Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.
Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.
复制标题
DOI：
10.1183/09031936.00093314
复制
发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
LifeLines Cohort Study group
中科院分区：
文献类型：
--
作者：
Dijkstra AE;Boezen HM;van den Berge M;Vonk JM;Hiemstra PS;Barr RG;Burkart KM;Manichaikul A;Pottinger TD;Silverman EK;Cho MH;Crapo JD;Beaty TH;Bakke P;Gulsvik A;Lomas DA;Bossé Y;Nickle DC;Paré PD;de Koning HJ;Lammers JW;Zanen P;Smolonska J;Wijmenga C;Brandsma CA;Groen HJ;Postma DS;LifeLines Cohort Study group
吸烟是慢性粘液分泌过多（CMH）的一个众所周知的危险因素。CMH常发生在慢性阻塞性肺疾病（COPD）中。问题是，是否相同的单核苷酸多态性（SNPs）与吸烟者伴或不伴COPD的CMH相关。我们在具有COPD（n=849，39.9%CMH）和不具有COPD（n= 1，348，25.4%CMH）的男性重度吸烟者（≥20包-年）中进行了两项加性遗传模型下的CMH全基因组关联研究，随后在可比人群中进行了复制和荟萃分析，并评估了显著相关SNP的功能相关性。对COPD和非COPD中CMH的GWA分析在复制后未产生全基因组显著性。在COPD中，我们的最高SNP（rs 10461985，p=5.43×10−5）位于与GDNF基因功能相关的GDNF反义基因中。GDNF在COPD患者支气管活检组织中的表达与CMH显著相关（p=0.007）。在非COPD患者中，4个SNP在荟萃分析中的p值<10−5，包括MAML 3基因中的SNP（rs 4863687），T等位基因显示与CMH适度相关（p=7.57×10−6，OR=1.48），并与肺组织中MAML 3表达显著增加（p=2.59×10−12）。我们的数据表明，慢性阻塞性肺疾病患者和非慢性阻塞性肺疾病患者CMH的遗传背景可能存在差异。
Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in Chronic Obstructive Pulmonary Disease (COPD). The question arises whether the same single nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome wide association studies on CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1,348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs. GWA analysis on CMH in COPD and non-COPD yielded no genome wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10−5) was located in the GDNF-antisense gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD, 4 SNPs had a p-value <10−5 in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10−6, OR=1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10−12). Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.
登录
查看更多内容
影响因子：
5.8
作者：
Agusti A;Calverley PM;Celli B;Coxson HO;Edwards LD;Lomas DA;MacNee W;Miller BE;Rennard S;Silverman EK;Tal-Singer R;Wouters E;Yates JC;Vestbo J;Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators
通讯作者：
Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators
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：
64.8
作者：
van Es, JH;van Gijn, ME;Clevers, H
通讯作者：
Clevers, H
影响因子：
39.2
作者：
Lapperre, Therese S.;Snoeck-Stroband, Jiska B.;Sterk, Peter J.
通讯作者：
Sterk, Peter J.
影响因子：
5
作者：
Bild, DE;Bluemke, DA;Tracy, RP
通讯作者：
Tracy, RP