Background
Despite antiretroviral therapy (ART), people with HIV (PWH) experience higher rates of morbidity and mortality than people without HIV (PWoH), which may be driven by chronic inflammation due to persistent virus. Inflammasome activation leading to proinflammatory cytokine production may be a major driver of this risk. Identification of genes associated with signaling cytokines could advance our understanding of the role genetic variation plays in inflammatory activation.
Methods
We performed whole genome sequencing of 1000 PWH from the U.S. Military HIV Natural History cohort in relation to circulating plasma levels of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome cytokines (IL-1β, IL-6, IL-18) during ART suppression. We performed genome-wide association (GWAS), rare variant association, and gene-based transcriptome-wide analyses (TWAS).
Results
After filtering for sequencing read depth and quality, a total of 993 participants and a total of 66,084,459 variants passed quality control. Participants were mostly of European (n=417) and African (n=387) ancestry. We identified 14 significant GWAS signals (p<5×10-8). Our GWAS and rare variant association signals including host genes involved in myeloid immune responses (ETV1), HIV replication (DDX17, DDX41, BCL11a), HIV cell-cell transmission (EEA1), HIV protease inhibitor transport (ABCC1), cardiovascular disease risk (KLHL29), angiogenesis (RNF213), and cholesterol metabolism (e.g., ABCA12, ABCA1, AGMO). Three GWAS loci were identified as expression quantitative trait loci (eQTLs) in coronary artery tissue (GTEx). Our TWAS identified several innate and adaptive immune related genes known to regulate the expression of NLRP3 cytokines.
Conclusions
In the first genome-wide and transcriptome-wide analyses of circulating NLRP3 inflammasome cytokines, we found several host genes involved in immune responses to HIV and cardiovascular disease pathogenesis associated with plasma IL-1β, IL-6, and IL-18 in PWH on ART. These data suggest that host genetics may contribute to the elevated risk of vascular events and inflammation in this population, even during suppressive ART; additional analyses are ongoing. Further studies are needed to validate these findings both within populations of people with and without HIV, and in relation to risk of incident vascular events.
Table or Figure
