Inhibitor kappaB-alpha haplotype GTC is associated with susceptibility to acute respiratory distress syndrome in Caucasians.
OBJECTIVE
The nuclear factor (NF)-kappaB regulates inflammatory responses and plays important roles in the pathogenesis of acute respiratory distress syndrome (ARDS). Inhibitor kappaB-alpha (NFKBIA) inhibits NF-kappaB and controls its activities. The objective was to determine whether polymorphisms in NFKBIA gene would be associated with ARDS development.


METHODS
Prospective cohort of adults with clinical risk factors for ARDS.


METHODS
Hospital system.


METHODS
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.


METHODS
Genetic polymorphisms in the NFKBIA promoter (-881A/G, -826C/T, -297C/T) were determined using TaqMan techniques.


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.
Zhai
Rihong
R
Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA.
Zhou
Wei
W
Gong
Michelle N
MN
Thompson
B Taylor
BT
Su
Li
L
Yu
Chuling
C
Kraft
Peter
P
Christiani
David C
DC
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D003422:Critical Care; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins; D012128:Respiratory Distress Syndrome / Q000235:genetics*; D012307:Risk Factors; D051996:Transcription Factor RelA / Q000235:genetics*; D044465:White People / Q000235:genetics*
D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C119612:PPP1R13L protein, human; C498143:RELA protein, human; D012097:Repressor Proteins; D051996:Transcription Factor RelA