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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Infect Dis. Author manuscript; available in PMC Jan 15, 2011.
Published in final edited form as:
PMCID: PMC2798005
NIHMSID: NIHMS155668

Polymorphisms in the Vitamin A Receptor and Innate Immunity Genes Influence the Antibody Response to Rubella Vaccination

Abstract

Background

Genetic polymorphisms play an important role in rubella vaccine-induced immunity.

Methods

We genotyped 714 healthy children after two age-appropriate doses of rubella-containing vaccine for 142 potential SNPs.

Results

Specific polymorphisms in the vitamin A receptor, RIG-I, TRIM5 and TRIM22 genes were significantly associated with rubella vaccine humoral immunity. The minor allele of the rs4416353 in the vitamin A receptor gene was associated with an allele dose-related decrease (P=.019) in rubella antibody response. The minor allele of rs6793694, in the vitamin A receptor gene, was associated with an allele dose-related antibody decrease (P=.039). The minor variant of nonsynonymous SNP rs10813831 (Arg7Cys) in the RIG-I gene was associated with an allele dose-related decrease in rubella antibody level from 37.4 IU/mL to 28.0 IU/mL (P=.035), while increased representation of the minor allele of the 5’UTR SNP (rs3824949, P=.015), in the antiretroviral TRIM5 gene, was associated with an allele dose-related increase in rubella antibody. It is of particular interest that the nonsynonymous SNP rs3740996 (His43Tyr) in the TRIM5 gene was associated with variations in rubella antibody response (P=.016) after having been previously found to have a significant functional role.

Conclusions

These findings further expand our immunogenetic understanding of mechanisms of rubella vaccine-induced immunity.

Keywords: Genetics, Immunogenetics, Rubella vaccine, Vitamin A receptor, RIG-I, TRIM, Immunity, Innate

INTRODUCTION

Rubella epidemics occasionally occur in developing countries and both rubella virus infection and congenital rubella syndrome remain a major health concern around the world. Although the importance of sustaining protective rubella humoral immunity is widely recognized, the host genetic influence on rubella vaccine-induced immunity remains incomplete. A previous study on the heritability for antibody response to rubella was estimated to be 46%, with a lower limit of the 95% one-sided confidence interval of 4.9% [1].

Our group and others have shown that polymorphisms at the human leukocyte antigen (HLA) loci are associated with significant variations in immune responses to rubella vaccine such as antibody level, lymphocyte proliferation and cytokine production [26]. Studies with other viral vaccines, such as measles and mumps, have also demonstrated associations between cytokine and cytokine receptor gene polymorphisms and immune responses [7, 8]. The regulatory complexity of the human immune system insures a high probability of functional redundancy in both cell-mediated and humoral immune responses [9, 10]. This is also true for loci/polymorphisms beyond those regulating HLA and cytokine and cytokine receptor groups. Several new genes (and molecules) have been identified as candidate immune response genes. Studies in a variety of other models (viruses, bacteria, microbial antigens) have recently demonstrated the importance of innate and vitamin receptor genes in regulating immune responses [1113]. In this regard, the discovery of genetic variations caused by single nucleotide polymorphisms (SNPs) has led to population-based immunogenetic studies intended to elucidate the potential relationship between host genomic variation and immune response [14].

In the present study, we investigated whether the humoral immune response to two-doses of rubella vaccination is associated with polymorphisms of non-HLA candidate immune response genes, such as the retinoic acid (vitamin A) receptor and the vitamin D receptor (VDR), the innate immunity toll-like receptors (TLR), the antiretroviral tripartite motif-containing (TRIM) factors, and the retinoic acid-inducible gene I (RIG-I) pathway genes.

SUBJECTS, MATERIALS, AND METHODS

Study subjects

The study cohort of 738 healthy children and young adults (age 11 to 19 years) from Olmsted County in Minnesota has previously been described [15]. All study subjects were immunized with two age-appropriate doses of live measles-mumps-rubella (MMR-II) vaccine containing the Wistar RA 27/3-strain of rubella virus. The majority of the study population was white (91%), with 47% being female, and a median age at enrollment of 15 years (Table 1). The median age at the first and second immunization were 15 months and 11 years, respectively, and the median time between last rubella immunization and sample draw was 5.8 years. The participants lived in a community where no case of rubella infection had been reported during their lifetimes. While 738 children and young adults were enrolled in the study, genotyping data were available for only 714 subjects. The Mayo Clinic Institutional Review Board granted approval for the study, and written informed consent (parental permission and assent for minors) was obtained.

