Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma.
Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma.
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循环IgE水平的表观基因组DNA甲基化关联研究确定了哮喘的新靶点
DOI：
10.1016/j.ebiom.2023.104758
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发表时间：
2023-09
期刊：
影响因子：
11.1
通讯作者：
DeMeo, Dawn L.
中科院分区：
文献类型：
--
作者：
Recto, Kathryn;Kachroo, Priyadarshini;Huan, Tianxiao;Van Den Berg, David;Lee, Gha Young;Bui, Helena;Lee, Dong Heon;Gereige, Jessica;Yao, Chen;Hwang, Shih-Jen;Joehanes, Roby;O'Cornor, George T.;Levy, Daniel;DeMeo, Dawn L.
识别与血清免疫球蛋白E(IgE)相关的新的表观遗传学特征可能有助于我们更好地理解哮喘和IgE介导性疾病的分子机制。我们使用弗雷明翰心脏研究(FHS；n=3,471，46%女性)参与者的全血进行了表观基因组范围的关联研究，并使用儿童哮喘管理计划(cAMP；n=1,674，39%女性)和哥斯达黎加哮喘遗传流行病学研究(CRA；n=1,787，41%女性)验证了结果。使用与每个与IgE相关的CpG最近的基因，我们强调了潜在的生物学上可信的IgE调控途径，并分析了与与IgE相关的CPGS(表达定量性状甲基化位点；eQTM)相关的转录模式。使用先前来自全基因组哮喘和过敏相关研究的英国生物库汇总数据，我们进行了孟德尔随机化(MR)，使用来自FHS的与IgE相关的CPGS，并以甲基化数量性状基因座(MQTL)为工具变量。我们在FHS中发现了490个与IgE相关的差异甲基化的CPGS，其中193个(39.3%)在cAMP和CRA中复制(FDR<；0.05)。基因本体论分析显示，与转录因子结合、哮喘和其他免疫过程相关的途径丰富。EQTM分析确定了106个表达基因的124个顺式-eQTM(FDR<；0.05)。结合药物靶点分析，MR显示CTSB和USP20可能是IgE水平的因果调节因素(Bonferroni调整后的P<；：7.94E-04)，可以作为潜在的治疗靶点进行探索。通过整合普通和临床哮喘人群中的eQTM和MR分析，我们的发现提供了对DNA甲基化、基因表达和IgE水平之间多维相互关系的更深层次的理解。美国/赠款：P01HL132825，K99HL159234。N01-HC-25195和HHSN268201500001I。
Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P < 7.94E-04) that can be explored as potential therapeutic targets. By integrating eQTM and MR analyses in general and clinical asthma populations, our findings provide a deeper understanding of the multidimensional inter-relations of DNA methylation, gene expression, and IgE levels. US / grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.
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DOI：
10.1016/j.jaci.2021.09.011
发表时间：
2021-12
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Daya M;Cox C;Acevedo N;Boorgula MP;Campbell M;Chavan S;Cho MH;David GL;Kachroo P;Lasky-Su J;Li X;McHugh CP;Qiao D;Rafaels N;Beck LA;Bleecker ER;Caraballo L;Cupples AL;Figueiredo CA;Gallo RL;Hanifin J;Hansel NN;Hata TR;Hersh CP;Knight-Madden J;Leung DYM;Guttman-Yassky E;Meyers DA;O'Connor G;Ober C;Ong PY;Ortega VE;Paller AS;Putcha N;Reed RM;Schneider LC;Silverman EK;Slifka MK;Spergel JM;Vasan RS;Viaud-Martinez KA;Watson H;Weiss ST;NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium;Ruczinski I;Beaty TH;Mathias RA;Barnes KC
通讯作者：
Barnes KC
影响因子：
12.3
作者：
Breeze CE;Batorsky A;Lee MK;Szeto MD;Xu X;McCartney DL;Jiang R;Patki A;Kramer HJ;Eales JM;Raffield L;Lange L;Lange E;Durda P;Liu Y;Tracy RP;Van Den Berg D;NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed MESA Multi-Omics Working Group;Evans KL;Kraus WE;Shah S;Tiwari HK;Hou L;Whitsel EA;Jiang X;Charchar FJ;Baccarelli AA;Rich SS;Morris AP;Irvin MR;Arnett DK;Hauser ER;Rotter JI;Correa A;Hayward C;Horvath S;Marioni RE;Tomaszewski M;Beck S;Berndt SI;London SJ;Mychaleckyj JC;Franceschini N
通讯作者：
Franceschini N
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
5.3
作者：
Celedon, Juan C.;Soto-Quiros, Manuel E.;Weiss, Scott T.
通讯作者：
Weiss, Scott T.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y