Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections

• Type of Material: Article
• Authors: Candelaria Vergara, Johns Hopkins University; Chloe Thio, Johns Hopkins University; Rachel Latanich, Johns Hopkins University; Andrea L. Cox, Johns Hopkins University; Gregory D. Kirk, Johns Hopkins University; Shruti H. Mehta, Johns Hopkins University; Michael Busch, University of California San Francisco; Edward L Murphy, University of California San Francisco; Maria C. Villacres, University of Southern California; Marion G. Peters, Blood Systems Research Institute; Audrey L. French, Stroger Hospital of Cook County; Elizabeth Golub, Johns Hopkins University; Joseph Eron, University of North Carolina; Cecile Lahiri, Emory University; Sadeep Shrestha, University of Alabama Birmingham; Deborah Gustafson, State University of New York; Mary Young, Georgetown University
• Language: English
• Date: 2017-03-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Macmillan Publishers Limited.
• Final Published Version (URL): http://dx.doi.org/10.1038/gene.2017.2
• Title of Journal or Parent Work: Genes and Immunity
• ISSN: 1466-4879
• Volume: 18
• Issue: 2
• Start Page: 82
• End Page: 87
• Grant/Funding Information: 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).; 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).
• Keywords: SERUM IL-18; PATHOGENESIS; METAANALYSIS; ANTAGONIST; INFLAMMASOMES; Science & Technology; GENOME-WIDE ASSOCIATION; DISEASE; Genetics & Heredity; INTERLEUKIN-18 LEVELS; Life Sciences & Biomedicine; INDIVIDUALS; Immunology; ACUTE-PHASE
• Research Categories: Biology, Virology; Health Sciences, Immunology

Abstract

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 (r 2 =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.