Gender-based precision care for asthma

基于性别的哮喘精准护理

• 批准号: 10223404
• 负责人: Joe Zein
• 金额: $ 13.41万
• 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 2023-06-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223404
• 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; 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; pulmonary function; 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大，但性别转换发生在青春期之后，哮喘在成年人中更常见。 女人比男人多。本研究计划调查性别对哮喘严重程度的影响。远景目标 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的性别相关差异。 我们对大型数据库的分析显示，重度哮喘在年轻男孩和中年男孩中表现出双峰， 年龄女性[1，2]，这表明性激素在哮喘严重程度的机制[1]。初步数据 严重哮喘研究项目（SARP I 2001- 2012）显示，低孕酮和低睾酮的男性和低睾酮的女性， 高雌二醇具有最严重的气流限制。此外，我们的全基因组关联分析， 欧美人群单核苷酸多态性与性别交互作用及候选基因分析 SARP I和II中的成人哮喘患者显示性别特异性遗传与预测的FEV 1百分比相关， 严重哮喘的标志物基于这些发现，我们假设严重哮喘的风险是性别 依赖于男性和/或女性性激素水平在整个生命过程中的变化， 性激素与哮喘风险变异体的相互作用导致严重哮喘的双峰， 儿童和妇女的哮喘在目标1中，我们将评估SNP ×性别在整个基因组中的相互作用， 全基因组相互作用研究（GWIS）。我们还将使用候选基因的方法，这将确定SNP 在先前描述的哮喘严重性基因位点中的x性别相互作用，例如肺功能和免疫 途径基因在目标2中，我们研究了性激素水平的变化对严重性痴呆风险的影响。 男性和女性的哮喘差异。与研究计划同样重要和平行的是， 发展计划是为教学课程，一对一的教育和职业指导，从 在哮喘、内分泌学和分析遗传学方面有很强的导师和合作者。这项研究将 在克利夫兰诊所Lerner研究所（LRI）Erzurum博士的实验室进行，并将 由基因组学和哮喘特有的生化途径专家提供建议。LRI提供了理想的 知识和研究环境取得成功。本研究具有创新性和重要意义， 可能为以个性化、性别特异性的方式护理重度哮喘患者奠定基础。 总的来说，该奖项将为候选人提供知识，实践经验，专业知识和 生产力发展成为一个独立的医生，科学家专注于以病人为中心的机械 research.

项目成果

Beyond tobacco - the secondary impact of substance misuse in chronic obstructive lung disease.

• DOI: 10.1080/02770903.2020.1847932
• 发表时间: 2022-03
• 期刊: The Journal of asthma : official journal of the Association for the Care of Asthma
• 作者: Macmurdo M;Lopez R;Udeh BL;Zein J
• 通讯作者: Zein J

A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19.

• DOI: 10.1371/journal.pbio.3000970
• 发表时间: 2020-11
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Zhou Y;Hou Y;Shen J;Mehra R;Kallianpur A;Culver DA;Gack MU;Farha S;Zein J;Comhair S;Fiocchi C;Stappenbeck T;Chan T;Eng C;Jung JU;Jehi L;Erzurum S;Cheng F
• 通讯作者: Cheng F

Alcohol use disorder and healthcare utilization in patients with chronic asthma and obstructive lung disease.

• DOI: 10.1016/j.alcohol.2021.03.002
• 发表时间: 2021-06
• 期刊: Alcohol (Fayetteville, N.Y.)
• 作者: MacMurdo M;Lopez R;Udeh BL;Zein JG
• 通讯作者: Zein JG

Eosinophilia Is Associated with Improved COVID-19 Outcomes in Inhaled Corticosteroid-Treated Patients.

• DOI: 10.1016/j.jaip.2021.12.034
• 发表时间: 2022-03
• 期刊: The journal of allergy and clinical immunology. In practice
• 作者: Zein JG;Strauss R;Attaway AH;Hu B;Milinovich A;Jawhari N;Chamat SS;Ortega VE
• 通讯作者: Ortega VE

Inhaled corticosteroids do not adversely impact outcomes in COVID-19 positive patients with COPD: An analysis of Cleveland Clinic's COVID-19 registry.

• DOI: 10.1371/journal.pone.0252576
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sen P;Majumdar U;Zein J;Hatipoğlu U;Attaway AH
• 通讯作者: Attaway AH