Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium; Kathryn Recto; Priyadarshini Kachroo; Tianxiao Huan; David Van Den Berg; Gha Young Lee; Helena Bui; Dong Heon Lee; Jessica Gereige; Chen Yao; Shih Jen Hwang; Roby Joehanes; Scott T. Weiss; Namiko Abe; Gonçalo Abecasis; Francois Aguet; Christine Albert; Laura Almasy; Alvaro Alonso; Seth Ament; Peter Anderson; Pramod Anugu; Deborah Applebaum-Bowden; Kristin Ardlie; Dan Arking; Donna K. Arnett; Allison Ashley-Koch; Stella Aslibekyan; Tim Assimes; Paul Auer; Dimitrios Avramopoulos; Najib Ayas; Adithya Balasubramanian; John Barnard; Kathleen Barnes; R. Graham Barr; Emily Barron-Casella; Lucas Barwick; Terri Beaty; Gerald Beck; Diane Becker; Lewis Becker; Rebecca Beer; Amber Beitelshees; Emelia Benjamin; Takis Benos; Marcos Bezerra; Larry Bielak; Joshua Bis; Thomas Blackwell; John Blangero; Nathan Blue; Eric Boerwinkle; Donald W. Bowden; Russell Bowler; Jennifer Brody; Ulrich Broeckel; Jai Broome; Deborah Brown; Karen Bunting; Esteban Burchard; Carlos Bustamante; Erin Buth; Brian Cade; Jonathan Cardwell; Vincent Carey; Julie Carrier; April P. Carson; Cara Carty; Richard Casaburi; Juan P. Casas Romero; James Casella; Peter Castaldi; Mark Chaffin; Christy Chang; Yi Cheng Chang; Daniel Chasman; Sameer Chavan; Bo Juen Chen; Wei Min Chen; Yii Der Ida Chen; Michael Cho; Seung Hoan Choi; Lee Ming Chuang; Mina Chung; Ren Hua Chung; Clary Clish; Suzy Comhair; Matthew Conomos; Elaine Cornell; Adolfo Correa; Carolyn Crandall; James Crapo; L. Adrienne Cupples; Joanne Curran; Jeffrey Curtis; Brian Custer; Coleen Damcott; Dawood Darbar; Sean David; Colleen Davis; Michelle Daya; Mariza de Andrade; Lisa de las Fuentes; Paul de Vries; Michael DeBaun; Ranjan Deka; Dawn DeMeo; Scott Devine; Huyen Dinh; Harsha Doddapaneni; Qing Duan; Shannon Dugan-Perez; Ravi Duggirala; Jon Peter Durda; Susan K. Dutcher; Charles Eaton; Lynette Ekunwe; Adel El Boueiz; Patrick Ellinor; Leslie Emery; Serpil Erzurum; Charles Farber; Jesse Farek; Tasha Fingerlin; Matthew Flickinger; Myriam Fornage; Nora Franceschini; Chris Frazar; Mao Fu; Stephanie M. Fullerton; Lucinda Fulton; Stacey Gabriel; Weiniu Gan; Shanshan Gao; Yan Gao; Margery Gass; Heather Geiger; Bruce Gelb; Mark Geraci; Soren Germer; Robert Gerszten; Auyon Ghosh; Richard Gibbs; Chris Gignoux; Mark Gladwin; David Glahn; Stephanie Gogarten; Da Wei Gong; Harald Goring; Sharon Graw; Kathryn J. Gray; Daniel Grine; Colin Gross; C. Charles Gu; Yue Guan; Xiuqing Guo; Namrata Gupta; Jeff Haessler; Michael Hall; Yi Han; Patrick Hanly; Daniel Harris; Nicola L. Hawley; Jiang He; Ben Heavner; Susan Heckbert; Ryan Hernandez; David Herrington; Craig Hersh; Bertha Hidalgo; James Hixson; Brian Hobbs; John Hokanson; Elliott Hong; Karin Hoth; Chao (Agnes) Hsiung; Jianhong Hu; Yi Jen Hung; Haley Huston; Chii Min Hwu; Marguerite Ryan Irvin; Rebecca Jackson; Deepti Jain; Cashell Jaquish; Jill Johnsen; Andrew Johnson; Craig Johnson; Rich Johnston; Kimberly Jones; Hyun Min Kang; Robert Kaplan; Sharon Kardia; Shannon Kelly; Eimear Kenny; Michael Kessler; Alyna Khan; Ziad Khan; Wonji Kim; D. C. Rao; Yun Ju Sung

doi:10.1016/j.ebiom.2023.104758

Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium, Kathryn Recto, Priyadarshini Kachroo, Tianxiao Huan, David Van Den Berg, Gha Young Lee, Helena Bui, Dong Heon Lee, Jessica Gereige, Chen Yao, Shih Jen Hwang, Roby Joehanes, Scott T. Weiss, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth AmentPeter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Nathan Blue, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April P. Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi Cheng Chang, Daniel Chasman, Sameer Chavan, Bo Juen Chen, Wei Min Chen, Yii Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee Ming Chuang, Mina Chung, Ren Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, D. C. Rao, Yun Ju Sung

