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

Date Published: February 3, 2017

Publisher: Public Library of Science

Author(s): Inna G. Ovsyannikova, Daniel J. Schaid, Beth R. Larrabee, Iana H. Haralambieva, Richard B. Kennedy, Gregory A. Poland, Güher Saruhan-Direskeneli.


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.

Partial Text

Host genetic factors are believed to be responsible for up to 90% of measles vaccine-induced inter-individual antibody response variations [1]. Among these genetic factors, the Human Leukocyte Antigen (HLA) genes (on chromosome 6p21) have been a focus of interest since these highly polymorphic HLA genes play an important role in the regulation of immune response, including immunity to measles virus [2]. The main role of HLA class I and class II molecules is to present antigens to CD8+ and CD4+ T cells, respectively, thus initiating adaptive immune responses [3]. There is a large body of evidence demonstrating that immune responses to measles vaccine are in part, guided by polymorphisms of the HLA genes [4–8]. In this regard, several HLA class I (B*57:01, B*35:03) and class II (DQB1*06:02, DQB1*03:03, DRB1*07:01, DRB1*15:01) alleles have been consistently associated with variations in measles virus-specific antibody responses following measles vaccination [8].

To achieve the greatest power to detect HLA or KIR alleles associated with measles immune response phenotypes, we pooled our data across the three cohorts. To remove the effects of potential confounders so that the cohorts could be combined, we first screened for potential confounders relevant to each ancestry group and cohort. Possible confounders were screened for their association with the trait as follows. Any categorical variable with a very large number of categories was binned using hierarchical clustering on the estimated regression coefficients. All categorical variables were coded as dummy variables such that the most common category was used as baseline. Univariate linear models were then used to evaluate potential confounders. Variables that were marginally associated with the trait with a p-value < 0.1 were then included in backwards selection with a p-value threshold of 0.1. This somewhat liberal p-value threshold achieves the goal of controlling for potential confounding covariates. For the final association models, the covariates used for adjustment differed by cohort. For the San Diego cohort, we adjusted for subject year of birth, the operator that ran the assays, and having self-reported Asian, Hawaiian, or Pacific Islander ancestry. For the Rochester cohort, we adjusted for population stratification eigenvectors, self-reported Native American or Native Alaskan ancestry, operator, and assay run. For the US cohort, we adjusted for design factors (needing to repeat a sample, plate, and plate position), population stratification (eigenvectors and self-reported ancestry), type of vaccine, and subject age. Residuals from the adjusted model were used as the primary adjusted traits for analyses. HLA supertype variables were constructed for locus A and locus B using the amino acid sequences available from IPD such that HLA alleles within a given HLA locus that shared peptide binding specificity were grouped together [38, 39]. See S1 Table for grouping of HLA-B alleles into supertype categories. We have previously described associations of HLA alleles with inter-individual variation in humoral immune response to measles vaccine. To expand upon our prior work, we performed a pooled analysis—with a much larger sample size—of the association of HLA loci with vaccine-induced immune measures using data obtained from three separate cohorts in order to maximize power. In addition, we examined HLA in terms of peptide-binding specificities through the use of HLA supertypes. Finally, we examined whether variation within the KIR genes, which display extensive genetic diversity, influences measles vaccine-induced antibody responses.   Source:


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