Genetic polymorphisms in host antiviral genes: Associations with humoral and cellular immunity to measles vaccine

Abstract

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 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 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.

Single nucleotide polymorphisms/haplotypes associated with multiple rubella-specific immune response outcomes post-MMR immunization in healthy children

“…For example, a non-synonymous rs2229857 (Lys384/Arg) in the antiviral RNA-specific ADAR gene, known to be involved in RNA editing and gene regulation, demonstrated an allele dose-related increase in IL-6 and IFN-γ secretion with the representation of a minor allele. Consistent with the current results, our earlier vaccine study with measles demonstrated an association between ADAR SNP rs2229857 and measles virus-specific IFN-γ ELISPOT responses (Haralambieva et al 2011b). We speculate that this genetic variant is likely to be involved in regulation of virus-induced cellular immune mechanisms.…”

Duration of Protection After Infant Hepatitis B Vaccination Series

“…Recent advances in examining the association of immune response between "high" and "low" responders to vaccines with genotype differences have emphasized the role of genetic make-up in vaccine response. [22][23][24][25] Race may serve as a proxy for these genetic differences. The clinical significance of this finding is unclear, however, because race was not significantly associated with the more clinically relevant outcome of seroprotection.…”

Genetic polymorphisms associated with rubella virus-specific cellular immunity following MMR vaccination

“…Two of these three SNPs (rs2229857, rs1127317) were also associated with variations in cytokine secretion after measles stimulation. (Haralambieva et al 2011) The non-synonymous SNP, rs2229857 encoding a K>R change, is also associated with sustained response to IFN therapy for chronic HCV infection. (Hwang et al 2006; Welzel et al 2009)…”