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. 2017 Feb 3;12(2):e0171261.
doi: 10.1371/journal.pone.0171261. eCollection 2017.

A large population-based association study between HLA and KIR genotypes and measles vaccine antibody responses

Inna G Ovsyannikova  1 , Daniel J Schaid  2 , Beth R Larrabee  2 , Iana H Haralambieva  1 , Richard B Kennedy  1 , Gregory A Poland  1
Affiliations

A large population-based association study between HLA and KIR genotypes and measles vaccine antibody responses

Inna G Ovsyannikova et al. PLoS One. .

Abstract

Human antibody response to measles vaccine is highly variable in the population. Host genes contribute to inter-individual antibody response variation. The killer cell immunoglobulin-like receptors (KIR) are recognized to interact with HLA molecules and possibly influence humoral immune response to viral antigens. To expand on and improve our previous work with HLA genes, and to explore the genetic contribution of KIR genes to the inter-individual variability in measles vaccine-induced antibody responses, we performed a large population-based study in 2,506 healthy immunized subjects (ages 11 to 41 years) to identify HLA and KIR associations with measles vaccine-induced neutralizing antibodies. After correcting for the large number of statistical tests of allele effects on measles-specific neutralizing antibody titers, no statistically significant associations were found for either HLA or KIR loci. However, suggestive associations worthy of follow-up in other cohorts include B*57:01, DQB1*06:02, and DRB1*15:05 alleles. Specifically, the B*57:01 allele (1,040 mIU/mL; p = 0.0002) was suggestive of an association with lower measles antibody titer. In contrast, the DQB1*06:02 (1,349 mIU/mL; p = 0.0004) and DRB1*15:05 (2,547 mIU/mL; p = 0.0004) alleles were suggestive of an association with higher measles antibodies. Notably, the associations with KIR genotypes were strongly nonsignificant, suggesting that KIR loci in terms of copy number and haplotypes are not likely to play a major role in antibody response to measles vaccination. These findings refine our knowledge of the role of HLA and KIR alleles in measles vaccine-induced immunity.

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Conflict of interest statement

Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. Dr. Poland offers consultative advice on vaccine development to Merck & Co. Inc., CSL Biotherapies, Avianax, Dynavax, Novartis Vaccines and Therapeutics, Emergent Biosolutions, Adjuvance, Microdermis, Seqirus, NewLink, Protein Sciences, GSK Vaccines, and Sanofi Pasteur. Drs. Poland and Ovsyannikova hold two patents related to measles and vaccinia peptide research. Dr. Kennedy has received funding from Merck Research Laboratories to study waning immunity to measles and mumps vaccine. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. P-values for association of each HLA allele with neutralizing antibodies.
The y-axis illustrates the–log10(p-value) for the association of an allele with neutralizing antibody titer based on linear regression of antibody titer on the dose of each allele. The Bonferroni threshold is based on 0.05/248.
Fig 2
Fig 2. Quantile-quantile plot of p-values for HLA alleles associated with neutralizing antibodies.
The p-values result from regression of neutralizing antibody titer on the dose of each allele, along with adjusting covariates that include eigenvectors to adjust for population stratification. The departure of the observed p-values from the diagonal line illustrates that many observed p-values departed from those expected when the null hypothesis of no association is true.
Fig 3
Fig 3. P-values for association of alleles and haplotypes for KIR loci with neutralizing antibodies.
The y-axis illustrates the–log10(p-value) for the association of an allele or haplotype with neutralizing antibody titer based on linear regression of antibody titer on the dose of each allele or haplotypes. The Bonferroni threshold is based on 0.05/27.
Fig 4
Fig 4. Quantile-quantile plot of p-values for KIR alleles and haplotypes associated with neutralizing antibodies.
The p-values result from regression of neutralizing antibody titer on the dose of each allele or haplotype, along with adjusting covariates that include eigenvectors to adjust for population stratification. The observed p-values were close to the diagonal line, suggesting that the observed p-values had a distribution that would be expected when the null hypothesis of no association is true.
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