Department of Bioengineering and Therapeutic Sciences and.
Department of Medicine, University of California, San Francisco, San Francisco, California.
Am J Respir Crit Care Med. 2020 Oct 1;202(7):962-972. doi: 10.1164/rccm.202002-0351OC.
Puerto Ricans have the highest childhood asthma prevalence in the United States (23.6%); however, the etiology is uncertain. In this study, we sought to uncover the genetic architecture of lung function in Puerto Rican youth with and without asthma who were recruited from the island ( = 836). We used admixture-mapping and whole-genome sequencing data to discover genomic regions associated with lung function. Functional roles of the prioritized candidate SNPs were examined with chromatin immunoprecipitation sequencing, RNA sequencing, and expression quantitative trait loci data. We discovered a genomic region at 1q32 that was significantly associated with a 0.12-L decrease in the lung volume of exhaled air (95% confidence interval, -0.17 to -0.07; = 6.62 × 10) with each allele of African ancestry. Within this region, two SNPs were expression quantitative trait loci of in nasal airway epithelial cells and in esophagus mucosa. The minor alleles of these SNPs were associated with significantly decreased lung function and decreased gene expression. Another admixture-mapping peak was observed on chromosome 5q35.1, indicating that each Native American ancestry allele was associated with a 0.15-L increase in lung function (95% confidence interval, 0.08-0.21; = 5.03 × 10). The region-based association tests identified four suggestive windows that harbored candidate rare variants associated with lung function. We identified common and rare genetic variants that may play a critical role in lung function among Puerto Rican youth. We independently validated an inflammatory pathway that could potentially be used to develop more targeted treatments and interventions for patients with asthma.
波多黎各人的儿童哮喘患病率居美国之首（23.6%）；然而，其病因尚不确定。在这项研究中，我们试图揭示有和无哮喘的波多黎各青年的肺功能的遗传结构，这些青年是从该岛招募的（ = 836）。我们使用混合映射和全基因组测序数据来发现与肺功能相关的基因组区域。通过染色质免疫沉淀测序、RNA 测序和表达数量性状基因座数据来检查优先候选 SNP 的功能作用。我们发现了一个位于 1q32 的基因组区域，与呼气空气肺容积减少 0.12L 显著相关（95%置信区间，-0.17 至-0.07； = 6.62 × 10），每个非洲裔等位基因都与该区域相关。在这个区域内，有两个 SNP 是鼻气道上皮细胞中的表达数量性状基因座和食管黏膜中的表达数量性状基因座。这些 SNP 的次要等位基因与肺功能显著降低和 基因表达显著降低有关。在染色体 5q35.1 上观察到另一个混合映射峰，表明每个美洲原住民等位基因与肺功能增加 0.15L 相关（95%置信区间，0.08-0.21； = 5.03 × 10）。基于区域的关联测试确定了四个可能含有与肺功能相关的候选稀有变异的提示窗口。我们确定了常见和罕见的遗传变异，这些变异可能在波多黎各青年的肺功能中发挥关键作用。我们独立验证了一个潜在的炎症途径，该途径可能用于为哮喘患者开发更有针对性的治疗和干预措施。
