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^-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.

Figure 1

Log plasma IL-18 by HCV and HIV infection status in all the individuals analyzed in the study. The thick horizontal line in each box plot represent the median for each category, the whiskers extend to 1.5 times the interquartile range from the box.

Figure 2

Association of variants in the IL18-BCO2 region. The variants included 14 genotyped (squares) and 177 imputed SNPs (circles) within the region from 112 Mb to 112.1 Mb on chromosome 11. The recombination in this region is plotted in the background in light blue. Pair wise LDs between rs80011693 and other variants in IL18-BCO2 were estimated using LD data in EUR population in the 1000 Genomes project (hg19/Nov 2014). The color from blue to red represents the r² values.