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

C. Vergara, C. Thio, R. Latanich, A. L. Cox, G. D. Kirk, S. H. Mehta, M. Busch, E. L. Murphy, M. C. Villacres, M. G. Peters, A. L. French, E. Golub, J. Eron, C. D. Lahiri, S. Shrestha, D. Gustafson, M. Young, K. Anastos, B. Aouizerat, A. Y. Kim & 3 others G. Lauer, D. L. Thomas, P. Duggal

Research output: Research - peer-reviewArticle

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.Genes and Immunity advance online publication, 16 March 2017; doi:10.1038/gene.2017.2.

LanguageEnglish (US)
JournalGenes and Immunity
DOIs
StateAccepted/In press - Mar 16 2017

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Interleukin-18
Chronic Hepatitis C
Virus Diseases
Hepacivirus
HIV-1
HIV
Inflammasomes
Genes
Single Nucleotide Polymorphism
Publications
Immunity
Linear Models
Alleles
Regression Analysis
RNA
Cytokines
Proteins
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)

Cite this

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

In: Genes and Immunity, 16.03.2017.

Research output: Research - peer-reviewArticle

Vergara, C, Thio, C, Latanich, R, Cox, AL, Kirk, GD, Mehta, SH, Busch, M, Murphy, EL, Villacres, MC, Peters, MG, French, AL, Golub, E, Eron, J, Lahiri, CD, Shrestha, S, Gustafson, D, Young, M, Anastos, K, Aouizerat, B, Kim, AY, Lauer, G, Thomas, DL & Duggal, P 2017, 'Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections' Genes and Immunity. DOI: 10.1038/gene.2017.2
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./ Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections. In: Genes and Immunity. 2017
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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.Genes and Immunity advance online publication, 16 March 2017; doi:10.1038/gene.2017.2.",
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AU - Thio,C.

AU - Latanich,R.

AU - Cox,A. L.

AU - Kirk,G. D.

AU - Mehta,S. H.

AU - Busch,M.

AU - Murphy,E. L.

AU - Villacres,M. C.

AU - Peters,M. G.

AU - French,A. L.

AU - Golub,E.

AU - Eron,J.

AU - Lahiri,C. D.

AU - Shrestha,S.

AU - Gustafson,D.

AU - Young,M.

AU - Anastos,K.

AU - Aouizerat,B.

AU - Kim,A. Y.

AU - Lauer,G.

AU - Thomas,D. L.

AU - Duggal,P.

PY - 2017/3/16

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N2 - 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.Genes and Immunity advance online publication, 16 March 2017; doi:10.1038/gene.2017.2.

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