88个变体突出了T细胞调节和气道重塑在哮喘发病机理中的作用
2020/02/11
摘要
哮喘是同时影响儿童和成人的最常见的慢性疾病之一。我们报告了来自冰岛和英国生物库的69,189例病例和702,199例对照的全基因组关联荟萃分析。我们在56个基因位点发现了88个哮喘风险变异体，其中19个以前未报道，并评估了它们对其他哮喘和过敏表型的影响。特别令人感兴趣的是与哮喘防护相关的两个低频变异，TNFRSF8中的错义变体和TGFBR1中的3'UTR变体。功能研究表明，TNFRSF8变体降低了TNFRSF8细胞表面和可溶形式的表达，从而丧失了功能。 eQTL分析表明，TGFBR1变异体通过功能获得而发挥作用，并与下游基因SMAD3中的内含子变异体一起，表明TGFβR1信号传导缺陷是增加哮喘风险的生物扰动之一。我们的结果增加了哮喘变体以及在哮喘发病机理中的T细胞调节、炎症和气道重塑中发挥作用的基因的数量。
Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.
Olafsdottir TA, Theodors F, Bjarnadottir K, Bjornsdottir US, Agustsdottir AB, Stefansson OA,Ivarsdottir EV, Sigurdsson JK, Benonisdottir S, Eyjolfsson GI, Gislason D, Gislason T,Guðmundsdóttir S, Gylfason A, Halldorsson BV, Halldorsson GH, Juliusdottir T, Kristinsdottir AM,Ludviksdottir D, Ludviksson BR, Masson G, Norland K, Onundarson PT, Olafsson I,Sigurdardottir O, Stefansdottir L, Sveinbjornsson G, Tragante V, Gudbjartsson DF, Thorleifsson G, Sulem P, Thorsteinsdottir U, Norddahl GL, Jonsdottir I, Stefansson K.
Nat Commun. 2020 Jan 20;11(1):393. doi: 10.1038/s41467-019-14144-8.
Abstract
Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.
哮喘是同时影响儿童和成人的最常见的慢性疾病之一。我们报告了来自冰岛和英国生物库的69,189例病例和702,199例对照的全基因组关联荟萃分析。我们在56个基因位点发现了88个哮喘风险变异体，其中19个以前未报道，并评估了它们对其他哮喘和过敏表型的影响。特别令人感兴趣的是与哮喘防护相关的两个低频变异，TNFRSF8中的错义变体和TGFBR1中的3'UTR变体。功能研究表明，TNFRSF8变体降低了TNFRSF8细胞表面和可溶形式的表达，从而丧失了功能。 eQTL分析表明，TGFBR1变异体通过功能获得而发挥作用，并与下游基因SMAD3中的内含子变异体一起，表明TGFβR1信号传导缺陷是增加哮喘风险的生物扰动之一。我们的结果增加了哮喘变体以及在哮喘发病机理中的T细胞调节、炎症和气道重塑中发挥作用的基因的数量。
(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 Commun. 2020 Jan 20;11(1):393. doi: 10.1038/s41467-019-14144-8.)
(Nat Commun. 2020 Jan 20;11(1):393. doi: 10.1038/s41467-019-14144-8.)
Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.
Olafsdottir TA, Theodors F, Bjarnadottir K, Bjornsdottir US, Agustsdottir AB, Stefansson OA,Ivarsdottir EV, Sigurdsson JK, Benonisdottir S, Eyjolfsson GI, Gislason D, Gislason T,Guðmundsdóttir S, Gylfason A, Halldorsson BV, Halldorsson GH, Juliusdottir T, Kristinsdottir AM,Ludviksdottir D, Ludviksson BR, Masson G, Norland K, Onundarson PT, Olafsson I,Sigurdardottir O, Stefansdottir L, Sveinbjornsson G, Tragante V, Gudbjartsson DF, Thorleifsson G, Sulem P, Thorsteinsdottir U, Norddahl GL, Jonsdottir I, Stefansson K.
Nat Commun. 2020 Jan 20;11(1):393. doi: 10.1038/s41467-019-14144-8.
Abstract
Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.
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重症哮喘患者中辣椒素敏感性的增加与严重的临床结果相关
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气道肌成纤维细胞在哮喘中的作用。
