Associations between Single Nucleotide Polymorphisms in Cellular Viral Receptors and Attachment Factor- Related Genes and Humoral Immunity to Rubella Vaccination Iana H. Haralambieva 1,4 , Nathaniel D. Lambert 1,4 , Inna G. Ovsyannikova 1,4 , Richard B. Kennedy 1,4 , Beth R. Larrabee 2 , V. Shane Pankratz 1,2 , Gregory A. Poland 1,3,4 * 1 Mayo Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America, 2 Division of Biostatistics, Mayo Clinic, Rochester, Minnesota, United States of America, 3 Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, United States of America, 4 Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, Minnesota, United States of America Abstract Background: Viral attachment and cell entry host factors are important for viral replication, pathogenesis, and the generation and sustenance of immune responses after infection and/or vaccination, and are plausible genetic regulators of vaccine-induced immunity. Methods: Using a tag-SNP approach in candidate gene study, we assessed the role of selected cell surface receptor genes, attachment factor-related genes, along with other immune genes in the genetic control of immune response variations after live rubella vaccination in two independent study cohorts. Results: Our analysis revealed evidence for multiple associations between genetic variants in the PVR, PVRL2, CD209/DC- SIGN, RARB, MOG, IL6 and other immune function-related genes and rubella-specific neutralizing antibodies after vaccination (meta p-value ,0.05). Conclusion: Our results indicate that multiple SNPs from genes involved in cell adhesion, viral attachment, and viral entry, as well as others in genes involved in signaling and/or immune response regulation, play a role in modulating humoral immune responses following live rubella vaccination. Citation: Haralambieva IH, Lambert ND, Ovsyannikova IG, Kennedy RB, Larrabee BR, et al. (2014) Associations between Single Nucleotide Polymorphisms in Cellular Viral Receptors and Attachment Factor-Related Genes and Humoral Immunity to Rubella Vaccination. PLoS ONE 9(6): e99997. doi:10.1371/journal.pone. 0099997 Editor: Tjeerd Kimman, Wageningen University and Research Centre, Netherlands Received February 7, 2014; Accepted May 21, 2014; Published June 19, 2014 Copyright: ß 2014 Haralambieva et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R37 AI048793-11 (which recently received a MERIT award). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: GP is the chair of a Safety Evaluation Committee for novel non-rubella investigational vaccine trials being conducted by Merck Research Laboratories. GP offers consultative advice on vaccine development to Merck & Co. Inc., CSL Biotherapies, Avianax, Sanofi Pasteur, Dynavax, Novartis Vaccines and Therapeutics, PAXVAX Inc, and Emergent Biosolutions. GP and IO hold two patents related to vaccinia peptide research: U.S. Patent ‘‘Vaccinia Virus Polypeptides,’’ U.S. Patent Number: 13/222,862 (issued 31 August 2011), and U.S. Patent ‘‘Naturally Processed Measles Virus Peptides from Class II HLA Molecules,’’ U.S. Patent Number US 2010/0119536 A1 (issued 13 May 2010). These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. This does not alter adherence to PLOS ONE policies on sharing data and materials. * Email: poland.gregory@mayo.edu Introduction Host genetic determinants play an important role in the generation and regulation of humoral and cellular immune responses after vaccination and/or infection [1,2]. Studying measles-mumps-rubella (MMR) vaccine immunogenicity in twins, we have previously demonstrated a high level of heritability, approximately 46%, of humoral immune response variance following rubella vaccination [3]. Multiple host genes operate at a gene and gene-network level to shape and regulate the quality, duration and magnitude of rubella vaccine-induced humoral and cellular immune responses [4,5,6,7,8,9,10]. Viral attachment, cell entry, fusion with the cell membrane, and viral genome translocation into target cells are essential early stages initiating the viral infectious cycle. These are key steps in viral replication and dissemination, as well as virus-host interac- tions involving the generation and maintenance of the immune response. Recent discoveries point to the role of newly discovered cellular receptors and attachment factors for several important human viruses, including rubella virus (Myelin Oligodendrocyte Glycoprotein, MOG), measles virus (measles virus epithelial cell receptor PVRL4, poliovirus receptor-related 4 gene, Nectin-4; and the transmembrane C-type lectin DC-SIGN/CD209), Rift Valley Fever virus/RVFV (DC-SIGN/CD209), poliovirus (Poliovirus PLOS ONE | www.plosone.org 1 June 2014 | Volume 9 | Issue 6 | e99997