COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression.
COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression.
复制标题
DOI：
10.1093/hmg/ddx390
复制
发表时间：
2018-01-15
影响因子：
3.5
通讯作者：
Amin N
中科院分区：
文献类型：
--
作者：
Nedeljkovic I;Lahousse L;Carnero-Montoro E;Faiz A;Vonk JM;de Jong K;van der Plaat DA;van Diemen CC;van den Berge M;Obeidat M;Bossé Y;Nickle DC;Consortium BIOS;Uitterlinden AG;van Meurs JBJ;Stricker BHC;Brusselle GG;Postma DS;Boezen HM;van Duijn CM;Amin N
慢性阻塞性肺疾病(COPD)是成人的主要健康负担之一。虽然吸烟是主要的风险因素，但越来越多的基因变异被发现会影响疾病的易感性。表观遗传修饰可能介导基因组对吸烟的反应，并调节基因表达。染色体19q13.2区域与吸烟和COPD相关，但其功能作用尚不清楚。我们的研究旨在确定19q13.2区域的顶级遗传变异rs7937(RAB4B，EGLN2)是否与血液(N = 1490)中的差异甲基化以及血液(N = 721)和肺(N = 1087)中的基因表达有关。我们结合了鹿特丹研究(RS)的遗传和表观遗传学数据，对rs7937进行了表观基因组范围的关联分析。此外，我们使用来自血液和肺组织的遗传和转录组数据(肺表达数量性状基因座定位研究)，进行了rs7937的转录组范围的关联研究。Rs7937显著(FDR <；DNA0.05)，并且一致地与顺式结构中4个 位点的不同DNA甲基化有关，与吸烟无关。1个甲基化位点(cg11298343-EGLn2)也与慢性阻塞性肺疾病相关(P = 0.001)。此外，rs7937还与血液中顺式(EGLN2)、cg11298343、肺组织、顺式和反式(NUMBL、EGLN2、DNMT3A、LOC101929709和PAK2)的基因表达水平有关。我们的结果提示，DNA甲基化和基因表达的变化可能是基因变异和COPD之间的中间步骤，但在肺组织中的进一步因果研究应该证实这一假说。
Chronic obstructive pulmonary disease (COPD) is among the major health burdens in adults. While cigarette smoking is the leading risk factor, a growing number of genetic variations have been discovered to influence disease susceptibility. Epigenetic modifications may mediate the response of the genome to smoking and regulate gene expression. Chromosome 19q13.2 region is associated with both smoking and COPD, yet its functional role is unclear. Our study aimed to determine whether rs7937 (RAB4B, EGLN2), a top genetic variant in 19q13.2 region identified in genome-wide association studies of COPD, is associated with differential DNA methylation in blood (N = 1490) and gene expression in blood (N = 721) and lungs (N = 1087). We combined genetic and epigenetic data from the Rotterdam Study (RS) to perform the epigenome-wide association analysis of rs7937. Further, we used genetic and transcriptomic data from blood (RS) and from lung tissue (Lung expression quantitative trait loci mapping study), to perform the transcriptome-wide association study of rs7937. Rs7937 was significantly (FDR < 0.05) and consistently associated with differential DNA methylation in blood at 4 CpG sites in cis, independent of smoking. One methylation site (cg11298343-EGLN2) was also associated with COPD (P = 0.001). Additionally, rs7937 was associated with gene expression levels in blood in cis (EGLN2), 42% mediated through cg11298343, and in lung tissue, in cis and trans (NUMBL, EGLN2, DNMT3A, LOC101929709 and PAK2). Our results suggest that changes of DNA methylation and gene expression may be intermediate steps between genetic variants and COPD, but further causal studies in lung tissue should confirm this hypothesis.
登录
查看更多内容
影响因子：
3.7
作者：
Lamontagne M;Couture C;Postma DS;Timens W;Sin DD;Paré PD;Hogg JC;Nickle D;Laviolette M;Bossé Y
通讯作者：
Bossé Y
影响因子：
16.6
作者：
Soler Artigas M;Wain LV;Miller S;Kheirallah AK;Huffman JE;Ntalla I;Shrine N;Obeidat M;Trochet H;McArdle WL;Alves AC;Hui J;Zhao JH;Joshi PK;Teumer A;Albrecht E;Imboden M;Rawal R;Lopez LM;Marten J;Enroth S;Surakka I;Polasek O;Lyytikäinen LP;Granell R;Hysi PG;Flexeder C;Mahajan A;Beilby J;Bossé Y;Brandsma CA;Campbell H;Gieger C;Gläser S;González JR;Grallert H;Hammond CJ;Harris SE;Hartikainen AL;Heliövaara M;Henderson J;Hocking L;Horikoshi M;Hutri-Kähönen N;Ingelsson E;Johansson Å;Kemp JP;Kolcic I;Kumar A;Lind L;Melén E;Musk AW;Navarro P;Nickle DC;Padmanabhan S;Raitakari OT;Ried JS;Ripatti S;Schulz H;Scott RA;Sin DD;Starr JM;UK BiLEVE;Viñuela A;Völzke H;Wild SH;Wright AF;Zemunik T;Jarvis DL;Spector TD;Evans DM;Lehtimäki T;Vitart V;Kähönen M;Gyllensten U;Rudan I;Deary IJ;Karrasch S;Probst-Hensch NM;Heinrich J;Stubbe B;Wilson JF;Wareham NJ;James AL;Morris AP;Jarvelin MR;Hayward C;Sayers I;Strachan DP;Hall IP;Tobin MD
通讯作者：
Tobin MD
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：
168.9
作者：
Gakidou, Emmanuela;Cowling, Krycia;Murray, Christopher J. L.
通讯作者：
Murray, Christopher J. L.
DOI：
10.1164/rccm.201403-0569oc
发表时间：
2014-08-15
影响因子：
24.7
作者：
Castaldi, Peter J.;Cho, Michael H.;Silverman, Edwin K.
通讯作者：
Silverman, Edwin K.