非洲人特有的等位基因改变了非洲裔美国人在17q12-q21位点上的哮喘风险
2022/10/17
摘要
背景：哮喘是儿童中最常见的慢性疾病，在非洲血统的儿童中发生的频率更高，病情更严重。
方法：我们测试了17q12-q21最常见和最显著的儿童哮喘发病位点的单倍型与欧美和非洲裔美国儿童哮喘的相关性。在此之后，我们使用了1060名非洲裔美国人和100名欧洲裔美国人的全基因组测序数据，以确定高风险非洲裔美国人特定单倍型的新变体。我们使用来自气道上皮细胞的基因表达和ATAC序列数据、来自ENCODE的功能注释以及气道上皮细胞中的启动子捕获（pc）Hi-C图，在电子版中对这些变体进行了表征。然后评估非洲裔美国儿童和成人的候选因果变异与哮喘相关表型的相关性。
结果：我们的研究揭示了九种新的非洲特异性常见变异体，丰富了高危哮喘单倍型，它们调节气道上皮细胞中GSDMA的表达，并与严重哮喘的特征相关。使用ENCODE注释、ATAC-seq和pcHi-C，我们缩小了与T2低重度哮喘特征相关的两个候选因果变量的关联。
结论：17q12-21儿童期哮喘发病基因座先前未知的遗传变异与非洲血统个体的哮喘严重程度有关。我们认为，在GWAS中尚未发现的许多其他人群特异性变异体有助于哮喘和其他常见疾病的遗传风险。
African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans
Washington C 3rd, Dapas M, Biddanda A, et al.
Abstract
BACKGROUND:Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry.
METHODS:We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American-specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults.
RESULTS:Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma.
CONCLUSION:Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.
背景：哮喘是儿童中最常见的慢性疾病，在非洲血统的儿童中发生的频率更高，病情更严重。
方法：我们测试了17q12-q21最常见和最显著的儿童哮喘发病位点的单倍型与欧美和非洲裔美国儿童哮喘的相关性。在此之后，我们使用了1060名非洲裔美国人和100名欧洲裔美国人的全基因组测序数据，以确定高风险非洲裔美国人特定单倍型的新变体。我们使用来自气道上皮细胞的基因表达和ATAC序列数据、来自ENCODE的功能注释以及气道上皮细胞中的启动子捕获（pc）Hi-C图，在电子版中对这些变体进行了表征。然后评估非洲裔美国儿童和成人的候选因果变异与哮喘相关表型的相关性。
结果：我们的研究揭示了九种新的非洲特异性常见变异体，丰富了高危哮喘单倍型，它们调节气道上皮细胞中GSDMA的表达，并与严重哮喘的特征相关。使用ENCODE注释、ATAC-seq和pcHi-C，我们缩小了与T2低重度哮喘特征相关的两个候选因果变量的关联。
结论：17q12-21儿童期哮喘发病基因座先前未知的遗传变异与非洲血统个体的哮喘严重程度有关。我们认为，在GWAS中尚未发现的许多其他人群特异性变异体有助于哮喘和其他常见疾病的遗传风险。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(Genome Med. 2022 Sep 29; DOI: 10.1186/s13073-022-01114-x)
(Genome Med. 2022 Sep 29; DOI: 10.1186/s13073-022-01114-x)
African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans
Washington C 3rd, Dapas M, Biddanda A, et al.
Abstract
BACKGROUND:Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry.
METHODS:We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American-specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults.
RESULTS:Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma.
CONCLUSION:Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.
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孟德尔随机分析揭示了特应性皮炎、哮喘和GERD之间复杂的遗传相互作用
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空气原油化学物质与基于症状哮喘间的相关性分析
