Abstract
Host genetic factors that modify risk of pneumococcal disease may help target future public health interventions to individuals at highest risk of disease. We linked data from population-based surveillance for invasive pneumococcal disease (IPD) with state-based newborn dried bloodspot repositories to identify biological samples from individuals who developed invasive pneumococcal disease. Genomic DNA was extracted from 366 case and 732 anonymous control samples. TagSNPs were selected in 34 candidate genes thought to be associated with host response to invasive pneumococcal disease, and a total of 326 variants were successfully genotyped. Among 543 European Americans (EA) (182 cases and 361 controls), and 166 African Americans (AA) (53 cases and 113 controls), common variants in surfactant protein D (SFTPD) are consistently underrepresented in IPD. SFTPD variants with the strongest association for IPD are intronic rs17886286 (allelic OR 0.45, 95% confidence interval (CI) [0.25, 0.82], with p = 0.007) in EA and 5′ flanking rs12219080 (allelic OR 0.32, 95%CI [0.13, 0.78], with p = 0.009) in AA. Variants in CD46 and IL1R1 are also associated with IPD in both EA and AA, but with effects in different directions; FAS, IL1B, IL4, IL10, IL12B, SFTPA1, SFTPB, and PTAFR variants are associated (p≤0.05) with IPD in EA or AA. We conclude that variants in SFTPD may protect against IPD in EA and AA and genetic variation in other host response pathways may also contribute to risk of IPD. While our associations are not corrected for multiple comparisons and therefore must be replicated in additional cohorts, this pilot study underscores the feasibility of integrating public health surveillance with existing, prospectively collected, newborn dried blood spot repositories to identify host genetic factors associated with infectious diseases.
Highlights
Streptococcus pneumoniae is a Gram-positive, encapsulated bacterium and a leading cause of pneumonia, meningitis and bloodstream infection in children and the elderly
Results tagSNPs associated with invasive pneumococcal disease (IPD) We performed single SNP allelic tests of association stratified by race/ethnicity in 543 European-Americans (EA), including 182 cases of IPD and 361 controls (Table 1) for 212 SNPs (Tables 2 and S1); and in 166 African-Americans (AA), including 53 cases and 113 controls for 287 SNPs
Overall, comparing IPD cases to controls, 17 tagSNPs in nine genes (CD46, SFTPA1, surfactant protein D (SFTPD), IL1B, ILIR1, IL4, IL10, IL12B, FAS) in European Americans (EA) and 11 tagSNPs in six genes (CD46, SFTPB, SFTPD, IL1B, ILIR1, and PTAFR) in AA have common variants that are associated at a liberal threshold of p#0.05 (Tables 3 and S2, and Figure 1)
Summary
Streptococcus pneumoniae (pneumococcus) is a Gram-positive, encapsulated bacterium and a leading cause of pneumonia, meningitis and bloodstream infection in children and the elderly. An estimated 62,000 cases and 6,000 deaths occur annually from invasive pneumococcal disease (IPD) in the US.[1] Globally, IPD causes over a million deaths in children under the age of 5. Asymptomatic nasopharyngeal colonization with S. pneumoniae is widespread, but overall few of those colonized develop IPD. In the U.S, race-dependent infection rates are higher in African Americans and American Indians than in persons of European descent.[2]. In 2000 a protein-polysaccharide conjugate vaccine (PCV7) was licensed in the U.S targeting seven of the 90 known serotypes of S. pneumoniae; in 2010 a 13-valent vaccine was licensed. Population-based surveillance for IPD through the Active
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