4G/5G plasminogen activator inhibitor-1 polymorphisms and haplotypes are associated with pneumonia.
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.
Yende
Sachin
S
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
Angus
Derek C
DC
Ding
Jingzhong
J
Newman
Anne B
AB
Kellum
John A
JA
Li
Rongling
R
Ferrell
Robert E
RE
Zmuda
Joseph
J
Kritchevsky
Stephen B
SB
Harris
Tamara B
TB
Garcia
Melissa
M
Yaffe
Kristine
K
Wunderink
Richard G
RG
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*
D016207:Cytokines; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D017395:Plasminogen Activator Inhibitor 1