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

IF 11.1 Q1 CELL BIOLOGY

Cell genomics Pub Date : 2025-03-12 Epub Date: 2025-03-04 DOI:10.1016/j.xgen.2025.100784

Hung-Hsin Chen, Heather M Highland, Elizabeth G Frankel, Alyssa C Scartozzi, Xinruo Zhang, Rashedeh Roshani, Priya Sharma, Asha Kar, Victoria L Buchanan, Hannah G Polikowsky, Lauren E Petty, Jungkyun Seo, Mohammad Yaser Anwar, Daeeun Kim, Mariaelisa Graff, Kristin L Young, Wanying Zhu, Kalypso Karastergiou, Douglas M Shaw, Anne E Justice, Lindsay Fernández-Rhodes, Mohanraj Krishnan, Absalon Gutierrez, Peter J McCormick, Carlos A Aguilar-Salinas, Maria Teresa Tusié-Luna, Linda Liliana Muñoz-Hernandez, Miguel Herrera-Hernandez, Miryoung Lee, Eric R Gamazon, Nancy J Cox, Päivi Pajukanta, Susan K Fried, Penny Gordon-Larsen, Ravi V Shah, Susan P Fisher-Hoch, Joseph B McCormick, Kari E North, Jennifer E Below

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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.

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多基因重度肥胖（体重指数[BMI]≥40 kg/m2）有所增加，尤其是在西班牙裔/拉丁裔人群中，但我们对其潜在的机理途径知之甚少。我们分析了卡梅伦县西班牙裔队列中墨西哥裔美国人的全血多组学数据，以确定在重度肥胖中受到不同调控的基因。我们的 RNA 测序分析确定了 124 个基因在重度肥胖病例（体重指数≥40 kg/m2）和对照组（体重指数 2）之间有显著的差异表达；33% 的基因在同一人群的独立样本中得到了重复。我们的综合方法确定了炎症基因，包括 IL4R、ZNF438 和 LILRA5。一些基因在皮下脂肪组织中显示出对重度肥胖的转录组学效应。我们进一步发现，这些基因的遗传调控与大型生物库中的一些特征有关，包括骨折、阻塞性睡眠呼吸暂停和高醛固酮症，从而揭示了潜在的风险机制。我们的研究结果提供了一个横跨多个分子领域的重度肥胖表型的分子结构。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell genomics

CiteScore

7.10

自引率

0.00%

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