were commonly regulated in response to these contexts compared to control and were thus considered environmentally responsive irrespective of the valance of the environment. Using the human orthologs, we build a polygenic score of environmental responsivity (ER-ePRS). We then tested whether this ER-ePRS moderated the relationship between the quality of the prevailing environment and anxiety-like or depression problems in four culturally distinctive human cohorts. Results reveal that the molecular underpinnings responsible for environmental responsivity in mice predict a greater propensity to develop psychopathological symptoms in humans in a context and sex dependent manner.
2020-05-20 | GSE150812 | GEO
Project description:We performed genome-wide DNA methylation analysis of 850,000 CpG sites in women and men with chronic Low Back Pain (LBP) and pain free-controls. T cells were isolated (Discovery Cohort, n=32) and used to identify differentially methylated CpG sites, and gene ontologies and molecular pathways were identified.T cells were isolated (Discovery Cohort, n=32) and used to identify differentially methylated CpG sites, and gene ontologies and molecular pathways were identified. A polygenic DNA methylation score for LBP was generated in both women and men. Validation was performed in an independent cohort (Validation Cohort, n=63) of chronic LBP and healthy controls. Analysis with the Discovery Cohort revealed a total of 2,496 and 419 differentially methylated CpGs in women and men, respectively. The majority of these sites were hypo-methylated in women and enriched in genes with functions in the extracellular matrix, the immune system (i.e. cytokines) or in epigenetic processes. In men, we identified a unique chronic LBP DNA methylation signature characterized by significant enrichment for genes from the major histocompatibility complex. A sex-specific polygenic DNA methylation score was generated to evaluate the pain status of each individual and confirmed in The Validation Cohort using pyrosequencing.
2021-11-10 | GSE162350 | GEO
Project description:Sickle cell disease (SCD) is a genetic disorder caused by a mutation in the beta hemoglobin gene, resulting in red blood cell distortion, hemolysis, and severe pain episodes. Chronic pain in SCD is believed to be largely driven by neuroinflammation and central sensitization, yet the exact neurobiological mechanisms remain unclear. Hemorphins, opioid peptides derived from beta-hemoglobin, may bridge this gap by influencing opioid signaling pathways that could alleviate the pain experienced in SCD. In this study, we investigated the levels of hemorphins in both plasma and brain tissues of transgenic SCD mice using liquid chromatography-mass spectrometry (LC-MS).
2025-11-25 | PXD056826 | Pride
Project description:Sickle cell disease (SCD) is a devastating hemoglobinopathy prevalent in Chhattisgarh and other states of central India. Clinical features in SCD arise mainly due to anemia and vaso-occlusion and inflammation leading to gradual multiple organ failure. Vaso-occlusive crisis (VOC) is a common cause of sudden death among SCD patients. Aim of the study was to evaluate gene expression in patients of SCD in a quest to search up-regulated genes in VOC.
2017-06-30 | GSE72999 | GEO
Project description:Genetic differences in endothelial biology could underlie development of phenotypic heterogeneity amongst individuals afflicted with vascular diseases. We obtained BOEC (blood outgrowth endothelial cells) from 20 subjects with sickle cell anemia (age 4-19) shown to be either at-risk (n=11) or not-at-risk (n=9) for ischemic stroke due to, respectively, having or not having occlusive disease at the Circle of Willis (CoW). Gene expression profiling identified no significant single gene differences between the two groups, as expected. However, analysis of Biological Systems Scores, using gene sets that were pre-determined to survey each of nine biological systems, showed that only changes in inflammation signaling are characteristic of the at-risk subjects, as supported by multiple statistical approaches Experiment Overall Design: We obtained BOEC (blood outgrowth endothelial cells) from 20 subjects with sickle cell anemia (age 4-19) shown to be either at-risk (n=11) or not-at-risk (n=9) for ischemic stroke due to, respectively, having or not having occlusive disease at the Circle of Willis (CoW). To allow power calculations to be done, we performed microarray analysis on BOEC from 27 normal subjects of diverse ages. Gene expression profilings were obtained by using Affymetrix U133A chips
2008-06-17 | E-GEOD-9877 | biostudies-arrayexpress