A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.
A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.
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DOI：
10.1186/s12863-015-0299-4
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发表时间：
2015-12-03
期刊：
影响因子：
2.9
通讯作者：
COPDGene Investigators
中科院分区：
文献类型：
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作者：
Lutz SM;Cho MH;Young K;Hersh CP;Castaldi PJ;McDonald ML;Regan E;Mattheisen M;DeMeo DL;Parker M;Foreman M;Make BJ;Jensen RL;Casaburi R;Lomas DA;Bhatt SP;Bakke P;Gulsvik A;Crapo JD;Beaty TH;Laird NM;Lange C;Hokanson JE;Silverman EK;ECLIPSE Investigators;COPDGene Investigators
肺功能下降是吸烟者发病率和死亡率的主要因素。后支气管扩张剂FEV1和FEV1/FVC比值被认为是气流阻塞的标准评估。我们在COPD基因研究中对9919名现在和以前吸烟的人(6659名非西班牙裔白人[nhw]和3260名非裔美国人[AA])进行了全基因组关联研究(Gwas)，以确定与肺活量测量(后支气管扩张剂FEV1和FEV1/FVC)的相关性。我们还在COPD基因、ECLIPSE和GenKOL队列(总计n = 13,532)中进行了FEV1和FEV1/FVC GWA的荟萃分析。在COPD基因队列中的nhw中，两项肺功能指标都与15q25位[包含CHRNA3/5、AGPHD1、IREB2、CHRNB4](最低p值 = 2.17 × 10−11)的SNP显著相关，FEV1/FVC与4号染色体[HHIP上游]上的基因组区域(最低p值 = 5.94 × 10−10)显著相关；这两个区域都曾与COPD相关。在Meta分析中，除了确认与CHRNA3/5和HHIP附近区域的关联外，还确定了染色体1[TGFB2](p值 = 8.99 × 10−9)、9[胸径](p值 = 9.69 × 10−9)和19[CYP2A6/7](p值 = 3.49 × 10−8)以及1号染色体上的FEV1/FVC[TGFB2](p值 = 8.99 × 10−9)的全基因组显著关联。4[FAM13A](p-Value = 3.88 × 10−12)、11[MMP3/12](p-Value = 3.29 × 10−10)和14[RIN3](p-Value = 5.64 × 10−9)。在一项关于吸烟者肺功能的大型全基因组关联研究中，我们发现在之前描述的几个与肺功能或COPD相关的基因座上，全基因组都存在显著关联。此外，在对三个研究群体的荟萃分析中，我们还发现了一个新的全基因组显著基因座，其FEV1位于染色体9[DBH]上。本文的在线版本(doi：10.1186/s12863-0150299-4)包含补充材料，授权用户可以使用。
Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532). Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10−11), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10−10); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10−9), 9 [DBH] (p-value = 9.69 × 10−9) and 19 [CYP2A6/7] (p-value = 3.49 × 10−8) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10−9), 4 [FAM13A] (p-value = 3.88 × 10−12), 11 [MMP3/12] (p-value = 3.29 × 10−10) and 14 [RIN3] (p-value = 5.64 × 10−9). In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations. The online version of this article (doi:10.1186/s12863-015-0299-4) contains supplementary material, which is available to authorized users.