TY - JOUR
T1 - The role of polymorphisms in Toll-like receptors and their associated intracellular signaling genes in measles vaccine immunity
AU - Ovsyannikova, Inna G.
AU - Haralambieva, Iana H.
AU - Vierkant, Robert A.
AU - Pankratz, V. Shane
AU - Jacobson, Robert M.
AU - Poland, Gregory A.
N1 - Funding Information:
Acknowledgments We thank the Mayo Clinic Vaccine Research Group staV and subjects who participated in our studies. We thank Megan M. O’Byrne and Matthew J. Phan for their help with this manuscript. This work was supported by NIH grants AI 33144, AI 48793 and 5UL1RR024150-03 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 oYcial view of NCRR or NIH.
PY - 2011/10
Y1 - 2011/10
N2 - 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 vaccinespeciWc 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 doserelated decrease (2,209 vs. 830 mIU/ml, p = 0.001) in measles-speciWc antibodies, respectively. A signiWcant association was found between lower measles antibody levels and the haplotype ACGGCGAGAAAAGAGAAG AGAGAGAA (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 × 105 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 measlesspeciWc 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 signiWcant eVects 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.
AB - 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 vaccinespeciWc 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 doserelated decrease (2,209 vs. 830 mIU/ml, p = 0.001) in measles-speciWc antibodies, respectively. A signiWcant association was found between lower measles antibody levels and the haplotype ACGGCGAGAAAAGAGAAG AGAGAGAA (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 × 105 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 measlesspeciWc 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 signiWcant eVects 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.
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U2 - 10.1007/s00439-011-0977-x
DO - 10.1007/s00439-011-0977-x
M3 - Article
C2 - 21424379
AN - SCOPUS:80054856821
SN - 0340-6717
VL - 130
SP - 547
EP - 561
JO - Human genetics
JF - Human genetics
IS - 4
ER -