一项全基因组范围内对CD4(+)淋巴细胞调节性遗传变异的调查鉴定出了新的哮喘相关基因。
A genome-wide survey of CD4(+) lymphocyte regulatory genetic variants identifies novel asthma genes.
作者信息
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, Avila Lydiana, Soto-Quiros Manuel, Barraza-Villareal Albino, Lemanske Robert F, 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, Celedón Juan C, Carey Vincent J, Weiss Scott T, Raby Benjamin A
机构信息
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Mass.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Mass.
出版信息
J Allergy Clin Immunol. 2014 Nov;134(5):1153-62. doi: 10.1016/j.jaci.2014.04.011. Epub 2014 Jun 13.
BACKGROUND
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.
OBJECTIVE
We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4(+) lymphocytes for association with asthma.
METHODS
eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by 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 using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes.
RESULTS
Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10(-8)). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P = .002), N-acetyl-α-D-galactosaminidase (NAGA; P = .0002), and Factor XIII, A1 (F13A1; P = .0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4(+) lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity.
CONCLUSIONS
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.
背景
全基因组关联研究尚未确定大多数与哮喘相关的基因变异。我们推测，表达数量性状基因座（eQTL）定位可通过对假定的功能变异进行关联测试的优先级排序来识别新的哮喘基因。
目的
我们评估了通过对CD4(+)淋巴细胞进行全基因组eQTL调查确定的6706个顺式作用表达相关变异（eSNP）与哮喘的关联性。
方法
在儿童哮喘管理项目的359例哮喘患者和846例对照受试者中测试eSNP与哮喘的关联性，并通过基于家系的测试进行验证。在来自哥斯达黎加的579个哮喘亲子三联体中测试显著关联以进行重复验证。通过在肺源性上皮细胞系（Beas-2B和A549）和Jurkat细胞（一种源自T淋巴细胞的白血病细胞系）中使用甲醛辅助调控元件分离（FAIRE）定量PCR和染色质免疫沉淀PCR进行进一步的功能验证。
结果
顺式作用eSNP在两个队列中均显示与哮喘有关联。我们证实了先前报道的ORMDL3/GSDMB变异与哮喘的关联（合并P = 2.9×10(-8)）。在另外3个基因中的eSNP也观察到可重复的关联：脂肪酸去饱和酶2（FADS2；P = 0.002）、N-乙酰-α-D-半乳糖苷酶（NAGA；P = 0.0002）和凝血因子ⅩⅢ，A1（F13A1；P = 0.0001）。随后，我们证明哮喘患者CD4(+)淋巴细胞中FADS2 mRNA增加，并且相关的eSNP位于具有组蛋白修饰的DNA片段内，这些修饰表示开放染色质状态并赋予增强子活性。
结论
我们的结果证明了eQTL定位在识别新的哮喘基因中的效用，并为FADS2、NAGA和F13A1在哮喘发病机制中的重要性提供了证据。
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