不同血统儿童罕见变异的基因关联研究表明TNFRSF21与过敏性哮喘的发展有关
2023/11/23
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共同变异上。研究罕见变异在不同祖先群体中定量表型和哮喘表型中的作用，可以为这些性状的发展提供额外的、重要的见解。
目的：本研究的目的是检查罕见变异对具有不同血统的儿童的不同哮喘或过敏相关特征的贡献，并探讨它们在哮喘表型中的作用。
方法：我们检查了哮喘纵向研究的儿童参与者的全基因组测序（WGS）数据（n = 1,035;父母确定为67%黑人和25%西班牙裔），以确定罕见的变异（次要等位基因频率<0.01）。我们为基因分配了变异，并使用综合变异集测试测试了 24,902 个基因中的每一个与八个哮喘相关的数量性状之间的关联。将我们的结果与人类预测基因表达的外部数据和小鼠敲除研究相结合，确定了三个候选基因。测试了每个基因和 3 基因组合评分中的罕见变异负担，以了解其与哮喘临床表型的关联。最后，使用过敏原攻击后下气道粘膜细胞中已发表的单细胞基因表达数据来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著相关(p=2.18x10);与总IgE相关的TNFRSF21 (p=6.47x10)和与嗜酸性粒细胞计数相关的PIK3R6 (p=4.10x10)的罕见变异具有提示意义。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基因评分的罕见变异负担与过敏相关表型相关。此外，在成人过敏性哮喘患者的支气管基底上皮细胞中，TNFRSF21显著上调，而在过敏(但不是哮喘)患者的支气管基底上皮细胞中，TNFRSF21在过敏原攻击后没有上调。
结论：我们报告了基因中罕见变异与具有不同祖先的儿童的过敏和炎症表型之间的新关联，强调TNFRSF21与过敏性哮喘的发展有关。
Gene based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma
Clay S, Alladina J, Smith NP, Visness CM,
Abstrast
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：The goal of this study was 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 (WGS) data from children participants in longitudinal studies of asthma (n=1,035; 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 eight asthma-associated quantitative traits. Combining our results with external data on predicted gene expression in humans and mouse knockout studies, three candidate genes were identified. 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 was used to assess transcriptional responses to allergen.
Results：Rare variants in USF1 were significantly associated with blood neutrophil count (p=2.18x10); rare variants in TNFRSF21 with total IgE (p=6.47x10) and PIK3R6 with eosinophil count (p=4.10x10) reached suggestive significance. These three findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score were 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.
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共同变异上。研究罕见变异在不同祖先群体中定量表型和哮喘表型中的作用，可以为这些性状的发展提供额外的、重要的见解。
目的：本研究的目的是检查罕见变异对具有不同血统的儿童的不同哮喘或过敏相关特征的贡献，并探讨它们在哮喘表型中的作用。
方法：我们检查了哮喘纵向研究的儿童参与者的全基因组测序（WGS）数据（n = 1,035;父母确定为67%黑人和25%西班牙裔），以确定罕见的变异（次要等位基因频率<0.01）。我们为基因分配了变异，并使用综合变异集测试测试了 24,902 个基因中的每一个与八个哮喘相关的数量性状之间的关联。将我们的结果与人类预测基因表达的外部数据和小鼠敲除研究相结合，确定了三个候选基因。测试了每个基因和 3 基因组合评分中的罕见变异负担，以了解其与哮喘临床表型的关联。最后，使用过敏原攻击后下气道粘膜细胞中已发表的单细胞基因表达数据来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著相关(p=2.18x10);与总IgE相关的TNFRSF21 (p=6.47x10)和与嗜酸性粒细胞计数相关的PIK3R6 (p=4.10x10)的罕见变异具有提示意义。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基因评分的罕见变异负担与过敏相关表型相关。此外，在成人过敏性哮喘患者的支气管基底上皮细胞中，TNFRSF21显著上调，而在过敏(但不是哮喘)患者的支气管基底上皮细胞中，TNFRSF21在过敏原攻击后没有上调。
结论：我们报告了基因中罕见变异与具有不同祖先的儿童的过敏和炎症表型之间的新关联，强调TNFRSF21与过敏性哮喘的发展有关。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(J Allergy Clin Immunol 2023 Nov 07;doi: 10.1016/j.jaci.2023.10.023. IF：10.228.)
(J Allergy Clin Immunol 2023 Nov 07;doi: 10.1016/j.jaci.2023.10.023. IF：10.228.)
Gene based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma
Clay S, Alladina J, Smith NP, Visness CM,
Abstrast
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：The goal of this study was 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 (WGS) data from children participants in longitudinal studies of asthma (n=1,035; 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 eight asthma-associated quantitative traits. Combining our results with external data on predicted gene expression in humans and mouse knockout studies, three candidate genes were identified. 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 was used to assess transcriptional responses to allergen.
Results：Rare variants in USF1 were significantly associated with blood neutrophil count (p=2.18x10); rare variants in TNFRSF21 with total IgE (p=6.47x10) and PIK3R6 with eosinophil count (p=4.10x10) reached suggestive significance. These three findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score were 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.
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