儿童呼出一氧化氮值的分数与17q11.2-q12和17q12-q21变异相关。
Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants.
作者信息
van der Valk Ralf Jp, Duijts Liesbeth, Timpson Nicolas J, Salam Muhammad T, Standl Marie, Curtin John A, Genuneit Jon, Kerhof Marjan, Kreiner-Møller Eskil, Cáceres Alejandro, Gref Anna, Liang Liming L, Taal H Rob, Bouzigon Emmanuelle, Demenais Florence, Nadif Rachel, Ober Carole, Thompson Emma E, Estrada Karol, Hofman Albert, Uitterlinden André G, van Duijn Cornélia, Rivadeneira Fernando, Li Xia, Eckel Sandrah P, Berhane Kiros, Gauderman W James, Granell Raquel, Evans David M, St Pourcain Beate, McArdle Wendy, Kemp John P, Smith George Davey, Tiesler Carla Mt, Flexeder Claudia, Simpson Angela, Murray Clare S, Fuchs Oliver, Postma Dirkje S, Bønnelykke Klaus, Torrent Maties, Andersson Martin, Sleiman Patrick, Hakonarson Hakon, Cookson William O, Moffatt Miriam F, Paternoster Lavinia, Melén Erik, Sunyer Jordi, Bisgaard Hans, Koppelman Gerard H, Ege Markus, Custovic Adnan, Heinrich Joachim, Gilliland Frank D, Henderson Alexander J, Jaddoe Vincent Wv, de Jongste Johan C
机构信息
The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.
出版信息
J Allergy Clin Immunol. 2014 Jul;134(1):46-55. doi: 10.1016/j.jaci.2013.08.053. Epub 2013 Dec 6.
BACKGROUND
The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes.
OBJECTIVE
We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma.
METHODS
Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110).
RESULTS
We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
CONCLUSION
This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.
背景
呼出一氧化氮分数（Feno）值是嗜酸性气道炎症的生物标志物，与儿童哮喘相关。识别与儿童Feno值相关的常见基因变异可能有助于明确与特定哮喘表型相关的生物学机制。
目的
我们试图识别与儿童Feno值相关的基因变异及其与哮喘的关系。
方法
测量了5至15岁儿童的Feno值。在14项全基因组关联研究（N = 8858）中，我们检测了约250万个单核苷酸多态性（SNP）与Feno值的关联。随后，我们评估了显著的SNP在淋巴母细胞系全基因组表达数据集中（n = 1830）是否为表达数量性状位点，以及在先前发表的全基因组关联数据集中（病例，n = 10365；对照受试者：n = 16110）是否与哮喘相关。
结果
我们识别出3个与Feno值相关的SNP：含LYR基序9（LYRM9）中的rs3751972（P = 1.97×10⁻¹⁰）和诱导型一氧化氮合酶2（NOS2）中的rs944722（P = 1.28×10⁻⁹），二者均位于17q11.2 - q12，以及17q12 - q21处gasdermin B（GSDMB）附近的rs8069176（P = 1.88×10⁻⁸）。我们发现转录本可溶性半乳糖苷结合凝集素9（LGALS9）的一个顺式表达数量性状位点，其与rs944722处于连锁不平衡状态。rs8069176与GSDMB和ORM1样3（ORMDL3）的表达相关。17q12 - q21处的rs8069176与医生诊断的哮喘相关，而17q11.2 - q12处的rs3751972和rs944722则不然。
结论
本研究识别出3个与Feno值相关的变异，解释了0.95%的变异。识别这些区域中的功能性SNP和单倍型可能为Feno值的调控提供新的见解。本研究强调了共同和独特的遗传因素均影响Feno值和儿童哮喘。
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