title: Rubella vaccine-induced cellular immunity: evidence of associations with polymorphisms in the Toll-like, vitamin A and D receptors, and innate immune response genes.
abstract: Toll-like, vitamin A and D receptors and other innate proteins participate in various immune functions. We determined whether innate gene-sequence variations are associated with rubella vaccine-induced cytokine immune responses. We genotyped 714 healthy children (11-19 years of age) after two doses of rubella-containing vaccine for 148 candidate SNP markers. Rubella virus-induced cytokines were measured by ELISA. Twenty-two significant associations (range of P values 0.002-0.048) were found between SNPs in the vitamin A receptor family (RARA, RARB, TOP2B and RARG), vitamin D receptor and downstream mediator of vitamin D signaling (RXRA) genes and rubella virus-specific (IFN-gamma, IL-2, IL-10, TNF-alpha, and GM-CSF) cytokine immune responses. A TLR3 gene promoter region SNP (rs5743305, -8441A > T) was associated with rubella-specific GM-CSF secretion. Importantly, SNPs in the TRIM5 gene coding regions, rs3740996 (His43Tyr) and rs10838525 (Gln136Arg), were associated with an allele dose-related secretion of rubella virus-specific TNF-alpha and IL-2/GM-CSF, respectively, and have been previously shown to have functional consequences regarding the antiviral activity and susceptibility to HIV-1 infection. We identified associations between individual SNPs and haplotypes in, or involving, the RIG-I (DDX58) gene and rubella-specific TNF-alpha secretion. This is the first paper to present evidence that polymorphisms in the TLR, vitamin A, vitamin D receptor, and innate immunity genes can influence adaptive cytokine responses to rubella vaccination.
authors.affiliation: Mayo Vaccine Research Group, Mayo Clinic, Guggenheim 611C, Rochester, MN 55905, USA.
authors.forename: Inna G
authors.initials: IG
authors.lastname: Ovsyannikova
authors.forename: Neelam
authors.initials: N
authors.lastname: Dhiman
authors.forename: Iana H
authors.initials: IH
authors.lastname: Haralambieva
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Megan M
authors.initials: MM
authors.lastname: O'Byrne
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jacobson
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Poland
mesh_terms: D000293:Adolescent; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D016207:Cytokines / Q000378:metabolism*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics* / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic; D018168:Receptors, Retinoic Acid / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha / Q000235:genetics; D012411:Rubella Vaccine / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000235:genetics; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D055815:Young Adult; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D016207:Cytokines; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016753:Interleukin-10; D007376:Interleukin-2; D000075223:Poly-ADP-Ribose Binding Proteins; D011971:Receptors, Immunologic; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; D012411:Rubella Vaccine; D051196:Toll-Like Receptor 3; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C495344:TLR3 protein, human; C082925:retinoic acid receptor beta; C477346:TRIM5 protein, human; C452820:RIGI protein, human; C000618814:TOP2B protein, human