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: 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. Findings: 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. Interpretation: 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. Funding: US NIH/ NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.

Original language	English
Article number	104758
Journal	EBioMedicine
Volume	95
DOIs	https://doi.org/10.1016/j.ebiom.2023.104758
State	Published - Sep 2023

Keywords

Asthma
DNA methylation
Drug targets
EWAS
IgE
Lung
Mendelian randomization
RNA-Sequencing
eQTM

Access to Document

10.1016/j.ebiom.2023.104758

Cite this

NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium, Recto, K., Kachroo, P., Huan, T., Van Den Berg, D., Lee, G. Y., Bui, H., Lee, D. H., Gereige, J., Yao, C., Hwang, S. J., Joehanes, R., Weiss, S. T., Abe, N., Abecasis, G., Aguet, F., Albert, C., Almasy, L., Alonso, A., ... Sung, Y. J. (2023). Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma. EBioMedicine, 95, Article 104758. https://doi.org/10.1016/j.ebiom.2023.104758

@article{c2c26a1304484712b389dcb216c4df12,

title = "Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma",

abstract = "Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: 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. Findings: 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. Interpretation: 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. Funding: US NIH/ NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.",

keywords = "Asthma, DNA methylation, Drug targets, EWAS, IgE, Lung, Mendelian randomization, RNA-Sequencing, eQTM",

author = "{NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium} and Kathryn Recto and Priyadarshini Kachroo and Tianxiao Huan and {Van Den Berg}, David and Lee, {Gha Young} and Helena Bui and Lee, {Dong Heon} and Jessica Gereige and Chen Yao and Hwang, {Shih Jen} and Roby Joehanes and Weiss, {Scott T.} and Namiko Abe and Gon{\c c}alo Abecasis and Francois Aguet and Christine Albert and Laura Almasy and Alvaro Alonso and Seth Ament and Peter Anderson and Pramod Anugu and Deborah Applebaum-Bowden and Kristin Ardlie and Dan Arking and Arnett, {Donna K.} and Allison Ashley-Koch and Stella Aslibekyan and Tim Assimes and Paul Auer and Dimitrios Avramopoulos and Najib Ayas and Adithya Balasubramanian and John Barnard and Kathleen Barnes and Barr, {R. Graham} and Emily Barron-Casella and Lucas Barwick and Terri Beaty and Gerald Beck and Diane Becker and Lewis Becker and Rebecca Beer and Amber Beitelshees and Emelia Benjamin and Takis Benos and Marcos Bezerra and Larry Bielak and Joshua Bis and Thomas Blackwell and John Blangero and Nathan Blue and Eric Boerwinkle and Bowden, {Donald W.} and Russell Bowler and Jennifer Brody and Ulrich Broeckel and Jai Broome and Deborah Brown and Karen Bunting and Esteban Burchard and Carlos Bustamante and Erin Buth and Brian Cade and Jonathan Cardwell and Vincent Carey and Julie Carrier and Carson, {April P.} and Cara Carty and Richard Casaburi and {Casas Romero}, {Juan P.} and James Casella and Peter Castaldi and Mark Chaffin and Christy Chang and Chang, {Yi Cheng} and Daniel Chasman and Sameer Chavan and Chen, {Bo Juen} and Chen, {Wei Min} and {Ida Chen}, {Yii Der} and Michael Cho and Choi, {Seung Hoan} and Chuang, {Lee Ming} and Mina Chung and Chung, {Ren Hua} and Clary Clish and Suzy Comhair and Matthew Conomos and Elaine Cornell and Adolfo Correa and Carolyn Crandall and James Crapo and Cupples, {L. Adrienne} and Joanne Curran and Jeffrey Curtis and Brian Custer and Coleen Damcott and Dawood Darbar and Sean David and Colleen Davis and Michelle Daya and {de Andrade}, Mariza and {de las Fuentes}, Lisa and {de Vries}, Paul and Michael DeBaun and Ranjan Deka and Dawn DeMeo and Scott Devine and Huyen Dinh and Harsha Doddapaneni and Qing Duan and Shannon Dugan-Perez and Ravi Duggirala and Durda, {Jon Peter} and Dutcher, {Susan K.} and Charles Eaton and Lynette Ekunwe and {El Boueiz}, Adel and Patrick Ellinor and Leslie Emery and Serpil Erzurum and Charles Farber and Jesse Farek and Tasha Fingerlin and Matthew Flickinger and Myriam Fornage and Nora Franceschini and Chris Frazar and Mao Fu and Fullerton, {Stephanie M.} and Lucinda Fulton and Stacey Gabriel and Weiniu Gan and Shanshan Gao and Yan Gao and Margery Gass and Heather Geiger and Bruce Gelb and Mark Geraci and Soren Germer and Robert Gerszten and Auyon Ghosh and Richard Gibbs and Chris Gignoux and Mark Gladwin and David Glahn and Stephanie Gogarten and Gong, {Da Wei} and Harald Goring and Sharon Graw and Gray, {Kathryn J.} and Daniel Grine and Colin Gross and Gu, {C. Charles} and Yue Guan and Xiuqing Guo and Namrata Gupta and Jeff Haessler and Michael Hall and Yi Han and Patrick Hanly and Daniel Harris and Hawley, {Nicola L.} and Jiang He and Ben Heavner and Susan Heckbert and Ryan Hernandez and David Herrington and Craig Hersh and Bertha Hidalgo and James Hixson and Brian Hobbs and John Hokanson and Elliott Hong and Karin Hoth and Hsiung, {Chao (Agnes)} and Jianhong Hu and Hung, {Yi Jen} and Haley Huston and Hwu, {Chii Min} and Irvin, {Marguerite Ryan} and Rebecca Jackson and Deepti Jain and Cashell Jaquish and Jill Johnsen and Andrew Johnson and Craig Johnson and Rich Johnston and Kimberly Jones and Kang, {Hyun Min} and Robert Kaplan and Sharon Kardia and Shannon Kelly and Eimear Kenny and Michael Kessler and Alyna Khan and Ziad Khan and Wonji Kim and Rao, {D. C.} and Sung, {Yun Ju}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = sep,

