title: Comprehensive genetic assessment of a functional TLR9 promoter polymorphism: no replicable association with asthma or asthma-related phenotypes.
abstract: BACKGROUND
  Prior studies suggest a role for a variant (rs5743836) in the promoter of toll-like receptor 9 (TLR9) in asthma and other inflammatory diseases. We performed detailed genetic association studies of the functional variant rs5743836 with asthma susceptibility and asthma-related phenotypes in three independent cohorts.
  
  
  METHODS
  rs5743836 was genotyped in two family-based cohorts of children with asthma and a case-control study of adult asthmatics. Association analyses were performed using chi square, family-based and population-based testing. A luciferase assay was performed to investigate whether rs5743836 genotype influences TLR9 promoter activity.
  
  
  RESULTS
  Contrary to prior reports, rs5743836 was not associated with asthma in any of the three cohorts. Marginally significant associations were found with FEV1 and FVC (p = 0.003 and p = 0.008, respectively) in one of the family-based cohorts, but these associations were not significant after correcting for multiple comparisons. Higher promoter activity of the CC genotype was demonstrated by luciferase assay, confirming the functional importance of this variant.
  
  
  CONCLUSIONS
  Although rs5743836 confers regulatory effects on TLR9 transcription, this variant does not appear to be an important asthma-susceptibility locus.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. renal@channing.harvard.edu
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lange
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.forename: Jessica
authors.initials: J
authors.lastname: Lasky-Su
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Manuel
authors.initials: M
authors.lastname: Soto-Quirós
authors.forename: Lydiana
authors.initials: L
authors.lastname: Avila
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hawrylowicz
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
mesh_terms: D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012129:Respiratory Function Tests; D051217:Toll-Like Receptor 9 / Q000235:genetics* / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism; D055815:Young Adult
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D014807:Vitamin D