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Genome-wide genetic associations with IFNγ response to smallpox vaccine

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Abstract

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.

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Acknowledgments

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.

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The authors have no conflicts of interest.

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All experiments described here followed current, applicable US laws.

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Authors and Affiliations

  1. Mayo Vaccine Research Group, Mayo Clinic, Guggenheim 611C, 200 First Street SW, Rochester, MN, 55905, USA

    Gregory A. Poland

  2. Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN, USA

    Richard B. Kennedy, Inna G. Ovsyannikova, Iana H. Haralambieva & Gregory A. Poland

  3. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    V. Shane Pankratz & Robert A. Vierkant

  4. Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA

    Robert M. Jacobson & Gregory A. Poland

  5. Mayo Vaccine Research Group, Mayo Clinic, Guggenheim 611D, 200 First Street SW, Rochester, MN, 55905, USA

    Richard B. Kennedy

  6. Mayo Vaccine Research Group, Mayo Clinic, Guggenheim 611B, 200 First Street SW, Rochester, MN, 55905, USA

    Inna G. Ovsyannikova

  7. Mayo Vaccine Research Group, Mayo Clinic, Guggenheim 695, 200 First Street SW, Rochester, MN, 55905, USA

    Iana H. Haralambieva

  8. Mayo Vaccine Research Group, Mayo Clinic, Rochester, USA

    Robert M. Jacobson

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  1. Richard B. Kennedy
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Kennedy, R.B., Ovsyannikova, I.G., Pankratz, V.S. et al. Genome-wide genetic associations with IFNγ response to smallpox vaccine. Hum Genet 131, 1433–1451 (2012). https://doi.org/10.1007/s00439-012-1179-x

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