Association of TNF-α (-308G/A) Gene Polymorphism with Circulating TNF-α Levels and Excessive Daytime Sleepiness in Adults with Coronary Artery Disease and Concomitant Obstructive Sleep Apnea

Afrouz Behboudi, Tilia Thelander, Duygu Yazici, Yeliz Celik, Tülay Yucel-Lindberg, Erik Thunström, Yüksel Peker, Afrouz Behboudi, Tilia Thelander, Duygu Yazici, Yeliz Celik, Tülay Yucel-Lindberg, Erik Thunström, Yüksel Peker

Abstract

Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), in which inflammatory activity has a crucial role. The manifestation of OSA varies significantly between individuals in clinical cohorts; not all adults with OSA demonstrate the same set of symptoms; i.e., excessive daytime sleepiness (EDS) and/or increased levels of inflammatory biomarkers. The further exploration of the molecular basis of these differences is therefore essential for a better understanding of the OSA phenotypes in cardiac patients. In this current secondary analysis of the Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA (RICCADSA) trial (Trial Registry: ClinicalTrials.gov; No: NCT00519597), we aimed to address the association of tumor necrosis factor alpha (TNF-α)-308G/A gene polymorphism with circulating TNF-α levels and EDS among 326 participants. CAD patients with OSA (apnea-hypopnea-index (AHI) ≥ 15 events/h; n = 256) were categorized as having EDS (n = 100) or no-EDS (n = 156) based on the Epworth Sleepiness Scale score with a cut-off of 10. CAD patients with no-OSA (AHI < 5 events/h; n = 70) were included as a control group. The results demonstrated no significant differences regarding the distribution of the TNF-α alleles and genotypes between CAD patients with vs. without OSA. In a multivariate analysis, the oxygen desaturation index and TNF-α genotypes from GG to GA and GA to AA as well as the TNF-α-308A allele carriage were significantly associated with the circulating TNF-α levels. Moreover, the TNF-α-308A allele was associated with a decreased risk for EDS (odds ratio 0.64, 95% confidence interval 0.41-0.99; p = 0.043) independent of age, sex, obesity, OSA severity and the circulating TNF-α levels. We conclude that the TNF-α-308A allele appears to modulate circulatory TNF-α levels and mitigate EDS in adults with CAD and concomitant OSA.

Keywords: coronary artery disease; obstructive sleep apnea; tumor necrosis factor.

Conflict of interest statement

A.B., T.T., D.Y., Y.C., T.Y.-L. and E.T. report no conflict of interest. Y.P. received institutional grants from ResMed Foundation for the main RICCADSA trial.

Figures

Figure 1
Figure 1
Flow of patients through the study. Abbreviations: AHI, apnea–hypopnea index; CAD; coronary artery disease; CPAP, continuous positive airway pressure; CSA-CSR, central sleep apnea–Cheyne Stokes respiration; ESS, Epworth Sleepiness Scale; OSA, obstructive sleep apnea; RICCADSA, Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnea.
Figure 2
Figure 2
(A) Genotype frequency of the TNF-α-308G/A promoter polymorphism and (B) allele frequency of the TNF-α-308G/A promoter polymorphism in the study cohort.
Figure 3
Figure 3
Variables associated with excessive daytime sleepiness in the study population in the multivariate logistic regression analysis. Abbreviations: TNF-α = tumor necrosis factor alpha; OSA = obstructive sleep apnea. * p < 0.05, ** p < 0.01, *** p < 0.001.

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