4G/5G plasminogen activator inhibitor-1 polymorphisms and haplotypes are associated with pneumonia

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.

Figure 1.

Single nucleotide polymorphisms within the plasminogen activator inhibitor (PAI)-1 gene (7q21.3-q22). Gray area denotes promoter region and black areas denote exons. The 12219 and 12750 polymorphisms are in the 3′ untranslated region.

Figure 2.

Changes in plasminogen activator inhibitor (PAI)-1, tumor necrosis factor (TNF), IL-6, and IL-10 concentrations after ex vivo whole blood stimulation with lipopolysaccharide (LPS) and peptidoglycan (PGN) for PAI4G,5G (A), PAI2846 (B), and PAI7343 (C) genotypes. Values for TNF, IL-6, and IL-10 are log converted. PAI4G,5G and PAI7343 genotype data were missing for two subjects and one subject. *Log-converted cytokine concentrations. (A) Solid bars, 4G/4G, 4G/5G (n = 16); open bars, 5G/5G (n = 5). (B) Solid bars, AG, AA (n = 4); open bars, GG (n = 19). (C) Solid bars, AA (n = 14); open bars AG or GG (n = 8).

Figure 2.

Changes in plasminogen activator inhibitor (PAI)-1, tumor necrosis factor (TNF), IL-6, and IL-10 concentrations after ex vivo whole blood stimulation with lipopolysaccharide (LPS) and peptidoglycan (PGN) for PAI4G,5G (A), PAI2846 (B), and PAI7343 (C) genotypes. Values for TNF, IL-6, and IL-10 are log converted. PAI4G,5G and PAI7343 genotype data were missing for two subjects and one subject. *Log-converted cytokine concentrations. (A) Solid bars, 4G/4G, 4G/5G (n = 16); open bars, 5G/5G (n = 5). (B) Solid bars, AG, AA (n = 4); open bars, GG (n = 19). (C) Solid bars, AA (n = 14); open bars AG or GG (n = 8).