R. Chung, N. S. Chalasani, A. S. Barbehenn, E. Lundgren, S. Savur, S. Shome, C. H. Sheikhzadeh, S. Sarvadhavabhatla, M. S. Donaire, V. Pae, X. Chu, D. Winder, C. T. Maguire, S. Topal, A. Ganesan, J. M. Yabes, D. T. Larson, T. Lalani, E. C. Ewers, R. E. Colombo, E. Dugan, U. Rathore, A. Marson, B. K. Agan, J. A. Tomalka, R.-P. Sekaly, N. M. Loannidis, S. A. Lee
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.