Published ahead of print on August 29, 2007, doi:10.1164/rccm.200605-644OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200605-644OC
4G/5G Plasminogen Activator Inhibitor-1 Polymorphisms and Haplotypes Are Associated with Pneumonia1 CRISMA Laboratory (Clinical Research, Investigation, and Systems Modeling of Acute Illness), Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 2 Sticht Center on Aging, Wake Forest University School of Medicine, Winston-Salem, North Carolina; 3 Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania; 4 Department of Preventive Medicine, University of Tennessee, Memphis, Tennessee; 5 Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania; 6 National Institute on Aging, Bethesda, Maryland; 7 Department of Psychiatry, Neurology, and Epidemiology, University of California, San Francisco, San Francisco, California; and 8 Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois Correspondence and requests for reprints should be addressed to Sachin Yende, M.D., M.S., Department of Critical Care Medicine, 642A Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail: yendes{at}upmc.edu Rationale: 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. Objectives: 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. Measurements and Main 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.
Key Words: pneumonia • inflammatory markers • PAI-1 • gene • haplotype
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