Yende Sachin, Angus Derek C, Ding Jingzhong, Newman Anne B, Kellum John A, Li Rongling, Ferrell Robert E, Zmuda Joseph, Kritchevsky Stephen B, Harris Tamara B, Garcia Melissa, Yaffe Kristine, Wunderink Richard G
CRISMA Laboratory (Clinical Research, Investigation, and Systems Modeling of Acute Illness), Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Am J Respir Crit Care Med. 2007 Dec 1;176(11):1129-37. doi: 10.1164/rccm.200605-644OC. Epub 2007 Aug 29.
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.
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).
Longitudinal analysis (>12 yr) of the Health, Aging, and Body Composition cohort, aged 65-74 years at start of analysis.
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.
Genotypes associated with increased expression of PAI-1 were associated with increased susceptibility to CAP in elderly whites.
纤溶酶原激活物抑制剂（PAI）-1可抑制尿激酶和组织纤溶酶原激活物，而这两种物质是宿主对感染作出反应所必需的。PAI-1基因内的变异是否与感染易感性增加相关尚不清楚。
确定PAI-1基因4G/5G多态性及其他基因变异的作用。我们假设与PAI-1表达增加相关的变异会与社区获得性肺炎（CAP）发生率增加相关。
对健康、衰老和身体成分队列进行纵向分析（>12年），分析开始时年龄为65 - 74岁。
我们对PAI-1基因的4G/5G多态性及另外6个单核苷酸多态性进行了基因分型。在3075名受试者中，272名（8.8%）至少因CAP住院一次。在白人中，PAI4G,5G、PAI2846和PAI7343位点的变异有更高的CAP风险（分别为P = 0.018、0.021和0.021）。在这些位点，与PAI-1表达较高相关的变异与CAP易感性增加相关。与PAI4G,5G位点的5G/5G基因型相比，4G/4G和4G/5G基因型与CAP风险增加1.98倍相关（95%置信区间，1.2 - 3.2；P = 0.006）。在全血刺激试验中，携带4G等位基因的受试者PAI-1表达分别增加3.3倍和1.9倍（分别为P = 0.043和0.034）。在单倍型分析中，PAI4G,5G、PAI2846、PAI4588和PAI7343单核苷酸多态性的4G/G/C/A单倍型与较高的CAP易感性相关，而5G/G/C/A单倍型与较低的CAP易感性相关。在黑人中未发现关联。
与PAI-1表达增加相关的基因型与老年白人CAP易感性增加相关。
