哮喘完全缓解的新基因及新理念
2018/08/16
摘要
背景：哮喘是一种可自发缓解但无法治愈的慢性呼吸道疾病。 全基因组关联分析已经确定了与哮喘发展相关的基因，但没有研究哮喘缓解现象。
目的：我们进行了一项全基因组关联分析，以阐释哮喘缓解的机制。
方法：临床缓解（ClinR）定义为最近3年内无哮喘发作，以及最近1年内停止哮喘治疗且无喘息症状。完全缓解（ComR）定义为上述条件外加肺功能正常且无气道高反应性（BHR）。 我们在790名哮喘患者中进行了一项关于临床缓解（ClinR）和完全缓解（ComR）的全基因组关联分析，初步诊断为哮喘和BHR，并进行长期随访。 我们评估了两个独立群组中25组单核苷酸多态性（SNPs）（总n = 456），然后对肺组织和上皮中的4组的SNPs进行表达定量基因座（eQTL）分析。
结果：在对790名哮喘患者进行随访后（随访时间中位数为15.5 [范围为3.3-47.8]年），178名（23％）患者达到临床缓解（ClinR），55名患者（7%）达到完全缓解（ComR）。 在达到临床缓解（ClinR）的患者中，25个SNP中的rs2740102在复制组群的荟萃分析中复制，为肺组织中POLI的eQTL。 在达到完全缓解（ComR）的患者中，3个SNP在复制群组的荟萃分析中复制。 其中复制最为显著的rs6581895几乎达到全基因组显着性（p值=4.68 * 10-7），为肺组织中FRS2和CCT的eQTL。 而其中的Rs1420101是IL1RL1和IL18R1的肺组织中的顺式-eQTL和IL13的反式-eQTL。
结论：通过定义严格的缓解表型，我们确定3个SNP与哮喘完全缓解相关，其中2个SNP与FRS2，CCT，IL1RL1，IL18R1和IL13具有合理的生物学相关性。
Novel genes and insights in complete asthma remission
Vonk JM et al.
Clin Exp Allergy. 2018 May 22
Abstract
Background:Asthma is a chronic respiratory disease without a cure, though there exists spontaneous remission. Genome wide association(GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission.
Objectives:We performed a GWA study to develop insights in asthma remission.
Methods:Clinical remission (ClinR) was defined by absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years, and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long term follow up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in two independent cohorts (total n=456), followed by expression quantitative loci (eQTL) analyses of the four replicated SNPs in lung tissue and epithelium.
Results:Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 [range 3.3-47.8] years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (p-value 4.68*10-7 ) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101, was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13.
Conclusion:By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1, and IL13.
背景：哮喘是一种可自发缓解但无法治愈的慢性呼吸道疾病。 全基因组关联分析已经确定了与哮喘发展相关的基因，但没有研究哮喘缓解现象。
目的：我们进行了一项全基因组关联分析，以阐释哮喘缓解的机制。
方法：临床缓解（ClinR）定义为最近3年内无哮喘发作，以及最近1年内停止哮喘治疗且无喘息症状。完全缓解（ComR）定义为上述条件外加肺功能正常且无气道高反应性（BHR）。 我们在790名哮喘患者中进行了一项关于临床缓解（ClinR）和完全缓解（ComR）的全基因组关联分析，初步诊断为哮喘和BHR，并进行长期随访。 我们评估了两个独立群组中25组单核苷酸多态性（SNPs）（总n = 456），然后对肺组织和上皮中的4组的SNPs进行表达定量基因座（eQTL）分析。
结果：在对790名哮喘患者进行随访后（随访时间中位数为15.5 [范围为3.3-47.8]年），178名（23％）患者达到临床缓解（ClinR），55名患者（7%）达到完全缓解（ComR）。 在达到临床缓解（ClinR）的患者中，25个SNP中的rs2740102在复制组群的荟萃分析中复制，为肺组织中POLI的eQTL。 在达到完全缓解（ComR）的患者中，3个SNP在复制群组的荟萃分析中复制。 其中复制最为显著的rs6581895几乎达到全基因组显着性（p值=4.68 * 10-7），为肺组织中FRS2和CCT的eQTL。 而其中的Rs1420101是IL1RL1和IL18R1的肺组织中的顺式-eQTL和IL13的反式-eQTL。
结论：通过定义严格的缓解表型，我们确定3个SNP与哮喘完全缓解相关，其中2个SNP与FRS2，CCT，IL1RL1，IL18R1和IL13具有合理的生物学相关性。
（复旦大学附属中山医院呼吸内科 罗锦龙 摘译 杨冬 审校）
（Clin Exp Allergy. 2018 May 22）
（Clin Exp Allergy. 2018 May 22）
Novel genes and insights in complete asthma remission
Vonk JM et al.
Clin Exp Allergy. 2018 May 22
Abstract
Background:Asthma is a chronic respiratory disease without a cure, though there exists spontaneous remission. Genome wide association(GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission.
Objectives:We performed a GWA study to develop insights in asthma remission.
Methods:Clinical remission (ClinR) was defined by absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years, and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long term follow up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in two independent cohorts (total n=456), followed by expression quantitative loci (eQTL) analyses of the four replicated SNPs in lung tissue and epithelium.
Results:Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 [range 3.3-47.8] years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (p-value 4.68*10-7 ) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101, was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13.
Conclusion:By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1, and IL13.