Table 1
Characteristics of the study population and their associations with rubella-specific IgG antibody levels.

Humoral immunity assays

Rubella-specific IgG antibodies after two doses of the rubella vaccine were detected in serum by a whole rubella virus-specific chemiluminescent immunoassay (Beckman Coulter Access, Fullerton, CA) according to the manufacturer’s instructions. The limit of detection for this assay was 0.5 IU/mL and the coefficient of variation in our laboratory was 6%.

TagSNP selection

We selected tagSNPs from innate immune response candidate genes (n=12) belonging to the vitamin A family (RARA, RARB, RARG and RXRA), vitamin D receptor (VDR), TLR family (TLR3 and TLR4), RIG-I pathway (DDX58, CASP10 and VISA) and cellular antiretroviral TRIM factors (TRIM5 and TRIM22). The details of SNP selection were described previously [16]. Briefly, we used a linkage disequilibrium (LD) tagSNPs selection approach [17] to generate a list of SNPs within and 10 kb upstream and downstream of these 12 genes using the Hapmap Phase II (http://www.hapmap.org), Seattle SNPs (http://pga.mbt.washington.edu/), and NIEHS SNPs (http://egp.gs.washington.edu/) as source databases. We included SNPs that had validation data, successful predictive genotyping scores for Illumina GoldenGate assays, a minor allele frequency (MAF) ≥0.05, and a pairwise LD threshold of r2 <0.90 for Caucasians. We selected 142 potential SNPs in our candidate genes of interest using the ldSelect algorithm. We used the nomenclature described by den Dunnen and Antonarakis for all genotype variants [18].

Genotyping methods

Our genotyping methods were previously described in detail [7]. Briefly, genomic DNA samples (n=738, 250 ng each) obtained from frozen blood clots using the Puregene extraction kit (Gentra Systems Inc., Minneapolis, MN) were genotyped for 142 candidate SNPs using a custom designed 768-plex Illumina GoldenGate™ assay (Illumina Inc., San Diego, CA), following the manufacturer’s instructions [16]. All the SNPs selected for the custom Illumina panel had design scores > 0.4. A Corriel Trio DNA (mother: NA11875, father: NA10859, daughter: NA10858) and two other genomic DNA controls were used as standards to review and refine clustering. These controls were genotyped on each plate, which allowed us to assess genotyping concordance of replicate subjects.

Illumina 10% GenCall scores > 0.4 and call rates >90% were used as thresholds for the initial laboratory quality control. The data from genotype calls made by BeadStudio 2 software were transferred to SAS for further analysis. Our overall genotyping success rate for the Illumina 768-plex platform and Taqman platform was 94.53%. The study sample success rate was 96.75%. SNP-specific deviation from Hardy-Weinberg Equilibrium (HWE) was tested and we excluded any SNP that displayed violations of HWE (p<0.001). Subject exclusions were made on the basis of DNA quality (n=6), complete genotyping failure on both platforms (n=4), and low call rates below 95% (n=14), leaving a total of 714 subjects for the study.

We used PCR-based TaqMan assays (Applied Biosystems, Foster City, CA) as the secondary platform to genotype SNPs (n=6) that failed genotyping on the Illumina platform. All assays were performed according to the manufacturer’s instructions, and the results were analyzed on the ABI Prism 7900 using Sequence Detection Software (Applied Biosystems). Of these 6 SNPs, one also failed by Taqman and 4 were excluded because the minor allele frequency was <5%. This resulted in 137 SNPs available for analysis in 714 subjects.

Statistical methods

The purpose of the efforts reported here was to assess associations between genetic variation in candidate SNPs and rubella antibody levels (measured in units of IU/mL). Characteristics of the study participants were categorized, and the numbers of subjects in these categories were tabulated, along with summaries of rubella antibody levels. We compared the mean rubella antibody levels, transformed on the logarithmic scale, among the various classes of these descriptive variables using linear models methodologies (analysis of variance). Participants’ genotypes were used to estimate allele frequencies for each SNP of interest. We assessed departures from Hardy-Weinberg equilibrium (HWE), using a Pearson goodness-of-fit test or, for SNPs with a minor allele frequency of less than 5%, a Fisher exact test [19].

Individual SNP associations with antibody levels were formally evaluated using linear models approaches. Primary tests of association assumed no specific genetic model of the potential action of the SNPs on rubella antibody levels, although the degree to which the SNP’s association appeared to act in a dose-response fashion was also examined. Analyses were adjusted for the following set of covariates potentially associated with immune response: age at enrollment, race, gender, age at first rubella vaccination, age at second rubella vaccination, and cohort status. Due to data skewness, original antibody values were replaced with corresponding log-transformed values in all the linear regression models. All statistical tests were two-sided and, unless otherwise indicated, all analyses were carried out using the SAS software system (SAS Institute, Inc., Cary, NC).

