Relevance of RPS27L expression quantitative trait locus in pediatric obesity-related asthma

RPS27L 表达数量性状位点与儿童肥胖相关哮喘的相关性

基本信息

批准号：
10592469
负责人：
Deepa Rastogi
金额：
$ 10.91万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-07 至 2023-07-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592469
关键词：
Actins Adipose tissue Adolescent African African American Albuterol Alleles Asthma Biological Biology CXCL10 gene CXCR3 gene Cell Cycle Cell Differentiation process Cell Proliferation Cell physiology Cells Child Childhood Childhood Asthma Disease Down-Regulation Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Predisposition to Disease Genetic Risk Genotype Health Helper-Inducer T-Lymphocyte Hispanic Hispanic Americans Immune response Immunobiology Incidence Inhalation Interferon Type II Investigation Latinx Light Link Mediating Minor Minority Nature Obesity Overweight Pathogenesis Pathway interactions Pharmaceutical Preparations Phenotype Play Polymers Population Positioning Attribute Predisposition Primary Prevention Proliferating Proteins Pulmonary Function Test/Forced Expiratory Volume 1 Quantitative Trait Loci Reporting Research Ribosomal Proteins Risk Factors Risk Marker Role Sampling Single Nucleotide Polymorphism Small Interfering RNA Steroids TNF gene Testing Th1 Cells Therapeutic Intervention Up-Regulation Weight Gain biobank burden of illness cell motility cohort cytokine effective therapy genetic variant healthy weight migration minority children new therapeutic target novel obesity in children obesity risk obesity-associated asthma peripheral blood polarized cell polymerization preadolescence programs protein phosphatase inhibitor-2 pulmonary function recruit respiratory smooth muscle rho GTP-Binding Proteins risk variant targeted treatment tumor

项目摘要

Obesity-related asthma is the most consistently reported pediatric non-atopic asthma phenotype that is associated with high disease burden and is poorly responsive to asthma medications. It is a major subset of pediatric asthma that is increasing in incidence since 20% of children in the U.S. are overweight/obese, with higher rates observed in Hispanic and African American children. However, not all children who gain weight develop obesity-related asthma, suggesting that genetic susceptibility plays a role. Thus, identification of genetic risk markers for obesity-related asthma will offer opportunities for primary prevention. Investigation of biologic mechanisms underlying the genetic risk will identify novel therapeutic targets for obesity-related asthma, which has no effective treatment options. Our research program is leading the investigation of immunobiology of obesity-related asthma in minority children. In peripheral blood from Hispanic and African American children, we found non-atopic immune responses with T helper (TH)1 cell polarization that correlated with pulmonary function deficits in obesity-related asthma, and was associated with upregulation of Cell Division Cycle 42 (CDC42) pathway in TH cells, which plays an integral role in TH cell migration and differentiation, particularly to TH1 cells; inhibition of CDC42 led to inhibition of TH1 but not TH2 cytokines. Investigation of the contribution of genetic variants to immunobiology of obesity-related asthma in minority children identified a single nucleotide polymorphism (SNP) at rs6494395 locus that functions as an expression quantitative trait locus (eQTL) in TH cells for the gene encoding for ribosomal protein S27 like (RPS27L) protein. The minor allele (C allele), that is 2 to 4 times more prevalent in Hispanic and African populations, was associated with RPS27L downregulation. All three children with C/C genotype were obese with asthma. RPS27L downregulation and homozygosity for C allele were independent predictors of 14% and 10% (respectively) lower FEV1/FVC ratio in obese children with asthma. We therefore speculate that the C allele at the rs6494395 locus is relevant to pediatric obesity-related asthma. Although there is no known links between RPS27L, TH1 cells, CDC42, or asthma, RPS27L is a target and a modulator of p53, which plays a key role in control of TH cell proliferation and modulates CDC42 to control cell migration. These findings form the premise for this proposal. We hypothesize that C allele at rs6494395 locus is a novel at-risk allele that confers susceptibility to non-atopic obesity-related asthma in minority children by downregulating RPS27L which downregulates p53 activity in TH cells, causing increased TH1 cell proliferation and CDC42-mediated cell migration. To test our hypothesis, we will investigate 1) the ancestry of C allele at rs6494395, and its links with RPS27L expression, TH1 polarization, and disease burden in obese children with asthma, relative to obese children without asthma, and healthy-weight children with and without asthma, and 2) novel mechanistic links between RPS27L, p53, and CDC42 in healthy TH1 cells and the presence of these links in TH1 cells from obese children with asthma.

与肥胖有关的哮喘是最持续报道的小儿非原子哮喘表型与疾病负担高有关，对哮喘药物的反应不佳。这是一个主要子集由于20％的美国儿童超重/肥胖，发病率正在增加，儿科哮喘的发病率正在增加在西班牙裔和非裔美国儿童中观察到的较高的比率。但是，并非所有体重增加的孩子发展与肥胖有关的哮喘，表明遗传易感性起作用。因此，遗传的鉴定与肥胖有关的哮喘的风险标记将为初级预防提供机会。生物学研究遗传风险背后的机制将确定与肥胖有关的哮喘的新型治疗靶标，这没有有效的治疗选择。我们的研究计划领导了对免疫生物学的调查少数民族儿童中与肥胖有关的哮喘。在西班牙裔和非洲裔美国儿童的外围血液中，我们发现与肺功能相关的T辅助器（Th）1细胞极化的非正极免疫反应与肥胖有关的哮喘缺陷，与细胞分裂周期42的上调有关（CDC42） TH细胞中的途径在细胞迁移和分化中起着不可或缺的作用，尤其是对Th1细胞的作用。 Cdc42的抑制导致TH1的抑制作用，但没有抑制Th2细胞因子。研究遗传的贡献少数族裔儿童中肥胖相关哮喘免疫生物学的变体鉴定了单个核苷酸 RS6494395基因座的多态性（SNP）充当表达定量性状基因座（EQTL）用于编码核糖体蛋白S27的基因的细胞（RPS27L）蛋白。小等位基因（C等位基因），即在西班牙裔和非洲人口中，普遍存在的2至4倍与RPS27L下调有关。所有三个患有C/C基因型的儿童均肥胖患有哮喘。 C的RPS27L下调和C的纯合性等位基因是肥胖儿童的独立预测因素（分别为14％和10％）哮喘。因此，我们推测RS6494395基因座的C等位基因与儿科肥胖有关哮喘。尽管RPS27L，TH1细胞，CDC42或哮喘之间没有已知的联系，但RPS27L是目标 p53的调节剂，在控制细胞增殖中起着关键作用，并调节cdc42以控制细胞迁移。这些发现构成了该提案的前提。我们假设C等位基因在RS6494395上基因座是一个新颖的高风险等位基因，赋予了少数族裔儿童中与肥胖无关哮喘的敏感性通过下调RPS27L，该RPS27L下调TH细胞中的p53活性，从而导致Th1细胞增殖增加和CDC42介导的细胞迁移。为了检验我们的假设，我们将研究1）C等位基因的血统 rs6494395及其与肥胖儿童的RPS27L表达，Th1极化和疾病负担的联系哮喘，相对于没有哮喘的肥胖儿童，患有和没有哮喘的健康权重儿童，2）在健康的Th1细胞中，RPS27L，p53和cdc42之间的新机械连接以及这些链接的存在在肥胖儿童哮喘的Th1细胞中。