doi = "10.1016/j.ebiom.2023.104758",

language = "English",

volume = "95",

journal = "EBioMedicine",

issn = "2352-3964",

}

NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium, Recto, K, Kachroo, P, Huan, T, Van Den Berg, D, Lee, GY, Bui, H, Lee, DH, Gereige, J, Yao, C, Hwang, SJ, Joehanes, R, Weiss, ST, Abe, N, Abecasis, G, Aguet, F, Albert, C, Almasy, L, Alonso, A, Ament, S, Anderson, P, Anugu, P, Applebaum-Bowden, D, Ardlie, K, Arking, D, Arnett, DK, Ashley-Koch, A, Aslibekyan, S, Assimes, T, Auer, P, Avramopoulos, D, Ayas, N, Balasubramanian, A, Barnard, J, Barnes, K, Barr, RG, Barron-Casella, E, Barwick, L, Beaty, T, Beck, G, Becker, D, Becker, L, Beer, R, Beitelshees, A, Benjamin, E, Benos, T, Bezerra, M, Bielak, L, Bis, J, Blackwell, T, Blangero, J, Blue, N, Boerwinkle, E, Bowden, DW, Bowler, R, Brody, J, Broeckel, U, Broome, J, Brown, D, Bunting, K, Burchard, E, Bustamante, C, Buth, E, Cade, B, Cardwell, J, Carey, V, Carrier, J, Carson, AP, Carty, C, Casaburi, R, Casas Romero, JP, Casella, J, Castaldi, P, Chaffin, M, Chang, C, Chang, YC, Chasman, D, Chavan, S, Chen, BJ, Chen, WM, Ida Chen, YD, Cho, M, Choi, SH, Chuang, LM, Chung, M, Chung, RH, Clish, C, Comhair, S, Conomos, M, Cornell, E, Correa, A, Crandall, C, Crapo, J, Cupples, LA, Curran, J, Curtis, J, Custer, B, Damcott, C, Darbar, D, David, S, Davis, C, Daya, M, de Andrade, M, de las Fuentes, L, de Vries, P, DeBaun, M, Deka, R, DeMeo, D, Devine, S, Dinh, H, Doddapaneni, H, Duan, Q, Dugan-Perez, S, Duggirala, R, Durda, JP, Dutcher, SK, Eaton, C, Ekunwe, L, El Boueiz, A, Ellinor, P, Emery, L, Erzurum, S, Farber, C, Farek, J, Fingerlin, T, Flickinger, M, Fornage, M, Franceschini, N, Frazar, C, Fu, M, Fullerton, SM, Fulton, L, Gabriel, S, Gan, W, Gao, S, Gao, Y, Gass, M, Geiger, H, Gelb, B, Geraci, M, Germer, S, Gerszten, R, Ghosh, A, Gibbs, R, Gignoux, C, Gladwin, M, Glahn, D, Gogarten, S, Gong, DW, Goring, H, Graw, S, Gray, KJ, Grine, D, Gross, C, Gu, CC, Guan, Y, Guo, X, Gupta, N, Haessler, J, Hall, M, Han, Y, Hanly, P, Harris, D, Hawley, NL, He, J, Heavner, B, Heckbert, S, Hernandez, R, Herrington, D, Hersh, C, Hidalgo, B, Hixson, J, Hobbs, B, Hokanson, J, Hong, E, Hoth, K, Hsiung, C, Hu, J, Hung, YJ, Huston, H, Hwu, CM, Irvin, MR, Jackson, R, Jain, D, Jaquish, C, Johnsen, J, Johnson, A, Johnson, C, Johnston, R, Jones, K, Kang, HM, Kaplan, R, Kardia, S, Kelly, S, Kenny, E, Kessler, M, Khan, A, Khan, Z, Kim, W, Rao, DC & Sung, YJ 2023, 'Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma', EBioMedicine, vol. 95, 104758. https://doi.org/10.1016/j.ebiom.2023.104758

