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

Genes Immun. 2017 Mar;18(2):82-87. doi: 10.1038/gene.2017.2. Epub 2017 Mar 16.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Coinfection / immunology*
  • Dioxygenases / genetics
  • Female
  • HIV Infections / blood
  • HIV Infections / immunology*
  • HIV-1 / physiology*
  • Hepatitis C, Chronic / blood
  • Hepatitis C, Chronic / immunology*
  • Humans
  • Inflammasomes / immunology
  • Interleukin-18 / blood*
  • Interleukin-18 / genetics*
  • Male
  • Polymorphism, Single Nucleotide


  • Inflammasomes
  • Interleukin-18
  • Dioxygenases
  • BCO2 protein, human