Multiomics reveal key inflammatory drivers of severe obesity: IL4R, LILRA5, and OSM
Polygenic severe obesity (body mass index [BMI] ≥40 kg/m<sup>2</sup>) 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/m<sup>2</sup>) and controls (BMI <25 kg/m<sup>2</sup>); 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.
Authors
- Douglas M. Shaw (ORCID: https://orcid.org/0000-0001-8896-6659)
- Ravi V. Shah (ORCID: https://orcid.org/0000-0002-4471-7156)
- Hannah G. Polikowsky (ORCID: https://orcid.org/0000-0001-7226-9752)
- Kalypso Karastergiou (ORCID: https://orcid.org/0000-0002-1790-065X)
- Lauren E. Petty (ORCID: https://orcid.org/0000-0003-1619-6303)
- Susan P. Fisher‐Hoch (ORCID: https://orcid.org/0000-0002-7894-5114)
- Penny Gordon‐Larsen (ORCID: https://orcid.org/0000-0001-5322-4188)
- Alyssa Scartozzi (ORCID: https://orcid.org/0000-0003-1703-2423)
- Absalon Gutierrez (ORCID: https://orcid.org/0000-0002-5488-7028)
- Wanying Zhu (ORCID: https://orcid.org/0000-0002-6292-4108)
- Nancy Jean Cox (ORCID: https://orcid.org/0000-0001-9315-0830)
- Jennifer E Below (ORCID: https://orcid.org/0000-0002-1346-1872)
- Kristin L. Young (ORCID: https://orcid.org/0000-0003-0070-6145)
- Miguel Herrera-Hernández
- Mariaelisa Graff (ORCID: https://orcid.org/0000-0001-6380-1735)
- Joseph B. McCormick (ORCID: https://orcid.org/0000-0002-5844-8102)
- Victoria L. Buchanan (ORCID: https://orcid.org/0000-0001-9943-9950)
- Peter J. McCormick (ORCID: https://orcid.org/0000-0002-2225-5181)
- Mohanraj Krishnan (ORCID: https://orcid.org/0000-0002-8594-7863)
- Anne E. Justice (ORCID: https://orcid.org/0000-0002-8903-8712)
- Kari E. North (ORCID: https://orcid.org/0000-0002-8903-0366)
- Jungkyun Seo (ORCID: https://orcid.org/0000-0001-5514-4421)
- Päivi Pajukanta (ORCID: https://orcid.org/0000-0002-6423-8056)
- Mohammad Yaser Anwar (ORCID: https://orcid.org/0000-0002-2349-8214)
- Eitan Frankel (ORCID: https://orcid.org/0000-0003-2046-8500)
- Miryoung Lee (ORCID: https://orcid.org/0000-0003-4088-304X)
- DaeEun Kim (ORCID: https://orcid.org/0000-0003-0863-1694)
- Linda Liliana Muñóz-Hernández (ORCID: https://orcid.org/0000-0003-2803-4408)
- Lindsay Fernández‐Rhodes (ORCID: https://orcid.org/0000-0001-6985-423X)
- Susan K. Fried (ORCID: https://orcid.org/0000-0003-1101-9332)
- Hung‐Hsin Chen (ORCID: https://orcid.org/0000-0002-1921-2797)
- Marı́a Teresa Tusié-Luna (ORCID: https://orcid.org/0000-0003-4478-038X)
- Heather M. Highland (ORCID: https://orcid.org/0000-0002-3583-8239)
- Eric R. Gamazon (ORCID: https://orcid.org/0000-0003-4204-8734)
- Rashedeh Roshani (ORCID: https://orcid.org/0009-0001-2696-2852)
- Asha Kar (ORCID: https://orcid.org/0009-0000-1717-1744)
- Priya Sharma (ORCID: https://orcid.org/0000-0001-8353-8057)
- Xinruo Zhang (ORCID: https://orcid.org/0000-0001-5789-4592)
- Carlos A. Aguilar-Salinas
Institutions
- Boston University (US)
- University of North Carolina at Chapel Hill (US)
- Pennsylvania State University (US)
- University of California, Los Angeles (US)
- Queen Mary University of London (GB)
- Vanderbilt University (US)
- University of Cambridge (GB)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX)
- Texas Diabetes & Endocrinology (US)
- William Harvey Research Institute (GB)
- Precision Research (United States) (US)
- MRC Epidemiology Unit (GB)
- Geisinger Health System (US)
- Sungkyunkwan University (KR)
- Vanderbilt University Medical Center (US)
- The University of Texas Health Science Center at Houston (US)
- Tecnológico de Monterrey (MX)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Genomics
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.xgen.2025.100784
- Citations
- 5
- Primary Topic
- Adipokines, Inflammation, and Metabolic Diseases
- Type
- article
- Field-Weighted Citation Impact
- 6.77