Inhibitor kappa B-alpha haplotype GTC is associated with susceptibility to acute respiratory distress syndrome in Caucasians

Objective: The nuclear factor (NF)-kappa B regulates inflammatory responses and plays important roles in the pathogenesis of acute respiratory distress syndrome (ARDS). Inhibitor kappa B-alpha (NFKBIA) inhibits NF-kappa B and controls its activities. The objective was to determine whether polymorphisms in NFKBIA gene would be associated with ARDS development. Design: Prospective cohort of adults with clinical risk factors for ARDS. Setting: Hospital system. Patients: Patients were 1,210 critically ill Caucasian patients meeting study criteria for a defined risk factor for ARDS who were enrolled and prospectively followed for 60 days; 382 had ARDS, and 828 were controls. Interventions. Genetic polymorphisms in the NFKBIA promoter (-861A/G, -826C/T, -297C/7) were determined using TaqMan techniques. Measurements and Main Results: The three polymorphisms were in Hardy-Weinberg equilibrium. No individual genotype was significantly associated with ARDS development. In contrast, haplotypes of NFKBIA were globally associated with ARDS development (p = .02, degree of freedom = 2). The frequency of haplotype GTC (-881G/- 826T/- 297C) was significantly higher among ARDS patients (7.4%) than that among controls (5.2%) (p = .03). Crude analysis showed that the haplotype GTC was significantly associated with higher risks of ARDS in the whole cohort compared with the common haplotype ACC (-881A/-826C/-297C) (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.03-2.09; p = .03), especially among male subjects (OR, 1.90; 95% CI, 1.20-2.97; p < .01). After adjustment for covariates, the haplotype GTC remained significantly associated with increased risk of ARDS in the whole cohort (OR, 1.66; 95% CI, 1.09-2.53; p = .02), particularly among male patients (OR, 1.98; 95% CI, 1.16-3.40; p = .02) and among subjects with direct pulmonary injury (OR, 1.75; 95% CI, 1.04-2.95; p = .04). Conclusions: The haplotype GTC of NFKBIA gene is associated with higher risk of ARDS in Caucasians, particularly in male patients and in patients with direct lung injury.