RESULTS

We performed a population-based study to investigate the contribution of polymorphisms in vitamin receptor and innate immunity genes to variations in antibody responses after rubella vaccination. A total of 8 significant SNP associations (P<.05) (in 4 of 12 candidate genes) were identified between the RARB retinoic acid beta (vitamin A), RIG-I (DDX58) and TRIM (TRIM5 and TRIM22) genes and humoral immunity following rubella vaccine (Table 2). These associations were identified while adjusting for several potential confounders, including gender and age at first and second vaccination. Results were similar without adjusting for these covariates (data not shown). Out of these, three SNPs were located in coding and regulatory regions of the genes corresponding to the RIG-I and TRIM5 molecules.

Table 2
Associations between SNPs in the vitamin A receptor, RIG-I and TRIM innate immunity genes and rubella-specific antibody responses after rubella vaccine.

We found significant associations between 3 intronic SNPs located in the retinoic acid receptor gene on chromosome 3 (3p24) and measures of rubella vaccine humoral immunity. Increased representation of the minor allele of an intronic SNP (rs4416353) in the RARB (retinoic acid receptor beta) gene was associated with an allele-dose related decrease (P=.019) in rubella-specific antibody response (Table 2). Similarly, the minor allele of a SNP (rs6793694) in the RARB gene was also associated with an allele-dose related decrease (P=.039) in rubella-induced antibody levels. In addition, an intronic SNP was significantly (rs1153600, P=.034) associated with variation in antibody levels; however, no allele dose-related association with rubella antibody levels was observed.

We also analyzed the relationship between SNPs belonging to the retinoic acid-inducible gene I (RIG-I/DDX58 gene) on chromosome 9 that encodes a pattern recognition receptor protein - RNA helicase, and rubella humoral immune responses. Increased representation of the minor allele of a nonsynonymous SNP in exon 1 of the RIG-I CARD domain (rs10813831, Arg→Cys at amino acid 7) was associated with an allele dose-related decrease (P=.035) in rubella antibody response from 37.4 (0 copies) IU/mL to 28.0 (2 copies) IU/mL. For another RIG-I SNP (rs669260, P=.048), the increased representation of the minor allele was associated with an allele dose-related increase in antibody response. None of the SNPs identified as associated with rubella antibody responses in RIG-I gene were found to be in LD.

Genotypes for SNPs from the antiretroviral TRIM5 (tripartite motif-containing 5) and TRIM22 (tripartite motif-containing 22) genes on chromosome 11 (11p15) were also analyzed, and two significantly associated SNPs located in the 5’UTR and coding regions of the TRIM5 gene are shown in Table 2. Increased representation of the minor allele of the 5’UTR SNP (rs3824949, P=.015) in the antiretroviral TRIM5 gene was associated with an allele dose-related increase in rubella antibody response from 31.5 (0 copies) IU/mL to 40.8 (2 copies) IU/mL. The TRIM5 A/G nonsynonymous polymorphism (rs3740996, P=.016) in exon 2 (loop 2 region of the RING domain leading to His→Tyr change at amino acid 43) was associated with variations in rubella antibody level; however, although without a clear allele dose-related effect. Finally, increased representation of the minor allele of an intronic SNP (rs2179) in the TRIM22 gene was associated with an allele dose-related decrease (P=.039) in rubella-specific antibody response in our study subjects.

None of the SNPs identified as associated with rubella humoral immunity in RARB, RIG-I and TRIM5 genes were found to be in LD with one another. No significant associations were found with polymorphisms in the TLR family (TLR3 and TLR4), RIG-I pathway (CASP10 and VISA), vitamin A family (RARA, RARG and RXRA) or vitamin D receptor (VDR) genes.

DISCUSSION

Because of the multigenic nature of immune responses to complex antigens, most genes that are important in influencing immune responses to vaccination are still unknown. In this study we examined the association of polymorphisms in vitamin A receptor, vitamin D receptor, and innate immune response genes to rubella vaccine-induced immunity. We assessed these candidate genes in the largest rubella vaccine immunogenetics study yet reported.

We previously reported a strong influence of gender on antibody responses following MMR-II vaccine [4, 8]. In fact, in our study, females demonstrated significantly higher rubella antibody levels than males (median 39.9 IU/mL versus 30.9 IU/mL, P=.007). A better understanding of the factors that influence gender differences in the innate and adaptive immune responses to vaccines may lead to the identification of immune-related genes and pathways as targets for the development of more uniformly immunogenic vaccines.

