131个遗传位点揭示鼻息肉和哮喘中的免疫通路及组织
2025/11/28
摘要
哮喘与伴鼻息肉的慢性鼻窦炎（CRSwNP）共存与过敏表型、疾病严重程度以及哮喘和CRSwNP一线治疗失败相关。近期研究强调了这些疾病存在共享的遗传成分。为更好地理解这一共享成分，我们对芬兰基因组（FinnGen）和英国生物银行（UKB）中的哮喘（n=71,481）、伴鼻息肉的慢性鼻窦炎（CRSwNP，n=9,626）及不伴鼻息肉的慢性鼻窦炎（CRSsNP，n=15,448）（共685,602名对照）进行了全基因组荟萃分析。我们检测到131个基因组关联，包括17个哮喘新位点、33个CRSwNP新位点和1个CRSsNP位点。在71个位点观察到对哮喘和CRSwNP的共同影响。利用所有疾病的跨性状荟萃分析进一步确定了17个与哮喘或哮喘和CRSwNP相关的位点。我们还发现了17个非同义关联变异，包括一个与CRSwNP相关的新型TP63错义变异（OR=1.519 [1.331-1.734]）。基因集分析证实了与2型炎症、Jak-STAT信号传导和FOXP3信号传导相关的基因富集。我们的结果揭示了CRSwNP和哮喘新的共享及独立遗传通路。这些结果为功能和流行病学后续研究提供了多个方向，并为两种疾病的免疫和非免疫机制提供了证据。
哮喘与伴鼻息肉的慢性鼻窦炎（CRSwNP）共存与过敏表型、疾病严重程度以及哮喘和CRSwNP一线治疗失败相关。近期研究强调了这些疾病存在共享的遗传成分。为更好地理解这一共享成分，我们对芬兰基因组（FinnGen）和英国生物银行（UKB）中的哮喘（n=71,481）、伴鼻息肉的慢性鼻窦炎（CRSwNP，n=9,626）及不伴鼻息肉的慢性鼻窦炎（CRSsNP，n=15,448）（共685,602名对照）进行了全基因组荟萃分析。我们检测到131个基因组关联，包括17个哮喘新位点、33个CRSwNP新位点和1个CRSsNP位点。在71个位点观察到对哮喘和CRSwNP的共同影响。利用所有疾病的跨性状荟萃分析进一步确定了17个与哮喘或哮喘和CRSwNP相关的位点。我们还发现了17个非同义关联变异，包括一个与CRSwNP相关的新型TP63错义变异（OR=1.519 [1.331-1.734]）。基因集分析证实了与2型炎症、Jak-STAT信号传导和FOXP3信号传导相关的基因富集。我们的结果揭示了CRSwNP和哮喘新的共享及独立遗传通路。这些结果为功能和流行病学后续研究提供了多个方向，并为两种疾病的免疫和非免疫机制提供了证据。
（北京朝阳医院呼吸与危重症医学科 顾宪民 摘译 中日友好医院呼吸与危重症医学科 林江涛 审校）
（Nat Commun. 2025 Nov 10;16(1):9879. doi: 10.1038/s41467-025-64847-4.）
131 genetic loci highlight immunological pathways and tissues in nasal polyposis and asthma
Elmo C Saarentaus, Kasper Fischer-Rasmussen, Eeva Sliz, Argyro Bizaki-Vallaskangas; FinnGen; Tarja Laitinen, Sanna Toppila-Salmi, Hannu Kankaanranta, Johannes Kettunen, Klaus Bønnelykke, Aarno Palotie, Antti Mäkitie
Abstract
The coexistence of asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with allergic phenotypes, disease severity and failure of first-line treatment for both asthma and CRSwNP. Recent studies have highlighted shared genetic components for these diseases. To better understand this shared component, we perform genome-wide meta-analyses of asthma (n = 71,481), CRSwNP (n = 9626) and chronic rhinosinusitis without nasal polyposis (CRSsNP, n = 15,448) in FinnGen and UKB (685,602 controls). We detect 131 genomic associations, including 17 novel loci for asthma, 33 novel loci for CRSwNP, and one for CRSsNP. A shared impact on asthma and CRSwNP is observed at 71 loci. A cross-trait meta-analysis using all disorders further implicates 17 loci associated with asthma or asthma and CRSwNP. We also find 17 nonsynonymous associating variants, including a novel TP63 missense variant association with CRSwNP (OR = 1.519 [1.331-1.734]). Gene set analyses confirm enrichment of genes involved with type 2 inflammation, Jak-STAT signaling, and FOXP3 signaling. Our results highlight new shared and separate genetic pathways for CRSwNP and asthma. These provide several avenues of further investigation in functional and epidemiological follow-up, and evidence for immunological and non-immunological mechanisms behind both diseases.
Elmo C Saarentaus, Kasper Fischer-Rasmussen, Eeva Sliz, Argyro Bizaki-Vallaskangas; FinnGen; Tarja Laitinen, Sanna Toppila-Salmi, Hannu Kankaanranta, Johannes Kettunen, Klaus Bønnelykke, Aarno Palotie, Antti Mäkitie
Abstract
The coexistence of asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with allergic phenotypes, disease severity and failure of first-line treatment for both asthma and CRSwNP. Recent studies have highlighted shared genetic components for these diseases. To better understand this shared component, we perform genome-wide meta-analyses of asthma (n = 71,481), CRSwNP (n = 9626) and chronic rhinosinusitis without nasal polyposis (CRSsNP, n = 15,448) in FinnGen and UKB (685,602 controls). We detect 131 genomic associations, including 17 novel loci for asthma, 33 novel loci for CRSwNP, and one for CRSsNP. A shared impact on asthma and CRSwNP is observed at 71 loci. A cross-trait meta-analysis using all disorders further implicates 17 loci associated with asthma or asthma and CRSwNP. We also find 17 nonsynonymous associating variants, including a novel TP63 missense variant association with CRSwNP (OR = 1.519 [1.331-1.734]). Gene set analyses confirm enrichment of genes involved with type 2 inflammation, Jak-STAT signaling, and FOXP3 signaling. Our results highlight new shared and separate genetic pathways for CRSwNP and asthma. These provide several avenues of further investigation in functional and epidemiological follow-up, and evidence for immunological and non-immunological mechanisms behind both diseases.
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依赖氧化还原的ATF3抑制通过MKP-1/p38 MAPK信号通路损害哮喘中的类固醇敏感性
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