Susceptibility to chronic mucus hypersecretion, a genome wide association study.
Susceptibility to chronic mucus hypersecretion, a genome wide association study.
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DOI：
10.1371/journal.pone.0091621
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
LifeLines Cohort study
中科院分区：
文献类型：
--
作者：
Dijkstra AE;Smolonska J;van den Berge M;Wijmenga C;Zanen P;Luinge MA;Platteel M;Lammers JW;Dahlback M;Tosh K;Hiemstra PS;Sterk PJ;Spira A;Vestbo J;Nordestgaard BG;Benn M;Nielsen SF;Dahl M;Verschuren WM;Picavet HS;Smit HA;Owsijewitsch M;Kauczor HU;de Koning HJ;Nizankowska-Mogilnicka E;Mejza F;Nastalek P;van Diemen CC;Cho MH;Silverman EK;Crapo JD;Beaty TH;Lomas DA;Bakke P;Gulsvik A;Bossé Y;Obeidat M;Loth DW;Lahousse L;Rivadeneira F;Uitterlinden AG;Hofman A;Stricker BH;Brusselle GG;van Duijn CM;Brouwer U;Koppelman GH;Vonk JM;Nawijn MC;Groen HJ;Timens W;Boezen HM;Postma DS;LifeLines Cohort study
在普通人群中，慢性粘液高分泌(CMH)与呼吸道感染频率增加、肺功能过度下降、住院率和死亡率增加有关。它与吸烟有关，但尚不清楚为什么只有一小部分吸烟者会患上CMH。对这一现象的一个看似合理的解释是易感的基因构成。因此，我们在高加索人群中进行了CMH的基因组广泛关联(GWA)研究。在Nelson研究中使用Illumina 610阵列进行了GWA分析，随后在另外11个队列中进行了重复和荟萃分析。总共有2,704名患有慢性肥厚性肥胖症的受试者和7,624名非肥胖症受试者被包括在内，均为现在或以前的重度吸烟者(≥为20包年)。对最显着的单核苷酸多态(SNP)的功能相关性进行了进一步的研究。位于3号染色体富含AT序列结合蛋白1基因内含子9的rs6577641(p = 4.25×10−6，或 = 1.17)与先天性巨噬细胞增多症有很强的相关性。易感等位基因(G)与肺组织中高表达的SATB 1(4.3×10−9)相关。慢性阻塞性肺疾病患者的支气管活检组织中CMH的存在与SATB1mRNA的表达增加有关。原代培养的人支气管上皮细胞在分化过程中可诱导SATB1的表达。我们的发现，SNP rs6577641在多个队列中与CMH相关，是SATB1的顺式eQTL，再加上我们进一步观察到SATB1在上皮分化过程中表达增加，提供了SATB1是影响CMH的基因的提示证据。
Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10−6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10−9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.
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影响因子：
64.5
作者：
DICKINSON, LA;JOH, T;KOHWISHIGEMATSU, T
通讯作者：
KOHWISHIGEMATSU, T
影响因子：
30.8
作者：
通讯作者：
--
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：
2
作者：
Baguma-Nibasheka, M.;Angka, H. E.;Kablar, B.
通讯作者：
Kablar, B.
DOI：
10.1083/jcb.201101148
发表时间：
2011-09-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fessing MY;Mardaryev AN;Gdula MR;Sharov AA;Sharova TY;Rapisarda V;Gordon KB;Smorodchenko AD;Poterlowicz K;Ferone G;Kohwi Y;Missero C;Kohwi-Shigematsu T;Botchkarev VA
通讯作者：
Botchkarev VA