哮喘、花粉热和湿疹存在共同遗传复制起点阐明变应性疾病生物学特点
2017/11/20
摘要
哮喘、花粉热（或过敏性鼻炎）和湿疹（或特异性皮炎）常出现在同一病人中，部分原因是由于它们有共同的遗传复制起点。为明确共有的风险变异，我们设计了一项广泛的过敏性疾病表型的全基因组关联分析研究（GWAS; n = 360,838），包括以上三种疾病中的任何一种。我们确定了136种独立的风险变异（P < 3 × 10−8），132种为变应性疾病病理生理相关的基因，其中73种未曾报导过。其中的6种变异型进行了疾病特异性作用检测，证实大多数存在共同的危险因素。组织特异的遗传力和生物富集过程分析表明共有风险变异影响了淋巴细胞介导的免疫力。6种靶基因为药物重新定位提供了可能，同时发现了36种基因CpG甲基化影响转录遗传效力。哮喘、花粉热（或过敏性鼻炎）和湿疹共存部分是由于它们有许多共同的基因风险变异，使得免疫相关基因表达调节异常。
Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology
Ferreira MA, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, Helmer Q, Tillander A, Ullemar V, van Dongen J, Lu Y, Rüschendorf F, Esparza-Gordillo J, Medway CW, Mountjoy E, Burrows K, Hummel O, Grosche S, Brumpton BM, Witte JS, Hottenga JJ, Willemsen G, Zheng J, Rodríguez E, Hotze M, Franke A, Revez JA, Beesley J, Matheson MC, Dharmage SC, Bain LM, Fritsche LG, Gabrielsen ME, Balliu B; 23andMe Research Team; AAGC collaborators; BIOS consortium; LifeLines Cohort Study, Nielsen JB, Zhou W, Hveem K, Langhammer A, Holmen OL, Løset M, Abecasis GR, Willer CJ, Arnold A, Homuth G, Schmidt CO, Thompson PJ, Martin NG, Duffy DL, Novak N, Schulz H, Karrasch S, Gieger C, Strauch K, Melles RB, Hinds DA, Hübner N, Weidinger S, Magnusson PKE, Jansen R, Jorgenson E, Lee YA, Boomsma DI, Almqvist C, Karlsson R, Koppelman GH, Paternoster L.
Abstract
Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.
哮喘、花粉热（或过敏性鼻炎）和湿疹（或特异性皮炎）常出现在同一病人中，部分原因是由于它们有共同的遗传复制起点。为明确共有的风险变异，我们设计了一项广泛的过敏性疾病表型的全基因组关联分析研究（GWAS; n = 360,838），包括以上三种疾病中的任何一种。我们确定了136种独立的风险变异（P < 3 × 10−8），132种为变应性疾病病理生理相关的基因，其中73种未曾报导过。其中的6种变异型进行了疾病特异性作用检测，证实大多数存在共同的危险因素。组织特异的遗传力和生物富集过程分析表明共有风险变异影响了淋巴细胞介导的免疫力。6种靶基因为药物重新定位提供了可能，同时发现了36种基因CpG甲基化影响转录遗传效力。哮喘、花粉热（或过敏性鼻炎）和湿疹共存部分是由于它们有许多共同的基因风险变异，使得免疫相关基因表达调节异常。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Nat Genet. 2017 Oct 30.)
(Nat Genet. 2017 Oct 30.)
Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology
Ferreira MA, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, Helmer Q, Tillander A, Ullemar V, van Dongen J, Lu Y, Rüschendorf F, Esparza-Gordillo J, Medway CW, Mountjoy E, Burrows K, Hummel O, Grosche S, Brumpton BM, Witte JS, Hottenga JJ, Willemsen G, Zheng J, Rodríguez E, Hotze M, Franke A, Revez JA, Beesley J, Matheson MC, Dharmage SC, Bain LM, Fritsche LG, Gabrielsen ME, Balliu B; 23andMe Research Team; AAGC collaborators; BIOS consortium; LifeLines Cohort Study, Nielsen JB, Zhou W, Hveem K, Langhammer A, Holmen OL, Løset M, Abecasis GR, Willer CJ, Arnold A, Homuth G, Schmidt CO, Thompson PJ, Martin NG, Duffy DL, Novak N, Schulz H, Karrasch S, Gieger C, Strauch K, Melles RB, Hinds DA, Hübner N, Weidinger S, Magnusson PKE, Jansen R, Jorgenson E, Lee YA, Boomsma DI, Almqvist C, Karlsson R, Koppelman GH, Paternoster L.
Abstract
Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.
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干扰素刺激哮喘基因表达，2型炎症和内质网应激
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内凝集素促进了过敏原诱导的IL-25、IL-33、TSLP表达及哮喘、特异性皮炎中的2型过敏反应
