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

Genes & Immunity volume 18, pages 82–87 (2017)Cite this article

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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 (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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Acknowledgements

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).

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Authors and Affiliations

  1. School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    C Vergara, C Thio, R Latanich, A L Cox & D L Thomas

  2. Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    G D Kirk, S H Mehta, E Golub & P Duggal

  3. University of California, San Francisco, CA, USA

    M Busch & E L Murphy

  4. Blood Systems Research Institute, San Francisco, CA, USA

    E L Murphy & M G Peters

  5. Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    M C Villacres

  6. CORE Center/Stroger Hospital of Cook County, Chicago, IL, USA

    A L French

  7. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    J Eron

  8. School of Medicine, Emory University, Atlanta, GA, USA

    C D Lahiri

  9. The University of Alabama at Birmingham, AL, USA

    S Shrestha

  10. State University of New York—Downstate Medical Center, New York, NY, USA

    D Gustafson

  11. Georgetown University Medical Center, Washington, DC, USA

    M Young

  12. Albert Einstein College of Medicine and Montefiore Medical Center, New York, NY, USA

    K Anastos

  13. Bluestone Center for Clinical Research, New York University, New York, NY, USA

    B Aouizerat

  14. Department of Oral and Maxillofacial Surgery, New York University, New York, NY, USA

    B Aouizerat

  15. Massachusetts General Hospital, Boston, MA, USA

    A Y Kim & G Lauer

  16. Harvard Medical School, Boston, MA, USA

    A Y Kim & G Lauer

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  1. C Vergara
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Correspondence to P Duggal.

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Vergara, C., Thio, C., Latanich, R. et al. Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections. Genes Immun 18, 82–87 (2017). https://doi.org/10.1038/gene.2017.2

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