Genome-wide genetic associations with IFNγ response to smallpox vaccine
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Smallpox is a deadly and debilitating disease that killed hundreds of millions of people in the past century alone. The use of Vaccinia virus-based smallpox vaccines led to the eradication of smallpox. These vaccines are remarkably effective, inducing the characteristic pustule or “take” at the vaccine site in >97 % of recipients, and inducing a wide spectrum of long-lasting humoral and cellular immune responses. The mechanisms behind inter-individual vaccine-response variability are likely to involve host genetic variation, but have not been fully characterized. We report here the first smallpox vaccine response genome-wide association study of over 1,000 recent recipients of Dryvax®. The data presented here focus on cellular immune responses as measured by both production of secreted IFNγ and quantitation of IFNγ secreting cells by ELISPOT assay. We identified multiple significant SNP associations in genes (RASA1, ADRA1D, TCF7L1, FAS) that are critical components of signaling pathways that directly control lymphocyte IFNγ production or cytotoxic T cell function. Similarly, we found many associations with SNPs located in genes integral to nerve cell function; findings that, given the complex interplay between the nervous and immune systems, deserve closer examination in follow-up studies.
The authors thank the subjects who participated in this study and the research staff at the NHRC and Mayo Clinic that made this study possible—particularly, Drs. Meg Ryan and Kevin Russell. The authors also wish to recognize Dave Watson and Megan O’Byrne for their statistical programming and analytical support as well as Julie M. Cunningham and the Mayo Advanced Genomic Technology Center for the genotyping efforts. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of this manuscript. This project was funded by federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN266200400065C.
Conflict of interest
The authors have no conflicts of interest.
All experiments described here followed current, applicable US laws.
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