Association between Single‐Nucleotide Polymorphisms inMal/TIRAPandInterleukin‐10Genes and Susceptibility to InvasiveHaemophilus influenzaeSerotype b Infection in Immunized Children

Abstract

The development of invasive Haemophilus influenzae serotype b (Hib) disease after prior immunization with the Hib conjugate vaccine (ie, Hib vaccine failure) is extremely rare, suggesting that affected children may have an underlying genetic susceptibility in their immune response. The objective of this study was to investigate single-nucleotide polymorphisms (SNPs) known to affect function in biologically plausible genes in relation to the risk of Hib vaccine failure and its clinical manifestations. The families of UK children with Hib vaccine failure diagnosed during the period October 1992 through December 2005 were identified through enhanced national surveillance and approached for the study at a median interval of 4 years after invasive disease. The Wellcome Trust Case Control Consortium data sets were used as controls. Nineteen functional SNPs in 14 immune response genes were investigated in 172 white children. The recessive homozygous genotype for a SNP in the TIRAP (also known as MAL) gene (rs1893352) that is in strong linkage disequilibrium (r2=0.93) with the known functional Ser180Leu polymorphism in white persons was strongly associated with nonmeningitis cases of Hib vaccine failure (odds ratio, 5.6; 95% confidence interval, 2.7-11.5; P=1.2 x 10(-7)). In addition, the recessive homozygous genotype for another SNP (rs1554286) in strong linkage disequilibrium with both the C-819T (r2=0.87) and C-592A (r2=0.75) promoter polymorphisms in the interleukin-10 gene was associated with epiglottitis only (odds ratio, 5.8; 95% confidence interval, 2.4-14.2; P=1.1 x 10(-5)). Our findings strongly suggest that the development of invasive Hib disease after prior immunization is in part genetically determined and may direct the immune response to specific clinical manifestations.