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Sci Rep. 2019;9(1):20133.

Identification of a key gene module associated with glucocorticoid- induced derangement in bone mineral density in patients with asthma.

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제1저자 이서영 · 교신저자 박흥우

PMID 31882850 PMC6934743 DOI 10.1038/s41598-019-56656-9 IF 4.9 알레르기내과
소속 (10)
  1. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
  2. Department of Internal Medicine, Korea University Medical Center Anam Hospital, Seoul, Republic of Korea.
  3. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea.
  4. Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea.
  5. Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
  6. The Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  7. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  8. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. guinea71@snu.ac.kr.
  9. Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea. guinea71@snu.ac.kr.
  10. The Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. guinea71@snu.ac.kr.

Abstract

Derangement in bone mineral density (BMD) caused by glucocorticoid is well-known. The present study aimed to find key biological pathways associated with low BMD after glucocorticoid treatment in asthmatics using gene expression profiles of peripheral blood cells. We utilized immortalized B cells (IBCs) from 32 childhood asthmatics after multiple oral glucocorticoid bursts and peripheral blood mononuclear cells (PBMCs) from 17 adult asthmatics after a long-term use of oral glucocorticoid. We searched co-expressed gene modules significantly related with the BMD Z score in childhood asthmatics and tested if these gene modules were preserved and significantly associated with the BMD Z score in adult asthmatics as well. We identified a gene module composed of 199 genes significantly associated with low BMD in both childhood and adult asthmatics. The structure of this module was preserved across gene expression profiles. We found that the cellular metabolic pathway was significantly enriched in this module. Among 18 hub genes in this module, we postulated that 2 genes, CREBBP and EP300, contributed to low BMD following a literature review. A novel biologic pathway identified in this study highlighted a gene module and several genes as playing possible roles in the pathogenesis of glucocorticoid- induced derangement in BMD.

Figures

Figure 1
Figure 1 Co-expression modules identified in gene expression profiles of Sham-treated immortalized B cells from childhood asthmatics. Top panel shows a dendrogram of 5,000 genes. Bottom panel shows colors corresponding to the cluster membership labels for each gene.
Figure 2
Figure 2 Associations between eigengene values of the bone mineral density Z score-associated common module and the bone mineral density Z score. (A) Childhood asthmatics. (B) Adult asthmatics. Both P values were adjusted by covariates.
Figure 3
Figure 3 Preservation of modules identified in gene expression profiles of Sham-treated immortalized B cells from childhood asthmatics in gene expression profiles of Sham-treated peripheral mononuclear cell from adult asthmatics. The first (top) panel shows a heatmap of pair-wise correlations among the genes comprising the turquoise, magenta, and purple modules. The second panel shows a heatmap of the edge weights (connections) among the genes comprising the three modules. The third panel shows the distribution of scaled weight degrees (relative connectedness) among the genes comprising the three modules. The fourth panel shows the distribution of node contributions (correlation to module eigengene) among the genes comprising the three modules. Genes are ordered from left to right based on their weighted degree in the discovery cohort, so as to highlight the consistency of the network properties in the replication cohort.
Figure 4
Figure 4 Co-expression network of hub genes of the bone mineral density Z score-associated common module. (A) Sham-treated IBCs from childhood asthmatics. (B) Dex-treated IBCs from childhood asthmatics. For clarity, only the edges corresponding to the Pearson correlation coefficient >0.8 were shown. The edge width is proportional to the Pearson correlation coefficient between two nodes. The network was visualized using qgraph R package. ARM, ARMC5; ATP, ATP2A2; CCN, CCNK; CRE, CREBBP; EP3, EP300; EP4, EP400; GTF, GTF3C1; IPO, IPO13; MTF, MTF1; NOL, NOL8; NUP, NUP188; PCF, PCF11; RFX, RFX5; SDA, SDAD1; SET, SETD1A; SLC, SLC25A22; UBA, UBAP2L; WDR, WDR59.
Figure 5
Figure 5 Overall study design.

그림 출처: PubMed Central 공개 논문 (PMC6934743)

Conflict of interest statement

The authors declare no competing interests.

그 밖의 정보
출판 형태
Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
저널
Scientific reports · eISSN 2045-2322
전자 출판
2019-12-27
MeSH
Adolescent · Aged · Anti-Asthmatic Agents / adverse effects / therapeutic use · Asthma / complications / drug therapy / genetics · Biomarkers · Bone Density / genetics · Child · Computational Biology / methods · Female · Gene Expression Profiling · Gene Regulatory Networks · Genetic Predisposition to Disease · Genome-Wide Association Study · Glucocorticoids / adverse effects / therapeutic use · Humans · Male · Middle Aged · Osteoporosis / diagnostic imaging / etiology / metabolism / pathology · Transcriptome
Substances
Anti-Asthmatic Agents · Biomarkers · Glucocorticoids
연구비
NHLBI NIH HHS R01 HL127332 · NINR NIH HHS R01 NR013391 · NHLBI NIH HHS U01 HL065899
참고문헌
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