Genome-wide association study of antibody response to smallpox vaccine

We performed a genome-wide association study (GWAS) of antibody levels in a multi-ethnic group of 1071 healthy smallpox vaccine recipients. In Caucasians, the most prominent association was found with promoter SNP rs10489759 in the LOC647132 pseudogene on chromosome 1 (p = 7.77 × 10−8). In African-Americans, we identified eight genetic loci at p < 5 × 10−7. The SNP association with the lowest p-value (rs10508727, p = 1.05 × 10−10) was in the Mohawk homeobox (MKX) gene on chromosome 10. Other candidate genes included LOC388460, GPR158, ZHX2, SPIRE1, GREM2, CSMD1, and RUNX1. In Hispanics, the top six associations between genetic variants and antibody levels had p-values less than 5 × 10−7, with p = 1.78 × 10−10 for the strongest statistical association (promoter SNP rs12256830 in the PCDH15 gene). In addition, SNP rs4748153 in the immune response gene PRKCQ (protein kinase C, theta) was significantly associated with neutralizing antibody levels (p = 2.51 × 10−8). Additional SNP associations in Hispanics (p ≤ 3.40 × 10−7) were mapped to the KIF6/LOC100131899, CYP2C9, and ANKLE2/GOLGA3 genes. This study has identified candidate SNPs that may be important in regulating humoral immunity to smallpox vaccination. Replication studies, as well as studies elucidating the functional consequences of contributing genes and polymorphisms, are underway.

► We performed GWAS of antibody levels in a group of 1071 healthy smallpox recipients.
► In African-Americans, we identified eight novel genetic loci at p ≤ 5 × 10−7.
► Vaccination is the only defense against smallpox.
► Smallpox vaccine has one of the highest complication rates among all the vaccines.