The role of vitamin and vitamin-receptor genes in rubella vaccine-specific immunity is still unclear. Retinoic acid, the biologically active form of vitamin A, has hormone-like properties and can affect both innate and adaptive immune responses [20]. Recent studies have demonstrated that vitamin A has an immunomodulatory role and can influence lymphocyte functions, such as T and B cell proliferation, T cell activation, cytotoxicity and apoptosis [20]. Vitamin A can also activate monocytes, stimulate antigen presentation and cellular immune responses, suppress immunoglobulin production, lymphocyte proliferation, and modulate cytokine production [21, 22]. Dietary supplementation with vitamin A to children has been used to improve antibody responses to several vaccines, including measles, tetanus, diphtheria and polio [2225]. Benn et al. [26] demonstrated that vitamin A supplementation with measles vaccine in West Africa at age 9 months resulted in higher levels of measles-specific antibodies in children (especially in boys) at 18 months of age. Further, concurrent administration of vitamin A and measles vaccine at 9 months of age had a lasting effect on measles-specific antibody concentrations [25]. No information is available regarding the impact of vitamin A on rubella vaccine-induced antibody levels.

We demonstrated that the presence of specific genetic variations in the RARB gene that encodes retinoic acid (vitamin A) receptor beta, and a member of the thyroid-steroid hormone receptor superfamily of nuclear transcriptional regulators, was associated with rubella-specific antibody responses. The RARB receptor binds retinoic acid, and this gene was first identified in hepatocellular carcinoma where it surrounds a site of integration of hepatitis B virus [27]. Importantly, in our study an allele dose-related decrease in rubella antibody response was observed with increased representation of the minor alleles for SNPs rs4416353 and rs6793694. Further work will be needed to elucidate the exact mechanisms by which vitamin A receptor gene variations influence rubella vaccine-induced humoral immunity.

A large amount of work has been done investigating genes affecting innate immunity, including the discovery of pathogen recognition receptors and pathways [28]. A novel pathway of TLR-independent response to pathogens was described with the finding of RIG-like helicase proteins [29]. For example, IFN-α/β production in infected cells is important for resistance to viral infection and can be triggered through the cytoplasmic RNA helicase retinoic acid-inducible gene I (RIG-I) in a TLR-independent way [30, 31]. Known by its intracellular antiviral properties, it has been demonstrated that RIG-I is essential in triggering the host response to hepatitis C, influenza viruses and paramixoviruses [31, 32]. Our data show significant associations between coding (rs10813831) and intronic (rs669260) SNPs in the RIG-I [DDX58, DEAD (Asp-Glu-Ala-Asp) box polypeptide 58] gene and rubella vaccine-specific antibody response in an allele-dose related manner. These two SNPs had an opposite effect on rubella antibody levels. For example, a nonsynonymous SNP located in exon 1 (rs10813831) of the RIG-I gene, leading to an amino acid change of arginine to cysteine at position 7, was associated with an allele dose-related decrease in rubella IgG level. On the other hand, the intronic SNP (rs669260) in the RIG-I gene was associated with an allele dose-related increase in rubella antibodies. The discovery of allele dose-response relationships for rs10813831 and rs669260 more strongly suggests evidence of a functional role of these SNPs, or of SNPs in high LD with them. Interestingly, the same nonsynonymous RIG-I SNP, rs10813831, was shown to be of functional importance and influence the innate immune response to Newcastle disease viral infection in human dendritic cells by potentially affecting RIG-I folding or interaction with the mitochondrial antiviral signaling protein (MAVS) [33]. While SNPs found in coding regions clearly could have functional impact, intronic SNPs may also alter the binding site of a transcription factor in an intronic region of the gene [34]. These data suggest that the innate immune response to viral infection (or live viral vaccination) may be influenced by a functional polymorphism in the RIG-I (DDX58) gene.

Recently two groups [35, 36] reported the results of an analysis of gene expression in human fetal and adult fibroblasts and endothelial cells infected with rubella virus. Importantly, the retinoic acid receptor alpha (RARA), vitamin D (1.25-dihydroxyvitamin D3) receptor (VDR), DDX58 and TRIM5 genes were found to be upregulated by 3.20-, 3.16-, 19.76- and 3.37-fold, respectively, in fetal HEF cells infected with rubella virus [35]. The DDX58 gene also exhibited a 14.23-fold upregulation in rubella virus infected adult Hs888Lu cells. Likewise, the TRIM22 gene was upregulated in both rubella infected fetal/adult fibroblasts and endothelial cells [35, 36]. These observations cumulatively demonstrate how rubella virus infection alters host cells, and offer functional biologic insight into our findings.

