Genome-wide association study of gene by smoking interactions in coronary artery calcification.
Genome-wide association study of gene by smoking interactions in coronary artery calcification.
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DOI：
10.1371/journal.pone.0074642
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hixson JE
中科院分区：
文献类型：
--
作者：
Polfus LM;Smith JA;Shimmin LC;Bielak LF;Morrison AC;Kardia SL;Peyser PA;Hixson JE
许多GWAS已经确定了与常见疾病相关的新基因座，但只关注个体遗传变异的主要影响，而不是与环境因素（GxE）的相互作用。GxE相互作用的鉴定对于冠心病（CHD）尤其重要，CHD是具有强非遗传风险因素的发病率和死亡率的主要可预防来源。冠状动脉粥样硬化是冠心病的主要病因，冠状动脉钙化与冠状动脉粥样硬化斑块的数量直接相关。在当前的研究中，我们通过在动脉病遗传流行病学网络（GENOA）同胞（N = 915名欧洲裔美国人）中进行GXS发现GWAS，然后在心脏病研究（FHS）同胞（N = 1025名欧洲裔美国人）中进行复制，检测了通过与吸烟（GXS）相互作用影响CAC程度的遗传变异。 广义估计方程解释了吸烟者和非吸烟者的阶层特异性组中同胞关系的相关性，以及GxS相互作用。初步分析发现，在GENOA GWAS中显示出暗示性关联（p≤10−5）的SNP，但这些索引SNP在FHS中没有复制。然而，二次分析能够使用其他SNP（+/-250 kb的GENOA索引SNP）复制FHS中的候选基因区域。在吸烟者和非吸烟者组中，复制的基因分别包括TCF 7 L2（p = 6.0×10−5）和WWOX（p = 4.5×10−6）;以及TNFRSF 8（p = 7.8×10−5）。 对于GxS相互作用，复制的基因包括TBC 1D 4（p = 6.9×10−5）和ADAMTS 9（P = 7.1×10−5）。 有趣的是，这些基因参与NF-κB轴介导的炎症途径。由于已知吸烟可诱导慢性和全身性炎症，因此这些基因的关联可能反映了通过炎症途径在CAC发展中的作用。此外，NF-κB轴调节骨重建，这是CAC发展中的关键生理过程。总之，GxS GWAS已经提供了通过与吸烟的相互作用与CAC相关的新基因座的证据，为未来CAC发展的基于人群和功能研究提供了有希望的新目标。
Many GWAS have identified novel loci associated with common diseases, but have focused only on main effects of individual genetic variants rather than interactions with environmental factors (GxE). Identification of GxE interactions is particularly important for coronary heart disease (CHD), a major preventable source of morbidity and mortality with strong non-genetic risk factors. Atherosclerosis is the major cause of CHD, and coronary artery calcification (CAC) is directly correlated with quantity of coronary atherosclerotic plaque. In the current study, we tested for genetic variants influencing extent of CAC via interaction with smoking (GxS), by conducting a GxS discovery GWAS in Genetic Epidemiology Network of Arteriopathy (GENOA) sibships (N = 915 European Americans) followed by replication in Framingham Heart Study (FHS) sibships (N = 1025 European Americans). Generalized estimating equations accounted for the correlation within sibships in strata-specific groups of smokers and nonsmokers, as well as GxS interaction. Primary analysis found SNPs that showed suggestive associations (p≤10−5) in GENOA GWAS, but these index SNPs did not replicate in FHS. However, secondary analysis was able to replicate candidate gene regions in FHS using other SNPs (+/−250 kb of GENOA index SNP). In smoker and nonsmoker groups, replicated genes included TCF7L2 (p = 6.0×10−5) and WWOX (p = 4.5×10−6); and TNFRSF8 (p = 7.8×10−5), respectively. For GxS interactions, replicated genes included TBC1D4 (p = 6.9×10−5) and ADAMTS9 (P = 7.1×10−5). Interestingly, these genes are involved in inflammatory pathways mediated by the NF-κB axis. Since smoking is known to induce chronic and systemic inflammation, association of these genes likely reflects roles in CAC development via inflammatory pathways. Furthermore, the NF-κB axis regulates bone remodeling, a key physiological process in CAC development. In conclusion, GxS GWAS has yielded evidence for novel loci that are associated with CAC via interaction with smoking, providing promising new targets for future population-based and functional studies of CAC development.
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影响因子：
3.7
作者：
Muendlein A;Saely CH;Geller-Rhomberg S;Sonderegger G;Rein P;Winder T;Beer S;Vonbank A;Drexel H
通讯作者：
Drexel H
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
158.5
作者：
Detrano, Robert;Guerci, Alan D.;Kronmal, Richard A.
通讯作者：
Kronmal, Richard A.
全基因组关联研究，用于冠状动脉钙化，随访心肌梗塞。
影响因子：
37.8
作者：
O'Donnell CJ;Kavousi M;Smith AV;Kardia SL;Feitosa MF;Hwang SJ;Sun YV;Province MA;Aspelund T;Dehghan A;Hoffmann U;Bielak LF;Zhang Q;Eiriksdottir G;van Duijn CM;Fox CS;de Andrade M;Kraja AT;Sigurdsson S;Elias-Smale SE;Murabito JM;Launer LJ;van der Lugt A;Kathiresan S;CARDIoGRAM Consortium;Krestin GP;Herrington DM;Howard TD;Liu Y;Post W;Mitchell BD;O'Connell JR;Shen H;Shuldiner AR;Altshuler D;Elosua R;Salomaa V;Schwartz SM;Siscovick DS;Voight BF;Bis JC;Glazer NL;Psaty BM;Boerwinkle E;Heiss G;Blankenberg S;Zeller T;Wild PS;Schnabel RB;Schillert A;Ziegler A;Münzel TF;White CC;Rotter JI;Nalls M;Oudkerk M;Johnson AD;Newman AB;Uitterlinden AG;Massaro JM;Cunningham J;Harris TB;Hofman A;Peyser PA;Borecki IB;Cupples LA;Gudnason V;Witteman JC
通讯作者：
Witteman JC
影响因子：
2.1
作者：
Li, Yun;Willer, Cristen J.;Ding, Jun;Scheet, Paul;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.