title: 4G/5G plasminogen activator inhibitor-1 polymorphisms and haplotypes are associated with pneumonia.
abstract: BACKGROUND
  Plasminogen activator inhibitor (PAI)-1 inhibits urokinase and tissue plasminogen activator, required for host response to infection. Whether variation within the PAI-1 gene is associated with increased susceptibility to infection is unknown.
  
  
  OBJECTIVE
  To ascertain the role of the 4G/5G polymorphism and other genetic variants within the PAI-1 gene. We hypothesized that variants associated with increased PAI-1 expression would be associated with an increased occurrence of community-acquired pneumonia (CAP).
  
  
  METHODS
  Longitudinal analysis (>12 yr) of the Health, Aging, and Body Composition cohort, aged 65-74 years at start of analysis.
  
  
  RESULTS
  We genotyped the 4G/5G PAI-1 polymorphism and six additional single nucleotide polymorphisms. Of the 3,075 subjects, 272 (8.8%) had at least one hospitalization for CAP. Among whites, variants at the PAI4G,5G, PAI2846, and PAI7343 sites had higher risk of CAP (P = 0.018, 0.021, and 0.021, respectively). At these sites, variants associated with higher PAI-1 expression were associated with increased CAP susceptibility. Compared with the 5G/5G genotypes at PAI4G,5G site, the 4G/4G and 4G/5G genotypes were associated with a 1.98-fold increased risk of CAP (95% confidence interval, 1.2-3.2; P = 0.006). In whole blood stimulation assay, subjects with a 4G allele had 3.3- and 1.9-fold increased PAI-1 expression (P = 0.043 and 0.034, respectively). In haplotype analysis, the 4G/G/C/A haplotype at the PAI4G,5G, PAI2846, PAI4588, and PAI7343 single nucleotide polymorphisms was associated with higher CAP susceptibility, whereas the 5G/G/C/A haplotype was associated with lower CAP susceptibility. No associations were seen among blacks.
  
  
  CONCLUSIONS
  Genotypes associated with increased expression of PAI-1 were associated with increased susceptibility to CAP in elderly whites.
authors.affiliation: CRISMA Laboratory (Clinical Research, Investigation, and Systems Modeling of Acute Illness), Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. yendes@upmc.edu
authors.forename: Sachin
authors.initials: S
authors.lastname: Yende
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Ding
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
authors.forename: Rongling
authors.initials: R
authors.lastname: Li
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: Joseph
authors.initials: J
authors.lastname: Zmuda
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Kritchevsky
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Melissa
authors.initials: M
authors.lastname: Garcia
authors.forename: Kristine
authors.initials: K
authors.lastname: Yaffe
authors.forename: Richard G
authors.initials: RG
authors.lastname: Wunderink
mesh_terms: D000368:Aged; D001769:Blood / Q000187:drug effects; D015331:Cohort Studies; D017714:Community-Acquired Infections / Q000208:ethnology / Q000235:genetics*; D016207:Cytokines / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008137:Longitudinal Studies; D008297:Male; D009994:Osmolar Concentration; D010457:Peptidoglycan / Q000494:pharmacology; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics*; D011014:Pneumonia / Q000208:ethnology / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D017395:Plasminogen Activator Inhibitor 1