PMID- 36793728 OWN - NLM STAT- MEDLINE DCOM- 20230217 LR - 20240306 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Transcriptome-wide association study of circulating IgE levels identifies novel targets for asthma and allergic diseases. PG - 1080071 LID - 10.3389/fimmu.2023.1080071 [doi] LID - 1080071 AB - Measurement of circulating immunoglobulin E (IgE) concentration is helpful for diagnosing and treating asthma and allergic diseases. Identifying gene expression signatures associated with IgE might elucidate novel pathways for IgE regulation. To this end, we performed a discovery transcriptome-wide association study to identify differentially expressed genes associated with circulating IgE levels in whole-blood derived RNA from 5,345 participants in the Framingham Heart Study across 17,873 mRNA gene-level transcripts. We identified 216 significant transcripts at a false discovery rate <0.05. We conducted replication using the meta-analysis of two independent external studies: the Childhood Asthma Management Program (n=610) and the Genetic Epidemiology of Asthma in Costa Rica Study (n=326); we then reversed the discovery and replication cohorts, which revealed 59 significant genes that replicated in both directions. Gene ontology analysis revealed that many of these genes were implicated in immune function pathways, including defense response, inflammatory response, and cytokine production. Mendelian randomization (MR) analysis revealed four genes (CLC, CCDC21, S100A13, and GCNT1) as putatively causal (p<0.05) regulators of IgE levels. GCNT1 (beta=1.5, p=0.01)-which is a top result in the MR analysis of expression in relation to asthma and allergic diseases-plays a role in regulating T helper type 1 cell homing, lymphocyte trafficking, and B cell differentiation. Our findings build upon prior knowledge of IgE regulation and provide a deeper understanding of underlying molecular mechanisms. The IgE-associated genes that we identified-particularly those implicated in MR analysis-can be explored as promising therapeutic targets for asthma and IgE-related diseases. CI - Copyright (c) 2023 Recto, Huan, Lee, Lee, Gereige, Yao, Hwang, Joehanes, Kelly, Lasky-Su, O'Connor and Levy. FAU - Recto, Kathryn A AU - Recto KA AD - The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. AD - The Framingham Heart Study, Framingham, MA, United States. FAU - Huan, Tianxiao AU - Huan T AD - The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. AD - The Framingham Heart Study, Framingham, MA, United States. FAU - Lee, Dong Heon AU - Lee DH AD - The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. AD - The Framingham Heart Study, Framingham, MA, United States. FAU - Lee, Gha Young AU - Lee GY AD - The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. AD - The Framingham Heart Study, Framingham, MA, United States. FAU - Gereige, Jessica AU - Gereige J AD - Pulmonary Center, Boston University School of Medicine, Boston, MA, United States. FAU - Yao, Chen AU - Yao C AD - The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. AD - The Framingham Heart Study, Framingham, MA, United States. FAU - Hwang, Shih-Jen AU - Hwang SJ AD - The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. AD - The Framingham Heart Study, Framingham, MA, United States. FAU - Joehanes, Roby AU - Joehanes R AD - The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. AD - The Framingham Heart Study, Framingham, MA, United States. FAU - Kelly, Rachel S AU - Kelly RS AD - Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA, United States. FAU - Lasky-Su, Jessica AU - Lasky-Su J AD - Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA, United States. FAU - O'Connor, George AU - O'Connor G AD - Pulmonary Center, Boston University School of Medicine, Boston, MA, United States. FAU - Levy, Daniel AU - Levy D AD - The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States. AD - The Framingham Heart Study, Framingham, MA, United States. LA - eng GR - R01 HL123915/HL/NHLBI NIH HHS/United States GR - R01 HL155742/HL/NHLBI NIH HHS/United States GR - R01 HL141826/HL/NHLBI NIH HHS/United States GR - T32 HL007035/HL/NHLBI NIH HHS/United States GR - HHSN268201500001I/HL/NHLBI NIH HHS/United States GR - T32 GM144273/GM/NIGMS NIH HHS/United States GR - N01HC25195/HL/NHLBI NIH HHS/United States GR - K01 HL146980/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Meta-Analysis PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural DEP - 20230130 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 37341-29-0 (Immunoglobulin E) SB - IM MH - Humans MH - *Asthma/genetics MH - *Hypersensitivity/genetics MH - *Immunoglobulin E/blood MH - Immunologic Tests MH - Transcriptome PMC - PMC9922991 OTO - NOTNLM OT - GCNT1 OT - IgE OT - allergic diseases OT - asthma OT - gene expression OT - immunoglobulin OT - immunotherapy COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/02/17 06:00 MHDA- 2023/02/18 06:00 PMCR- 2023/01/01 CRDT- 2023/02/16 02:20 PHST- 2022/10/26 00:00 [received] PHST- 2023/01/13 00:00 [accepted] PHST- 2023/02/16 02:20 [entrez] PHST- 2023/02/17 06:00 [pubmed] PHST- 2023/02/18 06:00 [medline] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1080071 [doi] PST - epublish SO - Front Immunol. 2023 Jan 30;14:1080071. doi: 10.3389/fimmu.2023.1080071. eCollection 2023.