SNP/haplotype associations in cytokine and cytokine receptor genes and immunity to rubella vaccine

Abstract

An effective immune response to vaccination is, in part, a complex interaction of alleles of multiple genes regulating cytokine networks. We conducted a genotyping study of Th1/Th2/inflammatory cytokines/cytokine receptors in healthy children (n = 738, 11-19 years) to determine associations between individual single-nucleotide polymorphisms (SNPs)/haplotypes and immune outcomes after two doses of rubella vaccine. SNPs (n = 501) were selected using the ldSelect-approach and genotyped using Illumina GoldenGate and TaqMan assays. Rubella-IgG levels were measured by immunoassay and secreted cytokines by ELISA. Linear regression and post hoc haplotype analyses were used to determine associations between single SNPs/haplotypes and immune outcomes. Increased carriage of minor alleles for the promoter SNPs (rs2844482 and rs2857708) of the TNFA gene were associated with dose-related increases in rubella antibodies. IL-6 secretion was co-directionally associated (p < or = 0.01) with five intronic SNPs in the TNFRSF1B gene in an allele dose-related manner, while five promoter/intronic SNPs in the IL12B gene were associated with variations in IL-6 secretion. TNFA haplotype AAACGGGGC (t-statistic = 3.32) and IL12B promoter haplotype TAG (t-statistic = 2.66) were associated with higher levels of (p < or = 0.01) rubella-IgG and IL-6 secretion, respectively. We identified individual SNPs/haplotypes in TNFA/TNFRSF1B and IL12B genes that appear to modulate immunity to rubella vaccination. Identification of such "genetic fingerprints" may predict the outcome of vaccine response and inform new vaccine strategies.

Fig. 1

The linkage disequilibrium output for SNPs for TNFA gene from Haploview. a The r² plots with the r² values inside each box are shown for TNFA gene. Two promoter region SNPs (rs2844482 and rs2857708) in LD (r²=0.82) and a 3′ intergenic SNP (rs2256974) were found to be associated with rubella-specific antibody responses. Three other SNPs (rs2857706, rs2009658, and rs1800630) not genotyped in the current study were identified as tgSNPs with rs2844482 (r²≥0.9) by the SNPPicker algorithm. The r² color scheme is as follows: white (r²=0), shades of gray (0<r²<1), and black (r²=1). b Common TNFA haplotypes and association analysis with rubella antibodies, based on the SNPs reported in panel a (© Mayo Clinic 2010)

Fig. 2

The linkage disequilibrium output for TNFRSF1B SNPs from Haploview. a The r² plots with the r² values inside each box are shown for TNFRSF1B gene. Six intronic SNPs (rs5745993, rs17882988, rs472093, rs5746059, rs474247, and rs590977) in the TNFRSF1B gene were associated with rubella-specific secreted IL-6 levels. Strong LD (r²=0.97) was observed between rs5745993 and rs17882988. The r² color scheme is as follows: white (r²=0), shades of gray (0<r²<1), and black (r²=1). b Common TNFRSF1B haplotypes and association analysis with rubella-specific IL-6 secretion, based on the SNPs reported in panel a (© Mayo Clinic 2010)

Fig. 3

The linkage disequilibrium output for IL12B SNPs from Haploview. a The r² plots with the r² values inside each box are shown for IL12B gene. Two promoter (rs1422876 and rs6868898) and three intronic (rs2569253, rs730691, and rs2546893) SNPs from the IL12B gene were associated with IL-6 secretion. No strong linkage was observed among the genotyped SNPs in this gene. The r² color scheme is as follows: white (r²=0), shades of gray (0<r²<1), and black (r²=1). b Common IL12B promoter region SNP (rs1422876, rs7709212, and rs6868898) haplotypes and association analysis with rubella-specific IL-6 secretion (© Mayo Clinic 2010)