EBioMedicine (Sep 2023)

Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthmaResearch in context

  • 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,
  • George T. O’Connor,
  • Daniel Levy,
  • Dawn L. DeMeo,
  • 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,
  • John Kimoff,
  • Greg Kinney,
  • Barbara Konkle,
  • Charles Kooperberg,
  • Holly Kramer,
  • Christoph Lange,
  • Ethan Lange,
  • Leslie Lange,
  • Cathy Laurie,
  • Cecelia Laurie,
  • Meryl LeBoff,
  • Jiwon Lee,
  • Sandra Lee,
  • Wen-Jane Lee,
  • Jonathon LeFaive,
  • David Levine,
  • Daniel Levy,
  • Joshua Lewis,
  • Xiaohui Li,
  • Yun Li,
  • Henry Lin,
  • Honghuang Lin,
  • Xihong Lin,
  • Simin Liu,
  • Yongmei Liu,
  • Yu Liu,
  • Ruth J.F. Loos,
  • Steven Lubitz,
  • Kathryn Lunetta,
  • James Luo,
  • Ulysses Magalang,
  • Michael Mahaney,
  • Barry Make,
  • Ani Manichaikul,
  • Alisa Manning,
  • JoAnn Manson,
  • Lisa Martin,
  • Melissa Marton,
  • Susan Mathai,
  • Rasika Mathias,
  • Susanne May,
  • Patrick McArdle,
  • Merry-Lynn McDonald,
  • Sean McFarland,
  • Stephen McGarvey,
  • Daniel McGoldrick,
  • Caitlin McHugh,
  • Becky McNeil,
  • Hao Mei,
  • James Meigs,
  • Vipin Menon,
  • Luisa Mestroni,
  • Ginger Metcalf,
  • Deborah A. Meyers,
  • Emmanuel Mignot,
  • Julie Mikulla,
  • Nancy Min,
  • Mollie Minear,
  • Ryan L. Minster,
  • Braxton D. Mitchell,
  • Matt Moll,
  • Zeineen Momin,
  • May E. Montasser,
  • Courtney Montgomery,
  • Donna Muzny,
  • Josyf C. Mychaleckyj,
  • Girish Nadkarni,
  • Rakhi Naik,
  • Take Naseri,
  • Pradeep Natarajan,
  • Sergei Nekhai,
  • Sarah C. Nelson,
  • Bonnie Neltner,
  • Caitlin Nessner,
  • Deborah Nickerson,
  • Osuji Nkechinyere,
  • Kari North,
  • Jeff O'Connell,
  • Tim O'Connor,
  • Heather Ochs-Balcom,
  • Geoffrey Okwuonu,
  • Allan Pack,
  • David T. Paik,
  • Nicholette Palmer,
  • James Pankow,
  • George Papanicolaou,
  • Cora Parker,
  • Gina Peloso,
  • Juan Manuel Peralta,
  • Marco Perez,
  • James Perry,
  • Ulrike Peters,
  • Patricia Peyser,
  • Lawrence S. Phillips,
  • Jacob Pleiness,
  • Toni Pollin,
  • Wendy Post,
  • Julia Powers Becker,
  • Meher Preethi Boorgula,
  • Michael Preuss,
  • Bruce Psaty,
  • Pankaj Qasba,
  • Dandi Qiao,
  • Zhaohui Qin,
  • Nicholas Rafaels,
  • Laura Raffield,
  • Mahitha Rajendran,
  • Vasan S. Ramachandran,
  • D.C. Rao,
  • Laura Rasmussen-Torvik,
  • Aakrosh Ratan,
  • Susan Redline,
  • Robert Reed,
  • Catherine Reeves,
  • Elizabeth Regan,
  • Alex Reiner,
  • Muagututi‘a Sefuiva Reupena,
  • Ken Rice,
  • Stephen Rich,
  • Rebecca Robillard,
  • Nicolas Robine,
  • Dan Roden,
  • Carolina Roselli,
  • Jerome Rotter,
  • Ingo Ruczinski,
  • Alexi Runnels,
  • Pamela Russell,
  • Sarah Ruuska,
  • Kathleen Ryan,
  • Ester Cerdeira Sabino,
  • Danish Saleheen,
  • Shabnam Salimi,
  • Sejal Salvi,
  • Steven Salzberg,
  • Kevin Sandow,
  • Vijay G. Sankaran,
  • Jireh Santibanez,
  • Karen Schwander,
  • David Schwartz,
  • Frank Sciurba,
  • Christine Seidman,
  • Jonathan Seidman,
  • Frédéric Sériès,
  • Vivien Sheehan,
  • Stephanie L. Sherman,
  • Amol Shetty,
  • Aniket Shetty,
  • Wayne Hui-Heng Sheu,
  • M. Benjamin Shoemaker,
  • Brian Silver,
  • Edwin Silverman,
  • Robert Skomro,
  • Albert Vernon Smith,
  • Jennifer Smith,
  • Josh Smith,
  • Nicholas Smith,
  • Tanja Smith,
  • Sylvia Smoller,
  • Beverly Snively,
  • Michael Snyder,
  • Tamar Sofer,
  • Nona Sotoodehnia,
  • Adrienne M. Stilp,
  • Garrett Storm,
  • Elizabeth Streeten,
  • Jessica Lasky Su,
  • Yun Ju Sung,
  • Jody Sylvia,
  • Adam Szpiro,
  • Daniel Taliun,
  • Hua Tang,
  • Margaret Taub,
  • Kent Taylor,
  • Matthew Taylor,
  • Simeon Taylor,
  • Marilyn Telen,
  • Timothy A. Thornton,
  • Machiko Threlkeld,
  • Lesley Tinker,
  • David Tirschwell,
  • Sarah Tishkoff,
  • Hemant Tiwari,
  • Catherine Tong,
  • Russell Tracy,
  • Michael Tsai,
  • Dhananjay Vaidya,
  • David Van Den Berg,
  • Peter VandeHaar,
  • Scott Vrieze,
  • Tarik Walker,
  • Robert Wallace,
  • Avram Walts,
  • Fei Fei Wang,
  • Heming Wang,
  • Jiongming Wang,
  • Karol Watson,
  • Jennifer Watt,
  • Daniel E. Weeks,
  • Joshua Weinstock,
  • Bruce Weir,
  • Scott T. Weiss,
  • Lu-Chen Weng,
  • Jennifer Wessel,
  • Cristen Willer,
  • Kayleen Williams,
  • L. Keoki Williams,
  • Scott Williams,
  • Carla Wilson,
  • James Wilson,
  • Lara Winterkorn,
  • Quenna Wong,
  • Baojun Wu,
  • Joseph Wu,
  • Huichun Xu,
  • Lisa Yanek,
  • Ivana Yang,
  • Ketian Yu,
  • Seyedeh Maryam Zekavat,
  • Yingze Zhang,
  • Snow Xueyan Zhao,
  • Wei Zhao,
  • Xiaofeng Zhu,
  • Elad Ziv,
  • Michael Zody,
  • Sebastian Zoellner

Journal volume & issue
Vol. 95
p. 104758

Abstract

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Summary: 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