The antiviral activity and retroviral restriction of molecules within the tripartite motif (TRIM) family proteins has been previously recognized. Both TRIM5 and TRIM22 proteins are members of the TRIM family. TRIM5α has been identified as an important cellular antiretroviral restriction factor [37, 38]. It has been proposed that TRIM5α might neutralize retroviruses through a ubiquitin-mediated pathway requiring the RING finger motif [39]. TRIM22 is an E3 ubiquitin ligase that emerged as an IFN-induced protein involved in both innate and adaptive immunity; as a result its expression leads to antiviral properties [40]. It has been speculated that polymorphisms in human TRIM5 may influence susceptibility to HIV-1 infection [41]. However, data on TRIM5 protein’s activity against HIV in humans are lacking. We identified 2 nucleotide polymorphisms in the TRIM5 gene 5’UTR (rs3824949) and coding (rs3740996) regions, one of which (rs3824949) was associated with an allele dose-related increase in rubella antibody levels. Additionally, in our study rs2179 in the TRIM22 gene appeared to be an important SNP that was significantly associated with lower rubella-specific antibody in an allele dose-related manner. Speelmon et al. [42] demonstrated that the same G to C polymorphism at position -2 in the 5’UTR of the TRIM5 gene, rs3824949, (in combination with a nonsynonymous SNP Arg136Gln) was associated with enhanced HIV-1 susceptibility and disease progression. Thus, this nonsynonymous coding polymorphism, rs3824949, emerged as a key SNP that was significantly associated with higher rubella specific-antibody response and also had an effect on human HIV-1 infection. We speculate that polymorphisms in the TRIM5 gene may possibly contribute to the overall human antiviral response.

The associations between TRIM5 polymorphisms and rubella vaccine immunity are particularly intriguing since a nonsynonymous SNP (rs3740996, His43Tyr) at the human TRIM5α locus has been found to have a significant functional consequence [39]. Sawyer et al. reported [39] that this polymorphism lies in the RING loop 2 domain of the TRIM5α gene, may negatively affect E3 ubiquitin ligase activity and impair TRIM5α restriction of two retroviruses. The importance of this specific SNP with regard to the clinical course of HIV-I infection was demonstrated by a recent study showing that an accelerated disease progression was observed for subjects who were homozygous for the 43Tyr genotype as compared to subjects who were heterozygous or homozygous for the 43His genotype [43]. We found that the same TRIM5 nonsynonymous polymorphism in exon 2 (rs3740996, His43Tyr) was associated with variations in rubella-specific IgG antibody level, suggesting the functional importance of the TRIM5 gene in rubella vaccine-induced humoral immunity.

In conclusion, our data suggest significant associations between polymorphisms in the vitamin A receptor, RIG-I and antiretroviral TRIM innate immunity genes, and antibody responses to rubella vaccine. It is likely that other innate defense and immune regulation genes also contribute to the immunogenetic influence on rubella immunity. In this first study of genetic associations of candidate genes that are involved in vitamin A processing, we have studied a large number of SNPs, and have identified a number of SNPs that appear to be associated with rubella vaccine-induced antibody levels. We have not performed corrections for these multiple tests because of the power implications for analyses based on 714 subjects. Therefore, it is important that the results reported here be followed up in additional studies to validate these associations, and further clarify the genetic contributions of these candidate genes to rubella vaccine-induced antibody levels. These findings require further validation in an independent cohort. Understanding the mechanism by which vitamin A receptor and innate gene polymorphisms alter immune responses may provide important insights into new ways of modulating not only innate immune response but adaptive immune responses as well, and may have implications for developing new vaccine adjuvants and immunostimulant molecules. This information might be used in future applications to improve human vaccine responses and to develop personalized vaccines [14].

Acknowledgments

We thank the Mayo Clinic Vaccine Research Group and subjects who participated in our studies. We thank Robert A. Vierkant for his assistance with this study. This work was supported by the National Institutes of Health grants AI 48793 and AI 33144. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

Footnotes

Conflict of Interest Statement

Dr. Poland is the chair of a Safety Evaluation Committee for novel non-rubella vaccines undergoing clinical studies by Merck Research Laboratories. Dr. Jacobson serves on a Safety Review Committee for a post-licensure study of Gardasil for Kaiser-Permanente.

Presented in part: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA, 12–15 September 2009 (abstract 3009).

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