摘要
背景：17q21基因座是儿童期哮喘最强遗传高危因素，与病毒易感性增加和疾病进展有关。
目的：本研究旨在确定与17q21基因座介导的与临床表型相关的病毒易感性增加潜在生物学靶点。
方法：对ALLIANCE队列中261名儿童（78名健康儿童，79名学龄前喘息儿童，104名哮喘儿童）的鼻拭子行全基因组转录组分析，以探讨17q21基因型（SNP rs72163891）的影响。同时，收集同批患者和就诊者的鼻腔分泌物，并采用高灵敏度中尺度技术测量IFN蛋白水平。
结果：本研究表明，17q21风险等位基因可诱导基因型和哮喘/喘息表型依赖性的黏膜GSDMB表达升高，GSDMB是学龄前喘息儿童中唯一相关的17q21编码基因。GSDMB表达升高与1型促炎、细胞裂解免疫和NK信号的激活相关，包括与IFN II型信号相关的关键基因（IFNG、CXCL9、CXCL10、KLRC1、CD8A、GZMA）。相反，IFN-Ⅰ型和Ⅲ型在mRNA和蛋白质水平上的表达均有所减少。
结论：本研究证明了17q21风险等位基因诱导的一种新的疾病驱动机制。黏膜GSDMB表达增加与细胞裂解性免疫反应和气道免疫功能受损有关。上述发现表明，GSDMB相关气道细胞死亡和黏膜IFN亚型变化是17q21风险等位基因携带者在幼年期呼吸道病毒易感性增加的原因，为未来生物治疗开辟了新选择。
17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma.
Jakwerth CA, Weckmann M, Illi S, Charles H, Zissler UM, Oelsner M, Guerth F, Omony J, Nemani SSP, Grychtol R, Dittrich AM, Skevaki C, Foth S, Weber S, Alejandre Alcazar MA, van Koningsbruggen-Rietschel S, Brock R, Blau S, Hansen G, Bahmer T, Rabe KF, Brinkmann F, Kopp MV, Chaker AM, Schaub B, von Mutius E, Schmidt-Weber CB; ALLIANCE Study Group as part of the German Center for Lung Research (DZL).
Abstract
BACKGROUND:The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes.
OBJECTIVE:To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus.
METHODS:Genome-wide transcriptome analysis of nasal brushes from 261 children (78 healthy, 79 preschool wheezers, 104 asthmatics) within the ALLIANCE cohort, with a median age of 10.0 [1.0-20.0], was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology employed to measure IFN-protein levels.
RESULTS:This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Elevated GSDMB expression correlated with the activation of a type-1 pro-inflammatory, cell-lytic immune, and NK signature, encompassing key genes linked to an IFN-type-II-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN-type-I and type-III expression signatures at both mRNA and protein levels.
CONCLUSION:This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.
背景：17q21基因座是儿童期哮喘最强遗传高危因素，与病毒易感性增加和疾病进展有关。
目的：本研究旨在确定与17q21基因座介导的与临床表型相关的病毒易感性增加潜在生物学靶点。
方法：对ALLIANCE队列中261名儿童（78名健康儿童，79名学龄前喘息儿童，104名哮喘儿童）的鼻拭子行全基因组转录组分析，以探讨17q21基因型（SNP rs72163891）的影响。同时，收集同批患者和就诊者的鼻腔分泌物，并采用高灵敏度中尺度技术测量IFN蛋白水平。
结果：本研究表明，17q21风险等位基因可诱导基因型和哮喘/喘息表型依赖性的黏膜GSDMB表达升高，GSDMB是学龄前喘息儿童中唯一相关的17q21编码基因。GSDMB表达升高与1型促炎、细胞裂解免疫和NK信号的激活相关，包括与IFN II型信号相关的关键基因（IFNG、CXCL9、CXCL10、KLRC1、CD8A、GZMA）。相反，IFN-Ⅰ型和Ⅲ型在mRNA和蛋白质水平上的表达均有所减少。
结论：本研究证明了17q21风险等位基因诱导的一种新的疾病驱动机制。黏膜GSDMB表达增加与细胞裂解性免疫反应和气道免疫功能受损有关。上述发现表明，GSDMB相关气道细胞死亡和黏膜IFN亚型变化是17q21风险等位基因携带者在幼年期呼吸道病毒易感性增加的原因，为未来生物治疗开辟了新选择。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Am J Respir Crit Care Med. 2023 Dec 8. doi: 10.1164/rccm.202305-0934OC.)
(Am J Respir Crit Care Med. 2023 Dec 8. doi: 10.1164/rccm.202305-0934OC.)
17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma.
Jakwerth CA, Weckmann M, Illi S, Charles H, Zissler UM, Oelsner M, Guerth F, Omony J, Nemani SSP, Grychtol R, Dittrich AM, Skevaki C, Foth S, Weber S, Alejandre Alcazar MA, van Koningsbruggen-Rietschel S, Brock R, Blau S, Hansen G, Bahmer T, Rabe KF, Brinkmann F, Kopp MV, Chaker AM, Schaub B, von Mutius E, Schmidt-Weber CB; ALLIANCE Study Group as part of the German Center for Lung Research (DZL).
Abstract
BACKGROUND:The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes.
OBJECTIVE:To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus.
METHODS:Genome-wide transcriptome analysis of nasal brushes from 261 children (78 healthy, 79 preschool wheezers, 104 asthmatics) within the ALLIANCE cohort, with a median age of 10.0 [1.0-20.0], was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology employed to measure IFN-protein levels.
RESULTS:This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Elevated GSDMB expression correlated with the activation of a type-1 pro-inflammatory, cell-lytic immune, and NK signature, encompassing key genes linked to an IFN-type-II-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN-type-I and type-III expression signatures at both mRNA and protein levels.
CONCLUSION:This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.
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