Gender-based precision care for asthma

基于性别的哮喘精准护理

• 批准号: 10225221
• 负责人: Joe Zein
• 金额: $ 10.04万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225221
• 关键词: 5q31; Adrenal Cortex Hormones; Adult; Affect; Age; American; Area; Asthma; Award; Biochemical Pathway; Biological; Body mass index; Candidate Disease Gene; Characteristics; Child; Childhood Asthma; Cilia; Clinic; Clinical; Clinical Research; Data; Data Set; Databases; Development; Development Plans; Dose; Drug Targeting; Education; Endocrinology; Environment; Epidemiology; Epithelial Cells; Estradiol; European; Exhibits; Female; Foundations; GTP-Binding Protein alpha Subunits, Gs; Gender; Genes; Genetic; Genetic Risk; Genetic Transcription; Genomics; Glucocorticoids; Glutamine; Goals; Gonadal Steroid Hormones; Hormonal; IRF1 gene; Immunity; Incidence; Inhalation; Interferons; Isoleucine; Knowledge; Laboratories; Life Cycle Stages; Linear Regressions; Longevity; Menopause; Mentors; Mucociliary Clearance; National Heart, Lung, and Blood Institute; Natural History; Outcome; Participant; Pathogenesis; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Physicians; Predisposition; Prevalence; Productivity; Progesterone; Proteins; Puberty; Pulmonary Function Test/Forced Expiratory Volume 1; Reporting; Research; Research Institute; Research Proposals; Respiratory physiology; Risk; Role; Scientist; Severities; Sex Differences; Single Nucleotide Polymorphism; Subgroup; Testing; Testosterone; Time; Ubiquitin; Variant; Vocational Guidance; Woman; activating transcription factor 1; airway obstruction; asthmatic; base; boys; career; career development; cohort; epidemiology study; experience; female sex hormone; gender difference; genetic association; genetic epidemiology; genetic variant; genome wide association study; genome-wide; genomic locus; girls; improved; innovation; male; men; middle age; patient oriented; personalized care; programs; response; risk variant; sex; success; tiotropium bromide; whole genome

ABSTRACT Asthma affects boys more than girls, but gender-switch occurs after puberty and asthma is more common in women than men. This research proposal investigates gender effect(s) on asthma severity. The long-term goal of our studies is to identify sex related differences in genetic risks and biological pathways of severe asthma. Our analyses of large databases reveal that severe asthma exhibits a bimodal peak in young boys and middle age women [1, 2], which pointes to sex hormones in mechanisms of asthma severity [1]. Preliminary data of sex hormone levels in participants with asthma from the Severe Asthma Research Program (SARP Iⅈ 2001- 2012) shows that men with both low progesterone and low testosterone and women with low testosterone and high estradiol have the most severe airflow limitation. Additionally, our genome-wide association analyses of single nucleotide polymorphism (SNP) x sex interaction and candidate gene analyses of European American adults with asthma in SARP I & II shows sex-specific genetic associations with percent predicted FEV1, a marker of severe asthma. Based on the findings, we hypothesize that risk of severe asthma is gender dependent due to variation in levels of male and/or female sex hormones over the lifecourse and the consequent interactions of sex hormones with asthma risk variants that result in a bimodal peak of severe asthma in boys and women. In aim 1, we will assess SNP × sex interactions across the whole genome using genome wide interaction study (GWIS). We will also use a candidate gene approach, which will determine SNP x sex interactions in previously described asthma severity gene loci, such as lung function and immunity pathway genes. In aim 2, we investigate the effect of variations in sex hormone levels on the risk for severe asthma differentially in males and females. Equally important and parallel to the research plan, the career development plan is constructed for didactic coursework, one-on-one education and career guidance from strong mentors and collaborators expert in asthma, endocrinology, and analytical genetics. This research will be performed in the laboratory of Dr. Erzurum, Lerner Research Institute (LRI), Cleveland Clinic, and will be advised by experts in genomics and biochemical pathways unique to asthma. The LRI offers the ideal intellectual and research environment for success. The proposed research is innovative and significant as it may lay the groundwork for the care of patients with severe asthma in a personalized, gender specific way. Altogether the award will provide the candidate the knowledge, hands-on experience, expertise and productivity to develop into an independent physician-scientist focused on patient-centered mechanistic research.

摘要 哮喘对男孩的影响比女孩更大，但性别转换发生在青春期之后，哮喘在 女人比男人多。本研究建议探讨性别(S)对哮喘严重程度的影响。长期目标 我们的研究之一是确定严重哮喘的遗传风险和生物学途径中与性别有关的差异。 我们对大型数据库的分析表明，严重哮喘在年轻男孩和中年男孩中呈现出双峰曲线 年龄妇女[1，2]，这表明性激素在哮喘严重程度的机制中[1]。初步数据： 重症哮喘研究项目中哮喘患者的性激素水平(SARP I&II；2001- 2012)显示，同时低孕酮和低睾酮的男性和低睾酮和低睾酮的女性 高雌二醇有最严重的气流受限。此外，我们的全基因组关联分析 欧洲裔美国人单核苷酸多态(SNP)x性别交互作用及候选基因分析 在SARP I和II中，成年哮喘患者显示性别特异的基因与预测的FEV1，a 严重哮喘的标志。根据研究结果，我们假设严重哮喘的风险与性别有关。 由于男性和/或女性性激素水平在生命过程中的变化和 随后性激素与哮喘风险变量的相互作用导致严重哮喘的双峰 男孩和妇女中的哮喘。在目标1中，我们将评估整个基因组中的SNP×性别交互作用 全基因组相互作用研究。我们还将使用候选基因方法，这将决定SNP 先前描述的哮喘严重程度基因座的性别交互作用，如肺功能和免疫 途径基因。在目标2中，我们调查了性激素水平的变化对重症发病风险的影响。 哮喘在男性和女性中存在差异。与研究计划、职业生涯同样重要和平行的是 发展计划是为教学课程、一对一教育和职业指导而构建的 强大的导师和合作者是哮喘、内分泌学和分析遗传学方面的专家。这项研究将 将在克利夫兰诊所勒纳研究所(LRI)Erzurum博士的实验室进行，并将 由哮喘特有的基因组学和生化途径专家提供建议。LRI提供了理想的 智力和研究环境为成功创造了条件。拟议的研究具有创新性和重要意义，因为它 可为以个性化、性别特定的方式护理严重哮喘患者奠定基础。 总之，该奖项将为候选人提供知识、实践经验、专业知识和 将生产力发展为以患者为中心的独立内科科学家 研究。