title: Identifying host genetic risk factors in the context of public health surveillance for invasive pneumococcal disease.
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.
authors.affiliation: Department of Global Health, University of Washington, Seattle, Washington, United States of America. lingappa@u.washington.edu
authors.forename: Jairam R
authors.initials: JR
authors.lastname: Lingappa
authors.forename: Logan
authors.initials: L
authors.lastname: Dumitrescu
authors.forename: Shanta M
authors.initials: SM
authors.lastname: Zimmer
authors.forename: Ruth
authors.initials: R
authors.lastname: Lynfield
authors.forename: Janet M
authors.initials: JM
authors.lastname: McNicholl
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Messonnier
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Whitney
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
mesh_terms: D001741:Black or African American / Q000235:genetics; D002675:Child, Preschool; D015331:Cohort Studies; D004247:DNA / Q000032:analysis / Q000097:blood; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D054884:Host-Pathogen Interactions; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics; D010865:Pilot Projects; D011008:Pneumococcal Infections / Q000208:ethnology / Q000235:genetics* / Q000382:microbiology; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance / Q000379:methods*; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D012307:Risk Factors; D013296:Streptococcus pneumoniae / Q000502:physiology; D044465:White People / Q000235:genetics
chemical_list: C497857:CD46 protein, human; C508590:IL1R1 protein, human; D051916:Membrane Cofactor Protein; D037663:Pulmonary Surfactant-Associated Protein D; D053573:Receptors, Interleukin-1 Type I; D004247:DNA