TY - JOUR
T1 - Genetic polymorphisms in host antiviral genes
T2 - Associations with humoral and cellular immunity to measles vaccine
AU - Haralambieva, Iana H.
AU - Ovsyannikova, Inna G.
AU - Umlauf, Benjamin J.
AU - Vierkant, Robert A.
AU - Shane Pankratz, V.
AU - Jacobson, Robert M.
AU - Poland, Gregory A.
N1 - Funding Information:
We thank the parents and children who participated in our studies and the Mayo Vaccine Research Group nurses for subject recruitment. We thank the Mayo Vaccine Research Group laboratory personnel for technical help with the assays and Matthew J. Phan and Caroline Vitse for assistance in preparing the manuscript. We thank also Megan O’Byrne for her contribution to statistical analyses and Rick Kennedy for the useful discussions. We thank David Rider and Ying Li for developing the SNP selection algorithm, and Julie M. Cunningham and the Mayo Advanced Genomic Technology Center for assistance with genotyping. The project described was supported by Award Numbers AI33144 and AI48793 (which recently received a MERIT Award) from the National Institute Of Allergy And Infectious Diseases , 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Allergy And Infectious Diseases or the National Institutes of Health. Disclosures : Dr. Poland is the chair of a DMSB for novel non-measles vaccines undergoing clinical study by Merck Research Laboratories. Dr. Jacobson recently served on a Safety Review Committee for a post-licensure study conducted by Kaiser-Permanente concerning Gardasil HPV vaccine funded by Merk & Co. Other authors do not have any conflicts of interest. Appendix A
PY - 2011/11/8
Y1 - 2011/11/8
N2 - Host antiviral genes are important regulators of antiviral immunity and plausible genetic determinants of immune response heterogeneity after vaccination. We genotyped and analyzed 307 common candidate tagSNPs from 12 antiviral genes in a cohort of 745 schoolchildren immunized with two doses of measles-mumps-rubella (MMR) vaccine. Associations between SNPs/haplotypes and measles virus-specific immune outcomes were assessed using linear regression methodologies in Caucasians and African-Americans.Genetic variants within the DDX58/RIG-I gene, including a coding polymorphism (rs3205166/Val800Val), were associated as single-SNPs (p≤ 0.017; although these SNPs did not remain significant after correction for false discovery rate/FDR) and in haplotype-level analysis, with measles-specific antibody variations in Caucasians (haplotype allele p-value = 0.021; haplotype global p-value = 0.076). Four DDX58 polymorphisms, in high LD, demonstrated also associations (after correction for FDR) with variations in both measles-specific IFN-γ and IL-2 secretion in Caucasians (p≤ 0.001, q= 0.193). Two intronic OAS1 polymorphisms, including the functional OAS1 SNP rs10774671 (p= 0.003), demonstrated evidence of association with a significant allele-dose-related increase in neutralizing antibody levels in African-Americans. Genotype and haplotype-level associations demonstrated the role of ADAR genetic variants, including a non-synonymous SNP (rs2229857/Arg384Lys; p= 0.01), in regulating measles virus-specific IFN-γ Elispot responses in Caucasians (haplotype global p-value = 0.017). After correction for FDR, 15 single-SNP associations (11 SNPs in Caucasians and 4 SNPs in African-Americans) still remained significant at the q-value < 0.20.In conclusion, our findings strongly point to genetic variants/genes, involved in antiviral sensing and antiviral control, as critical determinants, differentially modulating the adaptive immune responses to live attenuated measles vaccine in Caucasians and African-Americans.
AB - Host antiviral genes are important regulators of antiviral immunity and plausible genetic determinants of immune response heterogeneity after vaccination. We genotyped and analyzed 307 common candidate tagSNPs from 12 antiviral genes in a cohort of 745 schoolchildren immunized with two doses of measles-mumps-rubella (MMR) vaccine. Associations between SNPs/haplotypes and measles virus-specific immune outcomes were assessed using linear regression methodologies in Caucasians and African-Americans.Genetic variants within the DDX58/RIG-I gene, including a coding polymorphism (rs3205166/Val800Val), were associated as single-SNPs (p≤ 0.017; although these SNPs did not remain significant after correction for false discovery rate/FDR) and in haplotype-level analysis, with measles-specific antibody variations in Caucasians (haplotype allele p-value = 0.021; haplotype global p-value = 0.076). Four DDX58 polymorphisms, in high LD, demonstrated also associations (after correction for FDR) with variations in both measles-specific IFN-γ and IL-2 secretion in Caucasians (p≤ 0.001, q= 0.193). Two intronic OAS1 polymorphisms, including the functional OAS1 SNP rs10774671 (p= 0.003), demonstrated evidence of association with a significant allele-dose-related increase in neutralizing antibody levels in African-Americans. Genotype and haplotype-level associations demonstrated the role of ADAR genetic variants, including a non-synonymous SNP (rs2229857/Arg384Lys; p= 0.01), in regulating measles virus-specific IFN-γ Elispot responses in Caucasians (haplotype global p-value = 0.017). After correction for FDR, 15 single-SNP associations (11 SNPs in Caucasians and 4 SNPs in African-Americans) still remained significant at the q-value < 0.20.In conclusion, our findings strongly point to genetic variants/genes, involved in antiviral sensing and antiviral control, as critical determinants, differentially modulating the adaptive immune responses to live attenuated measles vaccine in Caucasians and African-Americans.
KW - Antiviral genes
KW - Haplotypes
KW - Immunity
KW - Measles vaccine
KW - Single nucleotide polymorphisms
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U2 - 10.1016/j.vaccine.2011.09.043
DO - 10.1016/j.vaccine.2011.09.043
M3 - Article
C2 - 21939710
AN - SCOPUS:82455175351
SN - 0264-410X
VL - 29
SP - 8988
EP - 8997
JO - Vaccine
JF - Vaccine
IS - 48
ER -