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

• 批准号: 10842666
• 负责人: Deepa Rastogi
• 金额: $ 17.36万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-07 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10842666
• 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

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.

肥胖相关性哮喘是最一致报道的儿童非特应性哮喘表型， 与高疾病负担相关，并且对哮喘药物反应不良。它是一个主要的子集， 儿童哮喘的发病率正在增加，因为美国20%的儿童超重/肥胖， 在西班牙裔和非洲裔美国儿童中观察到更高的发病率。然而，并非所有体重增加的儿童 患上与肥胖有关的哮喘，这表明遗传易感性发挥了作用。因此，鉴定遗传 肥胖相关哮喘的风险标志将为初级预防提供机会。生物学研究 遗传风险的潜在机制将确定肥胖相关哮喘的新治疗靶点， 没有有效的治疗方案。我们的研究计划是领导免疫生物学的调查， 少数民族儿童的肥胖相关性哮喘。在西班牙裔和非裔美国儿童的外周血中，我们 发现非特应性免疫反应与辅助性T细胞（TH）1极化，与肺功能相关 肥胖相关哮喘的缺陷，并与细胞分裂周期42（CDC 42）的上调有关 TH细胞中的通路，其在TH细胞的迁移和分化，特别是向TH 1细胞的迁移和分化中起不可或缺的作用; 抑制CDC 42导致抑制TH 1细胞因子，但不抑制TH 2细胞因子。遗传学贡献的调查 少数民族儿童肥胖相关哮喘的免疫生物学变异确定了一个单核苷酸 在TH中作为表达数量性状基因座（eQTL）发挥功能的rs6494395基因座处的多态性（SNP 细胞中编码核糖体蛋白S27样（RPS 27 L）蛋白的基因。次要等位基因（C等位基因）， 在西班牙裔和非洲人群中的流行率是其他人群的2 - 4倍，与RPS 27 L下调相关。 3名C/C基因型儿童均为肥胖伴哮喘。RPS 27 L下调和C基因纯合性 等位基因分别是肥胖儿童FEV 1/FVC比值降低14%和10%的独立预测因子， 哮喘因此，我们推测rs6494395位点的C等位基因与儿童肥胖相关。 哮喘虽然RPS 27 L、TH 1细胞、CDC 42和哮喘之间没有已知的联系，但RPS 27 L是一个靶点。 和p53的调节剂，其在控制TH细胞增殖中起关键作用并调节CDC 42以控制TH细胞增殖。 细胞迁移这些调查结果构成了这一提议的前提。我们假设rs6494395的C等位基因 基因座是一个新的危险等位基因，赋予少数民族儿童非特应性肥胖相关哮喘的易感性 通过下调RPS 27 L（其下调TH细胞中的p53活性），引起增加的TH 1细胞增殖， 和CDC 42介导的细胞迁移。为了验证我们的假设，我们将调查1）C等位基因的祖先， rs6494395及其与RPS 27 L表达、TH 1极化和肥胖儿童疾病负担的关系。 哮喘，相对于无哮喘的肥胖儿童，以及健康体重的有哮喘和无哮喘的儿童，以及2） 健康TH 1细胞中RPS 27 L、p53和CDC 42之间的新机制联系以及这些联系的存在 在患有哮喘的肥胖儿童的TH 1细胞中