title: Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections.
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-1of 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.
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Vergara
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Thio
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Latanich
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Cox
authors.affiliation: Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Kirk
authors.affiliation: Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Mehta
authors.affiliation: University of California, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Busch
authors.affiliation: University of California, San Francisco, CA, USA.|Blood Systems Research Institute, San Francisco, CA, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Murphy
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Villacres
authors.affiliation: Blood Systems Research Institute, San Francisco, CA, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Peters
authors.affiliation: CORE Center/Stroger Hospital of Cook County, Chicago, IL, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: French
authors.affiliation: Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Golub
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Eron
authors.affiliation: School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Lahiri
authors.affiliation: The University of Alabama at Birmingham, AL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: State University of New York-Downstate Medical Center, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gustafson
authors.affiliation: Georgetown University Medical Center, Washington, DC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Young
authors.affiliation: Albert Einstein College of Medicine and Montefiore Medical Center, New York, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Anastos
authors.affiliation: Bluestone Center for Clinical Research, New York University, New York, NY, USA.|Department of Oral and Maxillofacial Surgery, New York University, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Aouizerat
authors.affiliation: Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: A Y
authors.initials: AY
authors.lastname: Kim
authors.affiliation: Massachusetts General Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lauer
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Thomas
authors.affiliation: Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Duggal
mesh_terms: D000328:Adult; D060085:Coinfection / Q000276:immunology*; D049308:Dioxygenases / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology; D020382:Interleukin-18 / Q000097:blood* / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D049308:Dioxygenases; C506534:BCO2 protein, human