TY - JOUR

T1 - Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

AU - NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium

AU - Recto, Kathryn

AU - Kachroo, Priyadarshini

AU - Huan, Tianxiao

AU - Van Den Berg, David

AU - Lee, Gha Young

AU - Bui, Helena

AU - Lee, Dong Heon

AU - Gereige, Jessica

AU - Yao, Chen

AU - Hwang, Shih Jen

AU - Joehanes, Roby

AU - Weiss, Scott T.

AU - Abe, Namiko

AU - Abecasis, Gonçalo

AU - Aguet, Francois

AU - Albert, Christine

AU - Almasy, Laura

AU - Alonso, Alvaro

AU - Ament, Seth

AU - Anderson, Peter

AU - Anugu, Pramod

AU - Applebaum-Bowden, Deborah

AU - Ardlie, Kristin

AU - Arking, Dan

AU - Arnett, Donna K.

AU - Ashley-Koch, Allison

AU - Aslibekyan, Stella

AU - Assimes, Tim

AU - Auer, Paul

AU - Avramopoulos, Dimitrios

AU - Ayas, Najib

AU - Balasubramanian, Adithya

AU - Barnard, John

AU - Barnes, Kathleen

AU - Barr, R. Graham

AU - Barron-Casella, Emily

AU - Barwick, Lucas

AU - Beaty, Terri

AU - Beck, Gerald

AU - Becker, Diane

AU - Becker, Lewis

AU - Beer, Rebecca

AU - Beitelshees, Amber

AU - Benjamin, Emelia

AU - Benos, Takis

AU - Bezerra, Marcos

AU - Bielak, Larry

AU - Bis, Joshua

AU - Blackwell, Thomas

AU - Blangero, John

AU - Blue, Nathan

AU - Boerwinkle, Eric

AU - Bowden, Donald W.

AU - Bowler, Russell

AU - Brody, Jennifer

AU - Broeckel, Ulrich

AU - Broome, Jai

AU - Brown, Deborah

AU - Bunting, Karen

AU - Burchard, Esteban

AU - Bustamante, Carlos

AU - Buth, Erin

AU - Cade, Brian

AU - Cardwell, Jonathan

AU - Carey, Vincent

AU - Carrier, Julie

AU - Carson, April P.

AU - Carty, Cara

AU - Casaburi, Richard

AU - Casas Romero, Juan P.

