Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r2=0.98–1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml−1 of IL-18 after adjusting for covariates (rs80011693; rs111311302 β=−0.06, P-value=2.7 × 10−4). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections.
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We acknowledge support from the National Institutes of Health (NIH), National Institute on Drug Abuse R01DA013324 (Thomas), R01DA12568 (Mehta) and U01DA036297 (Kirk); National Institute of Allergy and Infectious Diseases (NIAID) R01 AI108403 (Cox); NIH K23 AI124913 (Lahiri); NIH U19AI066345, U01AI131314, R01DA033541 and U19AI082630 (Kim). Data in this manuscript were partially collected by the Women’s Interagency HIV Study (WIHS). WIHS (Principal Investigators): UAB-MS WIHS (Saag, Kempf and Konkle-Parker), U01-AI-103401; Atlanta WIHS (Ofotokun and Wingood), U01-AI-103408; Bronx WIHS (Anastos), U01-AI-035004; Brooklyn WIHS (Minkoff and Gustafson), U01-AI-031834; Chicago WIHS (Cohen and French), U01-AI-034993; Metropolitan Washington WIHS (Kassaye), U01-AI-034994; Miami WIHS (Fischl and Metsch), U01-AI-103397; UNC WIHS (Adimora), U01-AI-103390; Connie Wofsy Women’s HIV Study, Northern California (Greenblatt, Aouizerat and Tien), U01-AI-034989; WIHS Data Management and Analysis Center (Gange and Golub), U01-AI-042590; Southern California WIHS (Milam), U01-HD-032632 (WIHS I–WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA) and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD) and the NIH Office of Research on Women’s Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA).
The contents of this publication are solely the responsibility of the authors and do not represent the official views of the NIH.
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Supplementary Information accompanies this paper on Genes and Immunity website (http://www.nature.com/gene)