欧洲血统个体的中-重度哮喘：一项全基因组关联研究
2020/01/02
摘要
背景：目前关于中重度哮喘的遗传学研究几乎没有。我们的目标是识别与中重度哮喘相关的新基因变异，探讨既往识别的所有类型哮喘的基因变异是否促进中重度哮喘的发生，并通过分析其在哮喘患者中的表达提供新的机制上的见解。
方法：在这项全基因组关联研究中，我们采用了两阶段病例对照设计。在第一阶段,我们对两个来自英国的队列（哮喘严重程度和表观的遗传学【GASP】的能动性和无偏倚的生物标志物预测呼吸系统疾病的结果）的患者水平的数据进行了基因分型，并利用来自英国生物银行的数据，以1：5的比例收集欧洲血统的病例和对照组的水平基因组数据。如果患者正在服用适当的药物或已被医生诊断出患有中重度哮喘，则将其定义为哮喘。对照组被定义为没有医生诊断的哮喘、鼻炎、湿疹、过敏、肺气肿或慢性支气管炎。对于第2阶段，我们只从英国生物库中选择了独立的病例和对照队列(1:5)，与第1阶段的样本没有重叠。在第1阶段，我们对中重度哮喘进行了全基因组关联研究，在第2阶段，我们跟踪了在第1阶段达到p < 1×10-6的显著性阈值的独立变异。我们将基因组的广泛性设置为p < 5×10-8。对于新的信号，我们研究了它们对所有类型哮喘(轻度、中度和重度)的影响。对于所有符合全基因组意义的信号，我们研究了它们对哮喘患者和对照组基因表达的影响。
结果：我们在第1阶段纳入5135个病例和25675个对照，在第2阶段纳入5414个病例和21471个对照。我们鉴定了24个与中重度哮喘相关的全基因组重要信号，包括先天性或适应性免疫的几种信号、反应基因。鉴定了三个新信号：GATA3中的rs10905284（编码等位基因A，优势比[OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10），MUC5AC区域中的rs11603634 （编码等位基因G，OR1·09, 1·06-1·12; p=2·32 × 10-8），以及KIAA1109附近的rs560026225（编码等位基因GATT，或1·12, 1·08-1·16; p=3·06 × 10-9）。分析轻度哮喘时发现，MUC5AC信号与哮喘无关。通过rs11602802单核酸多态性测序发现，rs11603634 G等位基因与支气管上皮刷样中MUC5AC mRNA的表达增加有关(p=2·50 × 10-5)；重度哮喘患者支气管上皮中MUC5AC mRNA表达增加（在两个独立分析中，p=0·039 and p=0·022）。
结论：我们发现在轻度到中重度哮喘之间存在着大量的共同基因结构。我们还首次报道了与调节粘蛋白产生的中、重度哮喘的发病风险增加相关的基因变异。最后，我们确定了这些基因座中的候选致病基因，并对这一难以治疗的人群提供了更多的信息。
Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study
N Shrine, et al. Lancet Respir Med. 2018 Dec.
Abstract
BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severeasthma, and provide novel mechanistic insights using expression analyses in patients with asthma.
METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-widesignificance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.
FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).
INTERPRETATION: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.
背景：目前关于中重度哮喘的遗传学研究几乎没有。我们的目标是识别与中重度哮喘相关的新基因变异，探讨既往识别的所有类型哮喘的基因变异是否促进中重度哮喘的发生，并通过分析其在哮喘患者中的表达提供新的机制上的见解。
方法：在这项全基因组关联研究中，我们采用了两阶段病例对照设计。在第一阶段,我们对两个来自英国的队列（哮喘严重程度和表观的遗传学【GASP】的能动性和无偏倚的生物标志物预测呼吸系统疾病的结果）的患者水平的数据进行了基因分型，并利用来自英国生物银行的数据，以1：5的比例收集欧洲血统的病例和对照组的水平基因组数据。如果患者正在服用适当的药物或已被医生诊断出患有中重度哮喘，则将其定义为哮喘。对照组被定义为没有医生诊断的哮喘、鼻炎、湿疹、过敏、肺气肿或慢性支气管炎。对于第2阶段，我们只从英国生物库中选择了独立的病例和对照队列(1:5)，与第1阶段的样本没有重叠。在第1阶段，我们对中重度哮喘进行了全基因组关联研究，在第2阶段，我们跟踪了在第1阶段达到p < 1×10-6的显著性阈值的独立变异。我们将基因组的广泛性设置为p < 5×10-8。对于新的信号，我们研究了它们对所有类型哮喘(轻度、中度和重度)的影响。对于所有符合全基因组意义的信号，我们研究了它们对哮喘患者和对照组基因表达的影响。
结果：我们在第1阶段纳入5135个病例和25675个对照，在第2阶段纳入5414个病例和21471个对照。我们鉴定了24个与中重度哮喘相关的全基因组重要信号，包括先天性或适应性免疫的几种信号、反应基因。鉴定了三个新信号：GATA3中的rs10905284（编码等位基因A，优势比[OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10），MUC5AC区域中的rs11603634 （编码等位基因G，OR1·09, 1·06-1·12; p=2·32 × 10-8），以及KIAA1109附近的rs560026225（编码等位基因GATT，或1·12, 1·08-1·16; p=3·06 × 10-9）。分析轻度哮喘时发现，MUC5AC信号与哮喘无关。通过rs11602802单核酸多态性测序发现，rs11603634 G等位基因与支气管上皮刷样中MUC5AC mRNA的表达增加有关(p=2·50 × 10-5)；重度哮喘患者支气管上皮中MUC5AC mRNA表达增加（在两个独立分析中，p=0·039 and p=0·022）。
结论：我们发现在轻度到中重度哮喘之间存在着大量的共同基因结构。我们还首次报道了与调节粘蛋白产生的中、重度哮喘的发病风险增加相关的基因变异。最后，我们确定了这些基因座中的候选致病基因，并对这一难以治疗的人群提供了更多的信息。
(中国医科大学附属一院呼吸与危重症学科 李文扬 摘译 杨冬 审校)
(N Shrine, et al. Lancet Respir Med. 2018 Dec.)
(N Shrine, et al. Lancet Respir Med. 2018 Dec.)
Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study
N Shrine, et al. Lancet Respir Med. 2018 Dec.
Abstract
BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severeasthma, and provide novel mechanistic insights using expression analyses in patients with asthma.
METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-widesignificance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.
FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).
INTERPRETATION: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.
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重度哮喘患者运动期间存在喉梗阻的高发生率
下一篇：
已知哮喘基因座中有害和调控基因组变异的鉴定
