Browsing by Author "Dorsey, Susan"

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    Differential Gene Expression Among Patients With Heart Failure Experiencing Pain
    (Wolters kluwer Health, 2023-02-26) Smith, Asa; Jung, Miyeon; Pressler, Susan; Mocci, Evelina; Dorsey, Susan
    Background: Chronic pain is frequently experienced by patients with heart failure (HF) and is associated with higher mortality, higher symptom burden, and worsened health-related quality of life. However, the genomic mechanisms underlying chronic pain in HF are understudied. Building an understanding of the mechanistic underpinnings of pain may inform novel interventions. Objective: The objective was to identify genes associated with pain from mRNA sequence data collected from patients with HF with and without pain. Methods: The current study analyzed data from 40 patients with HF previously enrolled in a clinical trial. Pain presence was measured using the Health Utilities Index Mark-3. Genes were tested for differential expression using DESeq2, and differentially expressed genes were analyzed for protein–protein interaction (PPI) and relevant ontological pathways using Metascape. Genes located within the core of the PPI network were considered key in disease-relevant biological pathways. Differentially expressed genes within this PPI network were reviewed in existing literature to narrow down candidate genes of interest. These target genes of interest were reanalyzed in a second sample of 24 patients with HF using validation quantitative polymerase chain reaction. Results: A total of 334 genes (279 upregulated, 55 downregulated) were differentially expressed between patients with and without pain in the primary sample of 40. These genes were largely aligned with neutrophil degranulation pathways. Seven genes of interest were identified from a core network of 15 co-expressed genes in the PPI network and existing literature. Three of these seven genes: matrix metallopeptidase 8 (MMP8), proprotein convertase subtilisin/kexin type 9 (PCSK9), and neutrophil defensin 3 (DEFA3) were upregulated in patients with pain versus without pain in both the primary and validation samples. All seven genes of interest are involved in immune, inflammatory, and atherosclerotic processes. Discussion: These results identify potential genes that may play a mechanistic role in chronic pain in HF. Further research is needed to evaluate these potential genes among clearly delineated pain phenotypes.
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    Genes linked with inflammatory processes are differentially expressed in patients with chronic heart failure and pain
    (N/A, 2022-09) Smith, Asa; Dorsey, Susan; Mocci, Evelina; Jung, Miyeon; Pressler, Susan
    Background and Aims Pain is a significant problem among patients with chronic heart failure (HF). The mechanisms underlying pain in HF remain poorly understood. Gene expression analysis using mRNA sequencing can highlight mechanistic underpinnings of complex symptoms such as pain. The aim of this study was to identify differentially expressed genes linked with pain in patients with HF with pain compared with patients with HF but without pain. The research question was: what genes linked with pain are differentially expressed between patients with HF and pain compared to patients with HF without pain? Methods Data were collected as part of a parent randomized controlled trial to test the efficacy of a computerized cognitive intervention for memory among patients with chronic HF (R01 NR016116). Blood specimens, pain measures, and sociodemographic characteristics were collected during the baseline visit in the parent trial. Data from 40 patients with HF: 20 with pain and 20 without pain, were analyzed in the current study. Pain presence (yes/no) was assessed using 1 item of the Health Utilities Index Mark-3 questionnaire. Sociodemographic data collected were age, self-reported gender, race and ethnicity, years of education, marital status, depressive symptoms (Patient Health Questionnaire-8), and health-related quality of life (Minnesota Living with Heart Failure Questionnaire). Clinical characteristics included body mass index, left ventricular ejection fraction (LVEF), and New York Heart Association heart failure class. Differences in demographic and clinical variables between the pain and no pain groups were examined using independent samples t-tests and chi square. The mRNA was isolated from whole blood and sequenced using a 150bppaired-end read configuration. Genes were tested for differential expression between HF patients with pain and without pain using DESeq2. Genes were considered differentially expressed if the log fold change between groups was ≥ ± 0.58 with a false discovery p-value < 0.05. Differentially expressed genes were examined using protein-protein interactions analysis, disease-related biological pathways, and existing pain literature. Independent samples t-tests were used to identify statistically significant differences in gene expression between the pain and no pain groups. Target genes of interest were validated through real-time polymerase chain reaction in a different sample of 24 patients: 10 with pain and 14 without pain, selected from the parent study and matched to the discovery sample on age and gender. Results Among the patients with pain, the mean age was 66.45 ± 6.21 years compared to 62.65 ± 13.87 years in the patients with pain. Most patients were men (60% in the pain group vs. 70% in the no pain group) and White(75% vs. 60%, respectively). The sample was primarily New York Heart Association class II (42.5%), with an average LVEF of 42.56% ± 13.58%. There were no statistically significant differences in demographic or clinical status variables between patients with and without pain. A total of 334 differentially expressed genes were identified (279 upregulated and 55 downregulated); they were mostly involved in neutrophil degranulation pathways (n = 57, false discovery p-value = 7.9e-17), followed by extracellular matrix organization pathways (n = 19, false discovery p-value = 4.5e-03). The protein-protein interactions analysis produced a network of 288 nodes and 497 edges, compared to the expected number of 182 edges(enrichment p-value < 1.0e-16), with a core network consisting of 15 co-expressed genes. From this core network of 15 genes, 7 target genes of interest were identified: (1) cathepsin G (CTSG), (2) lactotransferrin(LTF), (3) lipocalin-2 (LCN2), (4) matrix metallopeptidase 8 (MMP8), (5) matrix metallopeptidase 9 (MMP9), (6)proprotein convertase subtilisin/kexin type 9 (PCSK9), and (7) neutrophil defensin 3 (DEFA3). All 7 genes were connected to inflammatory pathways and inflammatory pain conditions (e.g., arthritis) in existing pain literature. All 7 genes were upregulated in patients with HF and pain compared to those with HF and without pain. Three of these 7 genes (MMP8,PCSK9,andDEFA3) were also validated in the second sample of 24patients with HF. Conclusions This study identified 7 genes that were differentially expressed in patients with chronic HF and pain compared to patients with HF but no pain. Of these, 3 were validated in an additional sample which further strengthens the proposed connection of these genes with pain. The genes were significantly enriched in inflammatory and extracellular matrix organization and may play a role in development of chronic pain among patients with HF. This study is novel in that the biologic mechanisms underlying pain in this population have not been previously examined using gene expression analysis. Further research is needed with a more ethnically diverse sample and more robust pain measures, particularly regarding severity and locations of pain.