Polygenic risk and the development and course of asthma: an analysis of data from a four-decade longitudinal study
Polygenic risk and the development and course of asthma: an analysis of data from a four-decade longitudinal study
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DOI：
10.1016/s2213-2600(13)70101-2
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发表时间：
2013-08-01
影响因子：
76.2
通讯作者：
Caspi, Avshalom
中科院分区：
文献类型：
--
作者：
Belsky, Daniel W.;Sears, Malcolm R.;Caspi, Avshalom
背景 全基因组关联研究 (GWAS) 发现了导致个体易患哮喘的基因变异。为了将这些新发现与哮喘病理学的新兴模型相结合，我们旨在测试遗传发现如何与哮喘的发育和生物学特征相关。方法在这项前瞻性纵向研究中，我们研究了来自已发表的哮喘病例状态 GWAS 的遗传风险的多位点概况。然后，我们在达尼丁多学科健康与发展研究（n=1037）这一基于人群的长期出生队列的参与者中测试了该遗传风险评分与哮喘的发育和生物学特征之间的关联。我们使用了在 9 至 38 岁的 9 项前瞻性评估中获得的有关哮喘发作、哮喘持续性、特应性、气道高反应性、不完全可逆气流阻塞以及与哮喘相关的学校和工作缺勤和住院的数据。分析包括已获得遗传数据的欧洲血统队列成员。结果在我们的分析中纳入的 880 名队列成员中，遗传风险较高的人比遗传风险较低的人更早患哮喘（风险比 [HR] 1.12，95% CI 1.01-1.26）。在患有儿童期哮喘的队列成员中，遗传风险较高的人比遗传风险较低的人更有可能患上终生持续性哮喘（相对风险 [RR] 1.36，95% CI 1.14-1.63）。与遗传风险较低的哮喘参与者相比，遗传风险较高的哮喘参与者更常出现特应性（RR 1.07、1.01-1.14）、气道高反应性（RR 1.16、1.03-1.32）和不完全可逆气流阻塞（RR 1.28、1.04-1.57）。他们也更有可能因哮喘而缺课或缺勤（发病率 1.38、1.02-1.86）和入院（HR 1.38、1.07-1.79）。有关哮喘风险的基因型信息独立于队列成员哮喘家族史的信息，并且附加于来自队列成员哮喘家族史的信息。解释我们的研究结果证实，哮喘的 GWAS 发现与儿童期发病表型相关。遗传风险评估或许能够预测哪些儿童期发病的哮喘病例得到缓解，哪些病例会终生持续存在，哪些人可能会出现肺功能受损，以及因缺课、缺勤和住院而造成的哮喘负担，尽管这些预测不够敏感或具体，不足以支持立即进行临床转化。
Background Genome-wide association studies (GWAS) have discovered genetic variants that predispose individuals to asthma. To integrate these new discoveries with emerging models of asthma pathobiology, we aimed to test how genetic discoveries relate to developmental and biological characteristics of asthma.Methods In this prospective longitudinal study, we investigated a multilocus profile of genetic risk derived from published GWAS of asthma case status. We then tested associations between this genetic risk score and developmental and biological characteristics of asthma in participants enrolled in a population-based long-running birth cohort, the Dunedin Multidisciplinary Health and Development Study (n=1037). We used data on asthma onset, asthma persistence, atopy, airway hyper-responsiveness, incompletely reversible airflow obstruction, and asthma-related school and work absenteeism and hospital admissions obtained during nine prospective assessments spanning the ages of 9 to 38 years. Analyses included cohort members of European descent from whom genetic data had been obtained.Findings Of the 880 cohort members included in our analysis, those at higher genetic risk developed asthma earlier in life than did those with lower genetic risk (hazard ratio [HR] 1.12, 95% CI 1.01-1.26). Of cohort members with childhood-onset asthma, those with higher genetic risk were more likely to develop life-course-persistent asthma than were those with a lower genetic risk (relative risk [RR] 1.36, 95% CI 1.14-1.63). Participants with asthma at higher genetic risk more often had atopy (RR 1.07, 1.01-1.14), airway hyper-responsiveness (RR 1.16, 1.03-1.32), and incompletely reversible airflow obstruction (RR 1.28, 1.04-1.57) than did those with a lower genetic risk. They were also more likely to miss school or work (incident rate ratio 1.38, 1.02-1.86) and be admitted to hospital (HR 1.38, 1.07-1.79) because of asthma. Genotypic information about asthma risk was independent of and additive to information derived from cohort members' family histories of asthma.Interpretation Our findings confirm that GWAS discoveries for asthma are associated with a childhood-onset phenotype. Genetic risk assessments might be able to predict which childhood-onset asthma cases remit and which become life-course-persistent, who might develop impaired lung function, and the burden of asthma in terms of missed school and work and hospital admissions, although these predictions are not sufficiently sensitive or specific to support immediate clinical translation.