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

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

CD14-159C/T polymorphism in the development of delayed skin hypersensitivity to tuberculin

The skin tuberculin test (TST), an example of a delayed-type hypersensitivity (DTH) reaction, is based on measuring the extent of skin induration to mycobacterial tuberculin (PPD). Little is known about the genetic basis of TST reactivity, widely used for diagnosing TB infection. The study investigated the relationship of the single base change polymorphic variants in CD14 gene (CD14(-159C/T)) with the development of DTH to PPD in BCG-vaccinated Polish Caucasian individuals. We found persistent lack of TST reactivity in about 40% of healthy subjects despite receiving more than one dose of BCG. The TST size was negatively correlated with the number of BCG inoculations. The distribution of C/T genotype was significantly more frequent among TST-negative compared with TST-positive individuals. The concentration of serum sCD14 was positively associated with mCD14 expression, but not with the TST status or CD14(-159C/T) polymorphism. A significant increase in mCD14 expression and serum sCD14 levels was found in TB group. We hypothesize that CD14(-159C/T) polymorphic variants might be one of genetic components in the response to attenuated M. bovis BCG bacilli