AU - Casella, James

AU - Castaldi, Peter

AU - Chaffin, Mark

AU - Chang, Christy

AU - Chang, Yi Cheng

AU - Chasman, Daniel

AU - Chavan, Sameer

AU - Chen, Bo Juen

AU - Chen, Wei Min

AU - Ida Chen, Yii Der

AU - Cho, Michael

AU - Choi, Seung Hoan

AU - Chuang, Lee Ming

AU - Chung, Mina

AU - Chung, Ren Hua

AU - Clish, Clary

AU - Comhair, Suzy

AU - Conomos, Matthew

AU - Cornell, Elaine

AU - Correa, Adolfo

AU - Crandall, Carolyn

AU - Crapo, James

AU - Cupples, L. Adrienne

AU - Curran, Joanne

AU - Curtis, Jeffrey

AU - Custer, Brian

AU - Damcott, Coleen

AU - Darbar, Dawood

AU - David, Sean

AU - Davis, Colleen

AU - Daya, Michelle

AU - de Andrade, Mariza

AU - de las Fuentes, Lisa

AU - de Vries, Paul

AU - DeBaun, Michael

AU - Deka, Ranjan

AU - DeMeo, Dawn

AU - Devine, Scott

AU - Dinh, Huyen

AU - Doddapaneni, Harsha

AU - Duan, Qing

AU - Dugan-Perez, Shannon

AU - Duggirala, Ravi

AU - Durda, Jon Peter

AU - Dutcher, Susan K.

AU - Eaton, Charles

AU - Ekunwe, Lynette

AU - El Boueiz, Adel

AU - Ellinor, Patrick

AU - Emery, Leslie

AU - Erzurum, Serpil

AU - Farber, Charles

AU - Farek, Jesse

AU - Fingerlin, Tasha

AU - Flickinger, Matthew

AU - Fornage, Myriam

AU - Franceschini, Nora

AU - Frazar, Chris

AU - Fu, Mao

AU - Fullerton, Stephanie M.

AU - Fulton, Lucinda

AU - Gabriel, Stacey

AU - Gan, Weiniu

AU - Gao, Shanshan

AU - Gao, Yan

AU - Gass, Margery

AU - Geiger, Heather

AU - Gelb, Bruce

AU - Geraci, Mark

AU - Germer, Soren

AU - Gerszten, Robert

AU - Ghosh, Auyon

AU - Gibbs, Richard

AU - Gignoux, Chris

AU - Gladwin, Mark

AU - Glahn, David

AU - Gogarten, Stephanie

AU - Gong, Da Wei

AU - Goring, Harald

AU - Graw, Sharon

AU - Gray, Kathryn J.

AU - Grine, Daniel

AU - Gross, Colin

AU - Gu, C. Charles

AU - Guan, Yue

AU - Guo, Xiuqing

AU - Gupta, Namrata

AU - Haessler, Jeff

AU - Hall, Michael

AU - Han, Yi

AU - Hanly, Patrick

AU - Harris, Daniel

AU - Hawley, Nicola L.

AU - He, Jiang

AU - Heavner, Ben

AU - Heckbert, Susan

AU - Hernandez, Ryan

AU - Herrington, David

AU - Hersh, Craig

AU - Hidalgo, Bertha

AU - Hixson, James

AU - Hobbs, Brian

AU - Hokanson, John

AU - Hong, Elliott

AU - Hoth, Karin

AU - Hsiung, Chao (Agnes)

AU - Hu, Jianhong

AU - Hung, Yi Jen

AU - Huston, Haley

AU - Hwu, Chii Min

AU - Irvin, Marguerite Ryan

AU - Jackson, Rebecca

AU - Jain, Deepti

AU - Jaquish, Cashell

AU - Johnsen, Jill

AU - Johnson, Andrew

AU - Johnson, Craig

AU - Johnston, Rich

AU - Jones, Kimberly

AU - Kang, Hyun Min

AU - Kaplan, Robert

AU - Kardia, Sharon

AU - Kelly, Shannon

AU - Kenny, Eimear

AU - Kessler, Michael

AU - Khan, Alyna

AU - Khan, Ziad

AU - Kim, Wonji

AU - Rao, D. C.

AU - Sung, Yun Ju

PY - 2023/9

Y1 - 2023/9

N2 - Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: 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. Findings: 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. Interpretation: 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. Funding: US NIH/ NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.

AB - Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: 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. Findings: 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. Interpretation: 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. Funding: US NIH/ NHLBI grants: P01HL132825, K99HL159234. N01-HC-25195 and HHSN268201500001I.

KW - Asthma

KW - DNA methylation

KW - Drug targets

KW - EWAS

KW - IgE

KW - Lung

KW - Mendelian randomization

KW - RNA-Sequencing

KW - eQTM

UR - http://www.scopus.com/inward/record.url?scp=85168098669&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2023.104758

DO - 10.1016/j.ebiom.2023.104758

M3 - Article

C2 - 37598461

AN - SCOPUS:85168098669

SN - 2352-3964

VL - 95

JO - EBioMedicine

JF - EBioMedicine

M1 - 104758

ER -

Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

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