Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.
Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.
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DOI：
10.1016/s2213-2600(14)70002-5
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发表时间：
2014-03
影响因子：
76.2
通讯作者：
Beaty, Terri H.
中科院分区：
文献类型：
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作者：
Cho, Michael H.;McDonald, Merry-Lynn N.;Zhou, Xiaobo;Mattheisen, Manuel;Castaldi, Peter J.;Hersh, Craig P.;DeMeo, Dawn L.;Sylvia, Jody S.;Ziniti, John;Laird, Nan M.;Lange, Christoph;Litonjua, Augusto A.;Sparrow, David;Casaburi, Richard;Barr, R. Graham;Regan, Elizabeth A.;Make, Barry J.;Hokanson, John E.;Lutz, Sharon;Dudenkov, Tanda Murray;Farzadegan, Homayoon;Hetmanski, Jacqueline B.;Tal-Singer, Ruth;Lomas, David A.;Bakke, Per;Gulsvik, Amund;Crapo, James D.;Silverman, Edwin K.;Beaty, Terri H.
慢性阻塞性肺疾病（COPD）易感性的遗传危险因素在很大程度上仍然是未知的。在较大的队列或特定亚组中，可能通过全基因组关联研究确定其他遗传变异。COPDGene（非西班牙裔白人和非洲裔美国人）的全基因组关联分析与ECLIPSE，NETT/NAS和GenKOLS（挪威）研究的现有数据相结合。使用所有中重度病例和重度病例子集进行分析。在ICGN研究中，对先前未被描述为全基因组显著性的前几个位点进行了基因分型，并将结果合并到联合荟萃分析中。对6,633例中重度病例和5,704例对照的分析证实了三个已知位点的关联：CHRNA 3/CHRNA 5/IREB 2，FAM 13 A和HHIP（10−12 < P < 10−14），并且还显示了RIN 3附近新位点的显著关联证据（总P，包括ICGN = 5.4 ×10−9）。在重度COPD分析（n= 3，497）中，在先前描述的三个位点中的两个位点的影响显著更强;我们还确定了先前报道的影响MMP 12和TGFB 2基因表达的另外两个位点（总体P = 2.6x10 −9和8.3x10 −9）。与对照组相比，在一组肺组织研究协会COPD肺组织样本中RIN 3和TGFB 2表达水平降低。在COPD的全基因组研究中，我们证实了三个已知基因座的相关性，并发现RIN 3附近的中重度COPD和MMP 12和TGFB 2附近的重度COPD与其他全基因组显著相关。除了α-1抗胰蛋白酶缺乏症外，遗传变异也会增加COPD的风险。我们对严重COPD的分析表明，通过关注该亚组，可以识别出其他遗传变异。国家心肺血液研究所; COPD基金会（通过阿斯利康、勃林格殷格翰、诺华和Sepracor的捐款）;葛兰素史克;医疗保险和医疗补助服务中心;医疗保健研究和质量机构;美国退伍军人事务部。
The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. Genome-wide association analysis in COPDGene (non-Hispanic whites and African-Americans) was combined with existing data from the ECLIPSE, NETT/NAS, and GenKOLS (Norway) studies. Analyses were performed both using all moderate-to-severe cases and the subset of severe cases. Top loci not previously described as genome-wide significant were genotyped in the ICGN study, and results combined in a joint meta-analysis. Analysis of a total of 6,633 moderate-to-severe cases and 5,704 controls confirmed association at three known loci: CHRNA3/CHRNA5/IREB2, FAM13A, and HHIP (10−12 < P < 10−14), and also showed significant evidence of association at a novel locus near RIN3 (overall P, including ICGN = 5•4×10−9). In the severe COPD analysis (n=3,497), the effects at two of three previously described loci were significantly stronger; we also identified two additional loci previously reported to affect gene expression of MMP12 and TGFB2 (overall P = 2•6x10−9 and 8•3×10−9). RIN3 and TGFB2 expression levels were reduced in a set of Lung Tissue Research Consortium COPD lung tissue samples compared with controls. In a genome-wide study of COPD, we confirmed associations at three known loci and found additional genome-wide significant associations with moderate-to-severe COPD near RIN3 and with severe COPD near MMP12 and TGFB2. Genetic variants, apart from alpha-1 antitrypsin deficiency, increase the risk of COPD. Our analysis of severe COPD suggests additional genetic variants may be identified by focusing on this subgroup. National Heart, Lung, and Blood Institute; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; US Department of Veterans Affairs.