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

doi:10.3390/jcm10153413

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: NCT 00519597), 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.

Highlights

Coronary artery disease (CAD) is the most common type of heart disease and is characterized by a poor prognosis and a high risk of morbidity and mortality [1]
Obstructive sleep apnea (OSA) has been associated with increased inflammatory activity, probably due to intermittent hypoxia and oxidative stress resulting in increased concentrations of free radicals [10]
Elevated levels of high-sensitivity C-reactive protein, interleukin (IL)-6 and tumor necrosis factor (TNF)-α have been found in patients with OSA [11]

Summary

Introduction

Coronary artery disease (CAD) is the most common type of heart disease and is characterized by a poor prognosis and a high risk of morbidity and mortality [1]. Obstructive sleep apnea (OSA) is a common disorder characterized by repeated upper-airway collapse during sleep, resulting in intermittent hypoxia, fragmented sleep, fluctuations in blood pressure and increased sympathetic nervous system activity [4]. The prevalence of OSA among CAD patients is very high (50% as compared to 10–20% in the general adult population) [5], and OSA patients have an increased risk for the development of CAD compared to individuals without OSA [6]. Increased inflammatory activity plays a crucial role in the development of atherosclerotic plaques and CAD [7]. Circulating levels of inflammatory markers predict future cardiovascular events, both in the general population [8] and in adults with a known cardiovascular disease [9]. The treatment of OSA with continuous positive airway pressure (CPAP) has been shown to normalize the levels of circulating inflammatory markers, supporting the link between systemic inflammation and OSA [12]

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