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SNP/haplotype associations in cytokine and cytokine receptor genes and immunity to rubella vaccine

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Abstract

An effective immune response to vaccination is, in part, a complex interaction of alleles of multiple genes regulating cytokine networks. We conducted a genotyping study of Th1/Th2/inflammatory cytokines/cytokine receptors in healthy children (n = 738, 11–19 years) to determine associations between individual single-nucleotide polymorphisms (SNPs)/haplotypes and immune outcomes after two doses of rubella vaccine. SNPs (n = 501) were selected using the ldSelect-approach and genotyped using Illumina GoldenGate™ and TaqMan assays. Rubella-IgG levels were measured by immunoassay and secreted cytokines by ELISA. Linear regression and post hoc haplotype analyses were used to determine associations between single SNPs/haplotypes and immune outcomes. Increased carriage of minor alleles for the promoter SNPs (rs2844482 and rs2857708) of the TNFA gene were associated with dose-related increases in rubella antibodies. IL-6 secretion was co-directionally associated (p ≤ 0.01) with five intronic SNPs in the TNFRSF1B gene in an allele dose-related manner, while five promoter/intronic SNPs in the IL12B gene were associated with variations in IL-6 secretion. TNFA haplotype AAACGGGGC (t-statistic = 3.32) and IL12B promoter haplotype TAG (t-statistic = 2.66) were associated with higher levels of (p ≤ 0.01) rubella-IgG and IL-6 secretion, respectively. We identified individual SNPs/haplotypes in TNFA/TNFRSF1B and IL12B genes that appear to modulate immunity to rubella vaccination. Identification of such “genetic fingerprints” may predict the outcome of vaccine response and inform new vaccine strategies.

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Acknowledgments

We thank the Mayo Clinic Vaccine Research Group nurses for subject recruitment and the children who participated in our studies. We also thank David N. Rider and Hugues Sicotte from the Department of Biomedical Statistics and Informatics for development and optimization of the SNP selection algorithm for this study. This work was supported by NIH grants AI 48793, AI 33144, and 1 UL1 RR024150-01 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health, and the NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.

Financial Disclosure

Dr. Poland is the chair of a Safety Evaluation Committee for novel non-rubella vaccines undergoing clinical studies by Merck Research Laboratories. Dr. Jacobson serves on a Safety Review Committee for a post-licensure study of a human papillomavirus vaccine for Kaiser–Permanente. Other authors declare no conflict of interest.

This work was presented as oral presentation (abstract # G1-1110) at the 49th Annual ICAAC Meeting. San Francisco CA, Sep. 12–15, 2009.

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Authors and Affiliations

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

    Neelam Dhiman, Iana H. Haralambieva, Richard B. Kennedy, Inna G. Ovsyannikova, Robert M. Jacobson & Gregory A. Poland

  2. Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN, 55905, USA

    Neelam Dhiman, Iana H. Haralambieva, Richard B. Kennedy, Inna G. Ovsyannikova, Robert M. Jacobson & Gregory A. Poland

  3. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA

    Robert A. Vierkant & Megan M. O’Byrne

  4. Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, 55905, USA

    Robert M. Jacobson

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  1. Neelam Dhiman
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  2. Iana H. Haralambieva
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Dhiman, N., Haralambieva, I.H., Kennedy, R.B. et al. SNP/haplotype associations in cytokine and cytokine receptor genes and immunity to rubella vaccine. Immunogenetics 62, 197–210 (2010). https://doi.org/10.1007/s00251-010-0423-6

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