Predictors of elevated nuclear factor-kappaB-dependent genes in obstructive sleep apnea syndrome.
BACKGROUND
Circulating nuclear factor-kappaB (NF-kappaB)-dependent genes, particularly tumor necrosis factor-alpha (TNF-alpha), are elevated in obstructive sleep apnea syndrome (OSAS) and likely contribute to cardiovascular disease. Furthermore, TNF-alpha is associated with excessive daytime sleepiness. We investigated the predictors of TNF-alpha and related genes in large, well-selected cohorts of subjects with OSAS and control subjects.


METHODS
We performed a prospective study of 30 subjects who did not have OSAS (22 nonsleepy normal control subjects and 8 sleepy nonapneic subjects who snored), 36 subjects with mild to moderate OSAS, and 31 subjects with severe OSAS; all subjects were male. Groups were matched for age, body mass index, and other relevant variables. Subjects had no other disease and were not regularly taking medication. All had serum for TNF-alpha and related assays drawn after polysomnography. A total of 49 suitable subjects were treated with continuous positive airway pressure (CPAP); sleep studies together with serum assays were repeated 6 wk later.


RESULTS
TNF-alpha levels were higher in subjects with OSAS than in subjects without OSAS (p < 0.001). In multivariate analysis, TNF-alpha was independently associated with the desaturation index (r = 0.399, p < 0.001), Epworth Sleepiness Score (r = 0.243, p = 0.005), and cholesterol (r = 0.216, p = 0.018). Furthermore, TNF-alpha levels were higher in sleepy nonapneic subjects who snored than in normal control subjects (p = 0.002) but lower than in subjects with OSAS (p = 0.03). CPAP therapy lowered TNF-alpha levels (p = 0.004). Another NF-kappaB-dependent cytokine, interleukin-8 (IL-8), showed similar differences between groups and after CPAP therapy, but a range of other mediators of inflammation, including IL-1, IL-6, IL-10, and IL-12, showed no differences.


CONCLUSIONS
Intermittent hypoxia is the strongest predictor of TNF-alpha levels, supporting a role for inflammation in the cardiovascular pathophysiology of OSAS. Furthermore, TNF-alpha levels are independently associated with excessive daytime sleepiness.
Ryan
Silke
S
Sleep Research Laboratory, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
Taylor
Cormac T
CT
McNicholas
Walter T
WT
D000328:Adult; D000368:Aged; D045422:Continuous Positive Airway Pressure; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007378:Interleukins / Q000097:blood; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016328:NF-kappa B / Q000235:genetics*; D011446:Prospective Studies; D020181:Sleep Apnea, Obstructive / Q000097:blood* / Q000503:physiopathology / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
D016209:Interleukin-8; D007378:Interleukins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha