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Predictors of Elevated Nuclear Factor-B–dependent Genes in Obstructive Sleep Apnea Syndrome

Sleep Research Laboratory, St. Vincent's University Hospital, Dublin; and School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin, Ireland

Correspondence and requests for reprints should be addressed to Walter McNicholas, M.D., Department of Respiratory Medicine, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland. E-mail: walter.mcnicholas{at}ucd.ie

Background: Circulating nuclear factor-B (NF-B)–dependent genes, particularly tumor necrosis factor- (TNF-), are elevated in obstructive sleep apnea syndrome (OSAS) and likely contribute to cardiovascular disease. Furthermore, TNF- is associated with excessive daytime sleepiness. We investigated the predictors of TNF- 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- 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- levels were higher in subjects with OSAS than in subjects without OSAS (p < 0.001). In multivariate analysis, TNF- 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- 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- levels (p = 0.004). Another NF-B–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.

Conclusion: Intermittent hypoxia is the strongest predictor of TNF- levels, supporting a role for inflammation in the cardiovascular pathophysiology of OSAS. Furthermore, TNF- levels are independently associated with excessive daytime sleepiness.

Key Words: cardiovascular diseases • excessive daytime sleepiness • nuclear factor-B • obstructive sleep apnea syndrome • tumor necrosis factor-

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