Enhanced Th2 Cell Differentiation and Allergen-Induced Airway Inflammation in <i>Zfp35</i>-Deficient Mice

Kitajima, Masayuki; Iwamura, Chiaki; Miki-Hosokawa, Takako; Shinoda, Kenta; Endo, Yusuke; Watanabe, Yukiko; Shinnakasu, Ryo; Hosokawa, Hiroyuki; Hashimoto, Kimio; Motohashi, Shinichiro; Koseki, Haruhiko; Ohara, Osamu; Yamashita, Masakatsu; Nakayama, Toshinori

doi:10.4049/jimmunol.0804155

Cited by 9 publications

(7 citation statements)

References 72 publications

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“…20 Previous studies have shown that Zfp608 reduced Rag expression in thymocytes and impaired T-cell development. Based upon a total percent identity of 43.6% and a total sequence similarity of 57.6%, Zfp609 is the closest relative to Zfp608 (Supplementary Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609

et al. 2012

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Recombination-activating gene 1 (Rag1) and Rag2 enzymes are required for T cell receptor assembly and thymocyte development. The mechanisms underlying the transcriptional activation and repression of Rag1 and Rag2 are incompletely understood. The zinc-finger protein, Zfp608, represses Rag1 and Rag2 expression when expressed in thymocytes blocking T-cell maturation. Here we show that the related zinc-finger protein, Zfp609, is necessary for Rag1 and Rag2 expression in developing thymocytes. Zfp608 represses Rag1 and Rag2 expression indirectly by repressing the expression of Zfp609. Thus, the balance of Zfp608 and Zfp609 plays a critical role in regulating Rag1 and Rag2 expression, which may manifest itself not only during development of immature thymocytes into mature T cells but also in generation of the T-cell arm of the adaptive immune system, which does not fully develop until after birth.

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Section: Resultsmentioning

confidence: 99%

Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609

et al. 2012

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“…28 For example, mice experiments have demonstrated that ZNF271 negatively regulate T-helper cell type 2 cell proliferation and control T-helper cell type 2–dependent diseases, such as allergic asthma. 29 …”

Section: Discussionmentioning

confidence: 99%

Gene-based analysis identified the gene ZNF248 is associated with late-onset asthma in African Americans

Wang

Salinas

DeWan

2016

Annals of Allergy, Asthma & Immunology

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Background Late-onset asthma (LOA) has distinct characteristics and its pathogenesis might rely on unique pathways. Although current studies are focused primarily on childhood asthma, more research is needed to show the mechanisms underlying LOA. Objective To conduct genomewide association analysis and gene-based analysis to identify single-nucleotide polymorphisms and genes associated with LOA. Methods The Women’s Health Initiative (WHI) observational cohort and the Multi-Ethnic Study of Atherosclerosis (MESA) were used to identify subjects with LOA. The association between LOA and body mass index and smoking was evaluated. In the discovery stage of the genetic analysis, 1,218 African American subjects from WHI with genotype data (271 cases and 947 controls) were used for single-nucleotide polymorphism and gene-based association analyses. Significant or suggestive results were subsequently investigated in an independent African American population from MESA (38 cases and 806 controls). Results In WHI, the relative odds for LOA in obese vs normal-weight subjects was 2.55 (95% confidence interval 1.74–3.76). Ever smokers also had greater odds for LOA compared with never smokers (odds ratio 1.59, 95% confidence interval 1.21–2.09). The same trends were observed in MESA. In WHI, 6 single-nucleotide polymorphisms were associated with LOA at a genomewide-suggestive significance level (P < 1.0 × 10−5). The gene ZNF248 was associated with LOA and reached genomewide significance (P =4.0 ×10−7). In MESA, the association between ZNF248 and LOA was successfully replicated (P = .015). Conclusion Smoking and obesity are risk factors for LOA. ZNF248 confers increased susceptibility to LOA in African Americans.

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“…For example, Zfp35 ( ZNF271 ) appears to influence the pathogenesis of airway inflammation and hyperresponsiveness in asthma by controlling Th2 cell generation and Th2cytokine expression. 19 Many zinc finger proteins have been demonstrated to be involved in transcription. 20 ZNF432 has been found to be associated with inflammatory bowel disease, at P= 8.3 × 10 −5 .…”

Section: Discussionmentioning

confidence: 99%

Inhaled corticosteroid treatment modulates ZNF432 gene variant’s effect on bronchodilator response in asthmatics

Himes

Lasky‐Su

et al. 2014

Journal of Allergy and Clinical Immunology

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Background Single nucleotide polymorphisms (SNPs) influence a patient's response to inhaled corticosteroids and β2-agonists, and the effect of treatment with inhaled corticosteroids is synergistic with the effect of β2-agonists. We hypothesized that use of inhaled corticosteroids could influence the effect of SNPs associated with bronchodilator response. Objective To assess whether, among asthma subjects, the association of SNPs with bronchodilator response is different between those treated with inhaled corticosteroids vs. those on placebo. Methods A genome-wide association analysis was conducted using 581 white subjects from the Childhood Asthma Management Program (CAMP). Using data for 449,540 SNPs, we conducted a gene by environment analysis in PLINK with inhaled corticosteroid treatment as the environmental exposure and bronchodilator response as the outcome measure. We attempted to replicate the top 12 SNPs in the Leukotriene Modifier Or Corticosteroid or Corticosteroid-Salmeterol (LOCCS) Trial. Results The combined P-value for the CAMP and LOCCS populations was 4.81E-08 for rs3752120, which is located in the zinc finger protein gene ZNF432, and has unknown function. Conclusions Inhaled corticosteroids appear to modulate the association of bronchodilator response with variant(s) in the ZNF432 gene among adults and children with asthma. Clinical Implications Clinicians who treat asthma patients with inhaled corticosteroids should be aware that the patient's genetic makeup likely influences response as measured in lung function. Capsule Summary Our study suggests that inhaled corticosteroids could influence the effect of multiple SNPs associated with bronchodilator response across the genome.

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Enhanced Th2 Cell Differentiation and Allergen-Induced Airway Inflammation in Zfp35-Deficient Mice

Cited by 9 publications

References 72 publications

Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609

Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609

Gene-based analysis identified the gene ZNF248 is associated with late-onset asthma in African Americans

Inhaled corticosteroid treatment modulates ZNF432 gene variant’s effect on bronchodilator response in asthmatics

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