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  • Title: 4G/5G plasminogen activator inhibitor-1 polymorphisms and haplotypes are associated with pneumonia.
    Author: Yende S, Angus DC, Ding J, Newman AB, Kellum JA, Li R, Ferrell RE, Zmuda J, Kritchevsky SB, Harris TB, Garcia M, Yaffe K, Wunderink RG, Health ABC Study.
    Journal: Am J Respir Crit Care Med; 2007 Dec 01; 176(11):1129-37. PubMed ID: 17761618.
    Abstract:
    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.
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