title: The role of polymorphisms in Toll-like receptors and their associated intracellular signaling genes in measles vaccine immunity.
abstract: Toll-like receptors (TLRs) and their intracellular signaling molecules play an important role in innate immunity. In this study, we examined associations between polymorphisms in TLR family genes and measles vaccine-specific immune responses. We genotyped 764 subjects (11-22 years old) after two doses of measles vaccine for TLR signaling SNP markers (n = 454). The major alleles of coding SNPs in the TLR2 (rs3804100) and TLR4 (rs5030710) genes were associated with a dose-related increase (660 vs. 892 mIU/ml, p = 0.002) and a dose-related decrease (2,209 vs. 830 mIU/ml, p = 0.001) in measles-specific antibodies, respectively. A significant association was found between lower measles antibody levels and the haplotype ACGGCGAGAAAAGAGAAGAGAGAGAA (p = 0.01) in the MAP3K7 gene. Furthermore, the minor allele of a SNP (rs702966) of the KIAA1542 (IRF7) gene was associated with a dose-related decrease in IFN-γ Elispot responses (38 vs. 26 spot-forming cells per 2 × 10(5) PBMCs, p = 0.00002). We observed an additional 12 associations (p < 0.01) between coding (nonsynonymous and synonymous) polymorphisms within the TLRs (TLR2, 7, and 8), IKBKE, TICAM1, NFKBIA, IRAK2, and KIAA1542 genes and variations in measles-specific IL-2, IL-6, IFN-α, IFN-γ, IFNλ-1, and TNF-α secretion levels. Our data demonstrate that polymorphisms in TLR and other related immune response signaling molecules have significant effects on measles vaccine-associated immune responses. These data help to establish the genetic foundation for immune response variation in response to measles immunization and provide important insights for the rational development of new measles vaccines.
authors.affiliation: Mayo Vaccine Research Group, Mayo Clinic, Guggenheim 611C, 200 1st Street S.W., Rochester, MN 55905, USA.
authors.forename: Inna G
authors.initials: IG
authors.lastname: Ovsyannikova
authors.forename: Iana H
authors.initials: IH
authors.lastname: Haralambieva
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jacobson
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Poland
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral; D002648:Child; D015331:Cohort Studies; D004279:DNA, Viral / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics* / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008457:Measles / Q000276:immunology / Q000628:therapy / Q000821:virology; D008458:Measles Vaccine / Q000276:immunology* / Q000627:therapeutic use; D008459:Measles virus / Q000235:genetics / Q000276:immunology*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics*; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D004279:DNA, Viral; D047908:Intracellular Signaling Peptides and Proteins; D008458:Measles Vaccine; D051193:Toll-Like Receptors