A genome-wide survey of CD4(+) lymphocyte regulatory genetic variants identifies novel asthma genes.
A genome-wide survey of CD4(+) lymphocyte regulatory genetic variants identifies novel asthma genes.
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DOI：
10.1016/j.jaci.2014.04.011
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发表时间：
2014-11
影响因子：
14.2
通讯作者：
Raby, Benjamin A.
中科院分区：
文献类型：
--
作者：
Sharma, Sunita;Zhou, Xiaobo;Thibault, Derek M.;Himes, Blanca E.;Liu, Andy;Szefler, Stanley J.;Strunk, Robert;Castro, Mario;Hansel, Nadia N.;Diette, Gregory B.;Vonakis, Becky M.;Adkinson, N. Franklin, Jr.;Avila, Lydiana;Soto-Quiros, Manuel;Barraza-Villareal, Albino;Lemanske, Robert F., Jr.;Solway, Julian;Krishnan, Jerry;White, Steven R.;Cheadle, Chris;Berger, Alan E.;Fan, Jinshui;Boorgula, Meher Preethi;Nicolae, Dan;Gilliland, Frank;Barnes, Kathleen;London, Stephanie J.;Martinez, Fernando;Ober, Carole;Celedon, Juan C.;Carey, Vincent J.;Weiss, Scott T.;Raby, Benjamin A.
关键词：
全基因组关联研究尚未确定大多数与哮喘有关的基因变异。我们假设，表达数量性状基因座(EQTL)定位可以通过确定关联测试的假定功能变异的优先顺序来识别新的哮喘基因。我们评估了6,706个顺式作用表达相关变异体(ESNP)，这些变异体是通过对CD4+淋巴细胞进行全基因组eQTL调查确定的，与哮喘有关。来自儿童哮喘管理计划的359名哮喘患者和846名对照进行了ESNP与哮喘的相关性测试，并使用基于家庭的测试进行了验证。在来自哥斯达黎加的579名患有哮喘的亲子三人组中，对重要的相关性进行了重复测试。对肺源性上皮细胞系(BEAS-2B和A549)和T淋巴细胞白血病细胞系Jurkat细胞进行甲醛辅助分离调节元件(FAIRE)-qPCR和染色质免疫沉淀(CHIP)-PCR进一步的功能验证。顺式作用的ESNP在两个队列中都显示与哮喘有关。我们证实了先前报道的ORMDL3/GSDMB变异与哮喘的关联(合并p=2.9×108)。在另外三个基因：FADS2(p=0.002)、NAGA(p=0.0002)和F13A1(p=0.0001)中也观察到了ESNP的可重复性关联。我们随后证明了哮喘患者CD4+淋巴细胞中FADS2 mRNA的增加，并且相关的eSNP存在于DNA片段中，组蛋白修饰表示染色质开放状态并赋予增强子活性。我们的结果证明了eQTL定位在识别新的哮喘基因方面的应用，并为FADS2、NAGA和F13A1在哮喘发病机制中的重要性提供了证据。
Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. We evaluated 6,706 cis-acting expression-associated variants (eSNP) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. eSNP were tested for association with asthma in 359 asthma cases and 846 controls from the Childhood Asthma Management Program, with verification using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE)-qPCR and Chromatin-Immunoprecipitation (ChIP)-PCR in lung derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Cis-acting eSNP demonstrated associations with asthma in both cohorts. We confirmed the previously-reported association of ORMDL3/GSDMB variants with asthma (combined p=2.9 × 108). Reproducible associations were also observed for eSNP in three additional genes: FADS2 (p=0.002), NAGA (p=0.0002), and F13A1 (p=0.0001). We subsequently demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatics, and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes, and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.
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影响因子：
3.7
作者：
Gu W;Xu W;Ding T;Guo X
通讯作者：
Guo X
影响因子：
3.7
作者：
Rzehak P;Thijs C;Standl M;Mommers M;Glaser C;Jansen E;Klopp N;Koppelman GH;Singmann P;Postma DS;Sausenthaler S;Dagnelie PC;van den Brandt PA;Koletzko B;Heinrich J;KOALA study group;LISA study group
通讯作者：
LISA study group
影响因子：
14.2
作者：
Fukuda, T;Mochida, S;Makino, S
通讯作者：
Makino, S
影响因子：
2.5
作者：
Marioni, R. E.;Deary, I. J.;Price, J. F.
通讯作者：
Price, J. F.
影响因子：
6.5
作者：
Lattka, E.;Eggers, S.;Adamski, J.
通讯作者：
Adamski, J.