Genetics of lung function and asthma severity in African Americans

描述：严重的难治性哮喘是一种具有挑战性的疾病，影响约10%-15%的哮喘患者，尽管使用了大剂量的吸入性皮质类固醇(ICS)治疗，但仍与持续性呼吸道炎症和进行性肺功能障碍有关。尽管对严重哮喘的发病机制知之甚少，但在受影响的患者中存在明显的种族差异，这表明遗传学在调节这种疾病方面可能发挥了作用。在美国，与白人相比，非裔美国人目前患有严重哮喘的可能性几乎是白人的两倍，与社会经济地位无关，导致住院人数增加两倍，哮喘死亡人数增加四倍。此外，非洲裔美国人患有持续性气流受限和进行性肺功能丧失的可能性是其他人的两倍，尽管 同等待遇。然而，非洲裔美国人在哮喘研究中的代表性很低，因此迫切需要针对非洲裔美国人的研究，以揭示这一高危人群中严重哮喘的机制和基因基础。尽管遗传学研究已经确定了与哮喘患者横断面肺功能测量相关的单核苷酸多态(SNPs)，但这些研究主要是在欧洲白人的普通人群中进行的，因此与非裔美国人的相关性值得怀疑。此外，这些SNP在预测该人群中其他相关哮喘结果方面的临床“效用”或“意义”仍不清楚。因此，通过一项前瞻性的、分型分层的队列研究，这项应用将确定一组肺功能基因中的SNPs是否可以预测接受ICS治疗的非裔美国儿童和成人持续性哮喘的严重程度。其具体目的是：1)根据基因分型对非洲裔美国儿童和成人持续性哮喘进行分层和表型；2)确定基因是否可以预测非洲裔美国儿童和成人持续性哮喘的严重程度；以及3)完善具有祖传遗传标记的非洲裔美国儿童和成人哮喘严重程度的基因模型。埃默里和维克森林公司有着长期的合作历史，共同领导了对严重哮喘的表型和基因组分析的倡议。这里产生的发现有望产生关于基因组变异对非裔美国人严重哮喘的贡献的新信息。鉴于非裔美国人与哮喘相关的发病率增加，这些发现将为为这一具有挑战性和研究不足的人群推进个性化基因组学方法奠定重要基础。这项研究也符合NINR的使命，即通过管理慢性病(严重哮喘)的症状来提高生活质量，并通过应用跨学科方法来加强研究创新，以改善哮喘患者的健康。

DESCRIPTION: Severe, therapy-resistant asthma is a challenging disorder affecting ~10-15% of all asthmatics that is associated with persistent airway inflammation and progressive lung function deficits despite treatment with high doses of inhaled corticosteroids (ICS). Although the mechanisms underlying severe asthma are poorly understood, racial disparities are evident among affected patients and suggest a potential role for genetics in the modulation of the disorder. In the U.S., African Americans are nearly twice as likely (compared to whites) to have current severe asthma independent of socioeconomic status, resulting in a two-fold increase in hospitalizations and a four-fold increase in asthma death. Furthermore, African Americans are twice as likely to have persistent airflow limitation and progressive loss of lung function despite equivalent treatment. However, African Americans have been poorly represented in asthma studies and thus there is an urgent need for research targeting African Americans to unravel the mechanisms and genetic underpinnings of severe asthma in this high-risk population. Although genetic studies have identified single nucleotide polymorphisms (SNPs) associated with cross-sectional lung function measures in asthma patients, these studies were predominantly conducted in general populations of European whites and thus are of questionable relevance to African Americans. Furthermore, the clinical "utility" or "meaningfulness" of these SNPs in predicting other relevant asthma outcomes in this population remains unclear. Therefore, through a prospective, genotype- stratified cohort study, this application will determine whether SNPs in a panel of lung function genes predict asthma severity in African American children and adults with persistent asthma treated with ICS. The specific aims are to: 1) stratify and phenotype African American children and adults with persistent asthma by genotype 2) determine whether genotype predicts longitudinal asthma severity in African American children and adults with persistent asthma, and 3) refine the gene model for asthma severity in African American children and adults with ancestral genetic markers. Emory and Wake Forest have a long history of collaboration and together have led the initiative for phenotypic and genomic analyses of severe asthma. The findings generated here are expected to generate novel information on the contribution of genomic variants to severe asthma in African Americans. Given the increased morbidity associated with asthma in African Americans, these findings will lay important groundwork to advance personalized genomics approaches for this challenging and understudied population. This study is also in keeping with the mission of the NINR to improve quality of life by managing the symptoms of chronic illnesses (severe asthma) and to enhance research innovation through application of interdisciplinary approaches to improve the health of asthma patients.