Multiomics reveal key inflammatory drivers of severe obesity: IL4R, LILRA5, and OSM

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Chen, HH, Highland, HM, Frankel, EG, Scartozzi, AC, Zhang, X, Roshani, R, Sharma, P, Kar, A, Buchanan, VL, Polikowsky, HG et al (show 29 more authors) , Petty, LE, Seo, J, Anwar, MY, Kim, D, Graff, M, Young, KL, Zhu, W, Karastergiou, K, Shaw, DM, Justice, AE, Fernández-Rhodes, L, Krishnan, M, Gutierrez, A, McCormick, PJ ORCID: 0000-0002-2225-5181, Aguilar-Salinas, CA, Tusié-Luna, MT, Muñoz-Hernandez, LL, Herrera-Hernandez, M, Lee, M, Gamazon, ER, Cox, NJ, Pajukanta, P, Fried, SK, Gordon-Larsen, P, Shah, RV, Fisher-Hoch, SP, McCormick, JB, North, KE and Below, JE ORCID: 0000-0002-1346-1872 (2025) Multiomics reveal key inflammatory drivers of severe obesity: IL4R, LILRA5, and OSM Cell Genomics, 5 (3). 100784-. ISSN 2666-979X, 2666-979X

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Abstract

Polygenic severe obesity (body mass index [BMI] ≥40 kg/m²) has increased, especially in Hispanic/Latino populations, yet we know little about the underlying mechanistic pathways. We analyzed whole-blood multiomics data to identify genes differentially regulated in severe obesity in Mexican Americans from the Cameron County Hispanic Cohort. Our RNA sequencing analysis identified 124 genes significantly differentially expressed between severe obesity cases (BMI ≥40 kg/m²) and controls (BMI <25 kg/m²); 33% replicated in an independent sample from the same population. Our integrative approach identified inflammatory genes, including IL4R, ZNF438, and LILRA5. Several genes displayed transcriptomic effects on severe obesity in subcutaneous adipose tissue. We further showed that the genetic regulation of these genes is associated with several traits in a large biobank, including bone fractures, obstructive sleep apnea, and hyperaldosteronism, illuminating potential risk mechanisms. Our findings furnish a molecular architecture of the severe obesity phenotype across multiple molecular domains.

Item Type:	Article
Uncontrolled Keywords:	Humans, Obesity, Morbid, Inflammation, Body Mass Index, Adult, Middle Aged, Mexican Americans, Texas, Female, Male, Transcriptome, Multiomics
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	10 Apr 2025 08:02
Last Modified:	28 Feb 2026 14:29
DOI:	10.1016/j.xgen.2025.100784
Open Access URL:	https://doi.org/10.1016/j.xgen.2025.100784
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3191318
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