Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV
Chung, R.; Chalasani, N. S.; Barbehenn, A. S.; Lundgren, E.; Savur, S.; Shome, S.; Sheikhzadeh, C. H.; Sarvadhavabhatla, S.; Donaire, M. S.; Pae, V.; Chu, X.; Winder, D.; Maguire, C. T.; Topal, S.; Ganesan, A.; Yabes, J. M.; Larson, D. T.; Lalani, T.; Ewers, E. C.; Colombo, R. E.; Dugan, E.; Rathore, U.; Marson, A.; Agan, B. K.; Tomalka, J. A.; Sekaly, R.-P.; Loannidis, N. M.; Lee, S. A.
Show 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-1{beta}, 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.
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