Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility.
Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility.
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DOI：
10.1007/s00439-012-1262-3
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发表时间：
2013-04
期刊：
影响因子：
5.3
通讯作者：
Silverman, Edwin K.
中科院分区：
文献类型：
--
作者：
Siedlinski, Mateusz;Tingley, Dustin;Lipman, Peter J.;Cho, Michael H.;Litonjua, Augusto A.;Sparrow, David;Bakke, Per;Gulsvik, Amund;Lomas, David A.;Anderson, Wayne;Kong, Xiangyang;Rennard, Stephen I.;Beaty, Terri H.;Hokanson, John E.;Crapo, James D.;Lange, Christoph;Silverman, Edwin K.
吸烟是慢性阻塞性肺疾病（COPD）的主要环境危险因素。全基因组关联研究提供了三个基因座与COPD的令人信服的关联。在这项研究中，我们的目的是估计直接，即，独立于吸烟，以及使用中介分析这些位点对COPD发展的间接影响。我们共纳入了3,424例COPD病例和1,872例未受影响的对照组，并提供了两种吸烟相关表型的数据：终生平均吸烟强度和烟草烟雾累积暴露（包年）。我们的分析显示，AGPHD 1/CHRNA 3簇中的两个连锁变体（rs 1051730和rs 8034191）对COPD发展的影响显着，但不完全是由吸烟相关表型介导的。AGPHD 1/CHRNA 3簇中的变体对COPD发展的总效应的约30%由包年介导。同时分析CHRNA 3和IREB 2中的中度（r2 = 0.21）连锁标志物，发现在调整IREB 2单核苷酸多态性后，CHRNA 3基因座对COPD的总效应中有更大比例（约42%）是由包年介导的。本研究证实了AGPHD 1/CHRNA 3、IREB 2、FAM 13 A和HHIP基因座对COPD发展的直接影响。虽然AGPHD 1/CHRNA 3基因座与COPD的关联是由吸烟相关表型显著介导的，但IREB 2似乎独立于吸烟影响COPD。
Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30 % of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r2 = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42 %) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking.
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影响因子：
3.5
作者：
Cho, Michael H.;Castaldi, Peter J.;Silverman, Edwin K.
通讯作者：
Silverman, Edwin K.
影响因子：
7
作者：
Imai, Kosuke;Keele, Luke;Tingley, Dustin
通讯作者：
Tingley, Dustin
影响因子：
30.8
作者：
Repapi, Emmanouela;Sayers, Ian;Tobin, Martin D.
通讯作者：
Tobin, Martin D.
DOI：
10.1164/rccm.200910-1586oc
发表时间：
2010-09-01
影响因子：
24.7
作者：
Hersh, Craig P.;Pillai, Sreekumar G.;Silverman, Edwin K.
通讯作者：
Silverman, Edwin K.
在15q25染色体上的遗传变异与烟草暴露的客观度量之间的关联。
DOI：
10.1093/jnci/djs191
发表时间：
2012-05-16
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Munafò MR;Timofeeva MN;Morris RW;Prieto-Merino D;Sattar N;Brennan P;Johnstone EC;Relton C;Johnson PC;Walther D;Whincup PH;Casas JP;Uhl GR;Vineis P;Padmanabhan S;Jefferis BJ;Amuzu A;Riboli E;Upton MN;Aveyard P;Ebrahim S;Hingorani AD;Watt G;Palmer TM;Timpson NJ;EPIC Study Group;Davey Smith G
通讯作者：
Davey Smith G