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

• Published in: Genes and immunity Vol. 18; no. 2; pp. 82 - 87
• Main Authors: Vergara, C, Thio, C, Latanich, R, Cox, A L, Kirk, G D, Mehta, S H, Busch, M, Murphy, E L, Villacres, M C, Peters, M G, French, A L, Golub, E, Eron, J, Lahiri, C D, Shrestha, S, Gustafson, D, Young, M, Anastos, K, Aouizerat, B, Kim, A Y, Lauer, G, Thomas, D L, Duggal, P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2017; Nature Publishing Group
• Subjects: 45; 45/43; 631/208/205/2138; 631/250/255/1901; 631/250/255/234/2513/1551; Adult; Antiretroviral drugs; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chronic infection; Coinfection - immunology; Development and progression; Dioxygenases - genetics; Female; Gene Expression; Genetic aspects; Genetic diversity; Health aspects; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - immunology; HIV; HIV infection; HIV Infections - blood; HIV Infections - immunology; HIV-1 - physiology; Human Genetics; Human immunodeficiency virus; Humans; Immune response; Immune system; Immunological research; Immunology; Infections; Inflammasomes; Inflammasomes - immunology; Inflammation; Interleukin 18; Interleukin-18 - blood; Interleukin-18 - genetics; Lentivirus; Male; Measurement; original-article; Polymorphism, Single Nucleotide; Retroviridae; Ribonucleic acid; RNA; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Viral infections; Viruses; United States
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2017.2

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.