Functional Genomics of the Pediatric Obese Asthma Phenotype Reveal Enrichment of Rho-GTPase Pathways

Rastogi, Deepa; Johnston, Andrew D.; Nico, John; Loh, Lip Nam; Jorge, Yurydia; Suzuki, Masako; Macian, Fernando; Greally, John M.

doi:10.1164/rccm.201906-1199oc

Cited by 23 publications

(18 citation statements)

References 46 publications

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“…In the current study, blood CDC42 expression was negatively correlated with CRP, BASDAI score, ASDAS CRP score, TNF‐α, and IL‐17, whereas blood CDC42 expression was not associated with other clinical features or cytokines. Possible explanations could be that (1) CDC42 facilitates macrophage polarized to M2 phenotype and inhibits the differentiation of CD4 + T cells into Th17 cells, which leads to a negative correlation of CDC42 with their secreted cytokines (in detail: IL‐17A was mainly secreted by Th17 cells and TNF‐α was mainly secreted by macrophage) in AS patients 11‐18 . (2) Based on the evidence above, CDC42 inhibits immune response through multiple mechanisms; therefore, CDC42 leads to reduced disease activity in AS patients 22‐24,28,29 …”

Section: Discussionmentioning

confidence: 99%

“…Cell division cycle 42 (CDC42), a member of the small Rho GTPase family, mediates actin polymerization and epithelial polarity establishment 9,10 . More importantly, CDC42 has been reported to be involved in modulating the inflammation via regulating the cellular phenotypic change of macrophage and maintaining the T cell homeostasis 11‐18 . In detail, CDC42 facilitates the polarization of macrophage to M2 phenotype and decrease the release of TNF‐α in multiple inflammation‐related diseases 11‐14 .…”

Section: Introductionmentioning

confidence: 99%

“…In detail, CDC42 facilitates the polarization of macrophage to M2 phenotype and decrease the release of TNF‐α in multiple inflammation‐related diseases 11‐14 . Besides, CDC42 not only suppresses T cell differentiation into T helper 1 (Th1) and Th17 cells but also inhibits the development of autoimmunity and further modulates the corresponding cytokines’ production and their exocytosis 15‐18 . Additionally, it is supposed that the activation of macrophage, Th1, Th17 cells, and the recruitment of inflammation are closely involved in AS etiology 1,2 .…”

Section: Introductionmentioning

confidence: 99%

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PBMC CDC42 reveals the disease activity and treatment efficacy of TNF inhibitor in patients with ankylosing spondylitis

Zhang¹,

Du²,

Mou³

et al. 2022

Clinical Laboratory Analysis

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Objective Cell division cycle 42 (CDC42) regulates the polarization of M2 macrophage and maintains the T cell homeostasis, to participate in multiple autoimmune diseases, while its clinical involvement in ankylosing spondylitis (AS) remains unclear. Hence, the current study aimed to investigate the correlation of CDC42 with clinical characteristics and treatment outcome in AS patients receiving tumor necrosis factor (TNF) inhibitor therapy. Methods Peripheral blood mononuclear cell (PBMC) CDC42 expression was detected at baseline, week (W) 4, W8, and W12 after TNF inhibitor treatment in 91 AS patients and in 50 HCs after enrollment. Furthermore, serum TNF‐α, interferon‐γ (IFN‐γ), interleukin‐10 (IL‐10), and interleukin‐17A (IL‐17A) from AS patients were detected at baseline. Results Blood CDC42 was lower in AS patients compared with HCs (p < 0.001). Additionally, blood CDC42 was negatively linked with CRP (r = −0.349, p = 0.001), BASDAI score (r = −0.243, p = 0.020), and ASDASCRP score (r = −0.238, p = 0.023) in AS patients; however, blood CDC42 was not correlated with other clinical characteristics. Besides, CDC42 was negatively correlated with TNF‐α (r = −0.237, p = 0.024) and IL‐17A (r = −0.339, p = 0.001) but not with IFN‐γ (p = 0.083) or IL‐10 (p = 0.280). Moreover, blood CDC42 was elevated after TNF inhibitor treatment (p < 0.001). Meanwhile, blood CDC42 was not varied at baseline and W4 between response patients and non‐response patients, while it was higher at W8 (p = 0.019) and W12 (p = 0.002) in response patients than in non‐response patients after treatment. Conclusion Blood CDC42 deficiency links with elevated pro‐inflammatory cytokines, disease activity and unsatisfying response to TNF inhibitor in AS patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PBMC CDC42 reveals the disease activity and treatment efficacy of TNF inhibitor in patients with ankylosing spondylitis

