Genetic Variation in IL18R1 and IL18 Genes and Inteferon γ ELISPOT Response to Smallpox Vaccination: An Unexpected Relationship

Background. Genetic association studies demonstrated a role for cytokine proteins and cytokine or cytokine receptor gene polymorphisms in smallpox vaccine-induced adaptive immunity. Methods. We examined the association of genetic polymorphisms with cellular (interferon [IFN] gamma enzyme-linked immunospot assay [ELISPOT]) immune response to smallpox vaccine in 1076 immunized individuals. Results. The majority of significant associations were discovered between single-nucleotide polymorphisms/haplotypes in IL18R1 and IL18 genes, in which we previously reported an association with vaccinia virus-induced neutralizing antibody titers in this study cohort. A functional coding IL18R1 polymorphism (rs1035130/Phe251 Phe; P = .01) was significantly associated with an allele dose-related increase in IFN-gamma production and was also associated with vaccinia-specific neutralizing antibody titers. Significant associations were also found between IL18R1 haplotypes and variations in IFN-gamma ELISPOT responses (global P < .0001). Conclusions. Our data suggest the importance of variants in the IL18R1 and IL18 genetic loci for broad-based smallpox vaccine-induced adaptive immunity.