Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV.

Authors

Ryan Chung, Namratha Shivani Chalasani, Alton S Barbehenn, Erik Lundgren, Sonia Savur, Sayane Shome, Caroline H Sheikhzadeh, Sannidhi Sarvadhavabhatla, Maria Sophia Donaire, Vivian Pae, Xiuping Chu, Daniel Winder, Colin T Maguire, Senay Topal, Anuradha Ganesan, Joseph M Yabes, Derek T Larson, Tahaniyat Lalani, Evan C Ewers, Rhonda E Colombo, Eli Dugan, Ujjwal Rathore, Alexander Marson, Brian K Agan, Jeffrey A Tomalka, Rafick P Sekaly, Nilah M Ioannidis, Sulggi A Lee

Published in

medRxiv : the preprint server for health sciences. Aug 24, 2026. Epub Aug 24, 2026.

Abstract

People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1β, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4⁺ T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.

PMID:
42326826
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.

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