Zhang¹,

Du²,

Mou³

et al. 2022

Clinical Laboratory Analysis

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“…Methylation was analyzed with different techniques in the 23 epigenome-wide association studies (EWASs). Illumina arrays were the most widely used technique (N studies = 17 out of 23 studies), while a few studies used enzyme digestion-based tagging assay, 19,20 reduced representation bisulfite sequencing, 21 chromatin immunoprecipitation combined with DNA microarray, 22 targeted bisulfite sequencing, 23 and methylated DNA immunoprecipitation sequencing. 24 Peripheral blood was the most analyzed sample type (N = 15 studies), while a few studies used cord blood (N = 4 studies), 22,[25][26][27] saliva or buccal cells (N = 4 studies), 23,[28][29][30] neonatal blood spots samples (N = 1 study), 31 and placenta (N = 1 study).…”

Section: Epigenome-wide Association Studiesmentioning

confidence: 99%

Perspectives and challenges of epigenetic determinants of childhood obesity: A systematic review

et al. 2021

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The tremendous increase in childhood obesity prevalence over the last few decades cannot merely be explained by genetics and evolutionary changes in the genome, implying that gene-environment interactions, such as epigenetic modifications, likely play a major role. This systematic review aims to summarize the evidence of the association between epigenetics and childhood obesity. A literature search was performed via PubMed and Scopus engines using a combination of terms related to epigenetics and pediatric obesity. Articles studying the association between epigenetic mechanisms (including DNA methylation and hydroxymethylation, non-coding RNAs, and chromatin and histones modification) and obesity and/or overweight (or any related anthropometric parameters) in children (0-18 years) were included.The risk of bias was assessed with a modified Newcastle-Ottawa scale for nonrandomized studies. One hundred twenty-one studies explored epigenetic changes related to childhood obesity. DNA methylation was the most widely investigated mechanism (N = 101 studies), followed by non-coding RNAs (N = 19 studies) with evidence suggestive of an association with childhood obesity for DNA methylation of specific genes and microRNAs (miRNAs). One study, focusing on histones modification, was identified. Heterogeneity of findings may have hindered more insights into the epigenetic changes related to childhood obesity. Gaps and challenges that future research should face are herein described.

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“…In this issue of the Journal , Rastogi and colleagues (pp. 259–274 ) report the results of their genomics and epigenomic analyses of the pediatric obese asthma phenotype in minority populations ( 16 ). Using a multiomics approach including differential gene expression from CD4 + Th cells, expression quantitative trait loci (eQTL) mapping, differential methylation, and methylation quantitative trait loci, the authors demonstrate enrichment of genes in the Rho-GTPase pathway in the obese asthma phenotype in African American and Hispanic children.…”

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confidence: 99%

A Role for the Rho-GTPase Pathway in Pediatric Obese Asthma

Sharma

2020

Am J Respir Crit Care Med

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Functional Genomics of the Pediatric Obese Asthma Phenotype Reveal Enrichment of Rho-GTPase Pathways

Cited by 23 publications

References 46 publications

PBMC CDC42 reveals the disease activity and treatment efficacy of TNF inhibitor in patients with ankylosing spondylitis

PBMC CDC42 reveals the disease activity and treatment efficacy of TNF inhibitor in patients with ankylosing spondylitis

Perspectives and challenges of epigenetic determinants of childhood obesity: A systematic review

A Role for the Rho-GTPase Pathway in Pediatric Obese Asthma

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