PDF(Pubmed)
Abstract：
BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits.
OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes.
METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen.
RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge.
CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.
OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes.
METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen.
RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge.
CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.
摘要：
背景：大多数关于哮喘和过敏的遗传研究主要集中在欧洲血统个体的常见变异上。研究不同祖先群体中数量表型和哮喘表型中罕见变异的作用可以提供额外的,对这些性状发展的重要见解。
目的：本研究的目的是研究罕见变异对不同祖先儿童不同哮喘或过敏相关数量性状的影响，并探讨其在哮喘表型中的作用。
方法：我们检查了哮喘纵向研究儿童参与者的全基因组测序（WGS）数据（n=1,035；父母鉴定为67%的黑人和25%的西班牙裔），以鉴定罕见变异（次要等位基因频率<0.01）。我们将变异分配给基因，并使用24,902个基因中的每个基因与八个哮喘相关的定量性状之间的综合变异集测试来测试关联。将我们的结果与人类和小鼠基因敲除研究中预测基因表达的外部数据相结合，确定了三个候选基因。测试了每个基因和3基因组合评分中罕见变异的负担与哮喘临床表型的关联。最后,已发表的过敏原攻击后下气道粘膜细胞中的单细胞基因表达数据用于评估对过敏原的转录反应。
结果：USF1的罕见变异与血液中性粒细胞计数显着相关（p=2.18x10-7）；TNFRSF21的罕见变异与总IgE（p=6.47x10-6）和PIK3R6的嗜酸性粒细胞计数（p=4.10x10-5）达到提示意义。这三个发现得到了来自人类和小鼠研究的独立数据的支持。在轻度和重度哮喘儿童队列中，TNFRSF21和3基因评分中罕见变异的负担与过敏相关表型相关。此外，TNFRSF21在成人过敏性哮喘患者的支气管基底上皮细胞中显著上调，但在成人过敏患者（但非哮喘）中没有。
结论：我们报道了不同祖先儿童的罕见基因变异与过敏性和炎性表型之间的新关联，强调TNFRSF21有助于过敏性哮喘的发展。
目的：本研究的目的是研究罕见变异对不同祖先儿童不同哮喘或过敏相关数量性状的影响，并探讨其在哮喘表型中的作用。
方法：我们检查了哮喘纵向研究儿童参与者的全基因组测序（WGS）数据（n=1,035；父母鉴定为67%的黑人和25%的西班牙裔），以鉴定罕见变异（次要等位基因频率<0.01）。我们将变异分配给基因，并使用24,902个基因中的每个基因与八个哮喘相关的定量性状之间的综合变异集测试来测试关联。将我们的结果与人类和小鼠基因敲除研究中预测基因表达的外部数据相结合，确定了三个候选基因。测试了每个基因和3基因组合评分中罕见变异的负担与哮喘临床表型的关联。最后,已发表的过敏原攻击后下气道粘膜细胞中的单细胞基因表达数据用于评估对过敏原的转录反应。
结果：USF1的罕见变异与血液中性粒细胞计数显着相关（p=2.18x10-7）；TNFRSF21的罕见变异与总IgE（p=6.47x10-6）和PIK3R6的嗜酸性粒细胞计数（p=4.10x10-5）达到提示意义。这三个发现得到了来自人类和小鼠研究的独立数据的支持。在轻度和重度哮喘儿童队列中，TNFRSF21和3基因评分中罕见变异的负担与过敏相关表型相关。此外，TNFRSF21在成人过敏性哮喘患者的支气管基底上皮细胞中显著上调，但在成人过敏患者（但非哮喘）中没有。
结论：我们报道了不同祖先儿童的罕见基因变异与过敏性和炎性表型之间的新关联，强调TNFRSF21有助于过敏性哮喘的发展。
