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

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.

Association of TNF-α (-308G/A) Gene Polymorphism with Changes in Circulating TNF-α Levels in Response to CPAP Treatment in Adults with Coronary Artery Disease and Obstructive Sleep Apnea

“…As previously described in detail [ 35 ], genomic DNA was isolated from whole blood samples collected in EDTA-coated tubes using the PAXgene Blood DNA Kit (PreAnalytiX; Qiagen). The quality and concentration of DNA samples were determined using a nanodrop photometer (NanoDrop 2000; Thermo Scientific, Waltham, MA, USA), and DNA samples were stored at −80 degrees.…”

“…We recently demonstrated that patients with CAD and OSA carrying the TNF-α A allele had increased circulating TNF-α levels compared with the ones carrying the TNF-α G allele [ 35 ] in the “Randomized Intervention with CPAP in CAD and OSA” (RICCADSA) cohort [ 36 ]. In the current study, we addressed the role of TNF-α (-308G/A) gene polymorphism on circulating TNF-α levels in response to 12 months of CPAP therapy.…”

Evaluation of Blood Levels of Omentin-1 and Orexin-A in Adults with Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis

“…Several factors including environmental and genetic factors, and even internal conditions (hormones, cytokines, and other biomarkers), might lead to the emergence and maintenance of OSA. Smoking [ 12 ] and alcohol consumption [ 13 ], and alterations in the blood levels of intercellular adhesion molecule-1 [ 14 ], monocyte chemoattractant protein-1 [ 15 ], adiponectin [ 16 ], C-reactive protein [ 17 ], cortisol [ 18 ], interleukin-6 [ 19 ], tumor necrosis factor-alpha [ 20 ], astrocytic protein (S100B) [ 21 ], neuron-specific enolase [ 21 ], and polymorphisms [ 22 , 23 , 24 ] were observed among adults with OSA, compared to healthy controls.…”

Association of the TNF‐α‐308G>A gene polymorphism with left ventricular geometry and functional abnormalities in obstructive sleep apnea subjects

“…OSA patients have a high risk of secondary cardiovascular diseases (CVDs), especially abnormalities in left ventricular geometry (LVG), which is an influential factor in the prognosis and treatment complexity of OSA 3,4 . Repeated IH/R leads to an increase in free radical concentration in OSA patients, which leads to increased pro‐inflammatory cytokine activity, including tumor necrosis factor‐α (TNF‐α), thereby inducing a systemic inflammatory response 5 . In addition, an increase in TNF‐α concentrations in serum is considered a risk factor for CVDs, 6 and myocardial cell‐specific expressed TNF‐α is linked to left ventricular remodeling 7 …”

“…3,4 Repeated IH/R leads to an increase in free radical concentration in OSA patients, which leads to increased pro-inflammatory cytokine activity, including tumor necrosis factor-α (TNF-α), thereby inducing a systemic inflammatory response. 5 In addition, an increase in TNF-α concentrations in serum is considered a risk factor for CVDs, 6 and myocardial cell-specific expressed TNF-α is linked to left ventricular remodeling. 7 There is an increasing amount of evidence indicating that genetic factors are in part engaged in the occurrence of OSA.…”