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Published ahead of print on August 29, 2007, doi:10.1164/rccm.200605-644OC

Am. J. Respir. Crit. Care Med., Volume 176, Number 11, December 2007, 1129-1137

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Submitted on May 11, 2006
Accepted on August 29, 2007

4G/5G PAI-1 Polymorphisms and Haplotypes are Associated with Pneumonia

Sachin Yende1*, Derek C Angus1, Jingzhong Ding2, Anne B Newman3, John A Kellum1, Rongling Li4, Robert E Ferrel5, Joseph Zmuda5, Stephen B Kritchevsky2, Tamara B Harris6, Melissa Garcia6, Kristine Yaffe7, and Richard G Wunderink8

1 Department of Critical Care Medicine, CRISMA Laboratory (Clinical Research, Investigation, and Systems Modeling of Acute Illness), University of Pittsburgh, Pittsburgh, PA, USA, 2 Sticht Center on Aging, Wake Forest University School of Medicine, Winston-Salem, NC, USA, 3 Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA, 4 Department of Preventive Medicine, The University of Tennessee, Memphis, TN, USA, 5 Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA, 6 National Institute on Aging, Bethesda, MA, USA, 7 Department of Psychiatry, Neurology, and Epidemiology, University of California, San Francisco, CA, USA, 8 Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL, USA

* To whom correspondence should be addressed. 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 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 (>12y) of the Health, Aging, and Body Composition cohort, aged 65-74y at start of analysis. Measurements and main results: We genotyped the 4G/5G PAI-1 polymorphism and 6 additional single nucleotide polymorphisms (SNPs). Of the 3075 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 to 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% CI=1.2-3.2, p=0.006). In whole blood stimulation assay, subjects with a 4G allele had 3.3-fold and 1.9-fold increased PAI-1 expression (p=0.043 and 0.034). In haplotype analysis, the 4G/G/C/A haplotype at the PAI4G,5G/PAI2846/PAI4588/PAI7343 SNPs was associated with higher CAP susceptibility, whereas the 5G/A/C/G 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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