Elsevier

Vaccine

Volume 29, Issue 45, 19 October 2011, Pages 7883-7895
Vaccine

Associations between single nucleotide polymorphisms and haplotypes in cytokine and cytokine receptor genes and immunity to measles vaccination

https://doi.org/10.1016/j.vaccine.2011.08.083Get rights and content

Abstract

Identification of host genetic determinants of measles vaccine-induced immunity can be used to design better vaccines and ultimately predict immune responses to vaccination.

We performed a comprehensive candidate gene association study across 801 genetic markers in 56 cytokine/cytokine receptor genes, in a racially diverse cohort of 745 schoolchildren after two doses of MMR vaccine. Using linear regression methodologies we examined associations between SNPs/haplotypes and measles virus-specific immunity.

Forty-eight significant SNP associations with variations in neutralizing antibodies and measles-specific IFNγ Elispot responses were identified (p < 0.05). Our study replicated an important previously found association of a functional IL12B genetic variant rs3212227 with variations in measles-specific humoral immunity (p = 0.037). Similarly, two previously reported promoter IL10 and IL2 polymorphisms (rs1800890 and rs2069762) demonstrated associations with measles-specific cellular immunity in Caucasians (p  0.034). Multiple IL7R polymorphisms, including a non-synonymous functional SNP (rs6897932/Thr244Ile), were associated with humoral (p  0.024) and/or cellular (IFNγ Elispot, p  0.023) measles-specific immune responses in Caucasians, but not African-Americans. Haplotype level analysis confirmed the association of IL7R genetic variants with measles vaccine-induced immunity in the Caucasian group (global p-value = 0.003).

Our results validate previous findings and identify new plausible genetic determinants, including IL7R polymorphisms, regulating measles vaccine-induced immunity in a race-specific manner.

Highlights

► We studied 801 SNPs in 56 genes, in a cohort of 745 MMR-vaccinated schoolchildren. ► We found 48 significant associations with variations in vaccine immune responses. ► We replicated an association of IL12B rs3212227 with variations in humoral immunity. ► We replicated two IL10 and IL2 SNP associations with cellular immunity variations. ► Single SNP and haplotype analysis revealed IL7R associations with vaccine immunity.

Introduction

Recent advances in the field of immunogenetics have partly revealed the genetic basis of differential susceptibility to infectious diseases and inter-individual differences in vaccine response [1]. Studies (including ours) consistently implicate genetic polymorphisms in key immune response genes, such as cytokine and cytokine receptor genes as important determinants of adverse events and observed variations in immune responses to vaccines such as measles–mumps–rubella (MMR), influenza, smallpox, hepatitis A and B vaccines, pneumococcal conjugate vaccine and diphtheria–tetanus–pertussis vaccine [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Furthermore, racial, ethnic and gender differences have been associated with differences in immune responses to immunization and infection [2], [3], [13], [14], [15], [16], [17], [18]. Previous studies have also demonstrated race-specific distributions of allelic variants in cytokine genes across populations [19], [20]. Although much information has been accumulated in the field of measles immunity, the discovery and validation of genetic drivers of measles-specific immune responses still remains a challenge.

In the current study we performed a high-density, comprehensive, candidate gene genetic study to identify, replicate, and validate SNP associations across 56 key cytokine and cytokine receptor genes with measures of both humoral and cellular immunity to measles vaccine in a large racially diverse cohort of healthy schoolchildren and young adults after two doses of MMR vaccine.

Section snippets

Study subjects

The present study was based on a combined sample of 764 subjects from 2 independent age-stratified cohorts of randomly selected healthy schoolchildren and young adults from Olmsted County, MN: cohort 1 consisted of 388 subjects eligible for the current study (age 11–19 years, enrolled in 2006–2007 year) as previously reported [4], and cohort 2 consisted of 376 eligible subjects (age 11–22 years, enrolled in 2008–2009 year). Inclusion criteria required each participant to have documentation of

Subjects’ demographics and immune responses

All demographic and clinical variables of the study cohort, and the immune response measures, are summarized in Table 1. Briefly, our study population had a median age of 15 years at the time of sampling with a median time from second MMR immunization to enrollment of 7.4 years. The cohort consisted of 417 males (55.97%), 598 Caucasians (80.27%), but also included 89 African-Americans (11.95%) and a limited number of other races/ethnicities.

Genotyping of SNPs in cytokine and cytokine receptor genes

Genotyping was performed on 764 subjects for 994 known

Discussion

Cytokine and cytokine receptors are intrinsically linked to the generation and regulation of adaptive immune responses, and therefore are reasonable targets for candidate gene-based genetic studies [6], [29], [30], [31], [32]. We have previously sampled a smaller number of candidate cytokine and cytokine receptor gene polymorphisms/SNPs (n = 58) in Caucasians (n = 118) and African-Americans (n = 85) and reported initial moderate associations between SNPs in IL2, IL10, IL12B, IL4RA, IL12RB, IL6 and

Disclosures

Dr. Poland is the chair of a DMSB for novel 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 declare that they have no conflict of interest.

Acknowledgments

We thank the parents and children who participated in our study 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 for assistance in preparing the manuscript. We thank Megan O’Byrne for her contribution to statistical analyses. We thank David Rider and Ying Li for developing the SNP selection algorithm, and Julie M. Cunningham and the Mayo Advanced Genomic

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