The causal relationships between obstructive sleep apnea and elevated CRP and TNF-alpha protein levels

Background: Obstructive sleep apnea (OSA) and inflammation are closely related. This study aimed to evaluate the associations and causal effect between C-reactive protein (CRP) and tumour necrosis factor-alpha (TNF-alpha) levels andOSA. Methods: Pooled analysis was conducted to compare the expression differences of CRP and TNF-alpha between OSA patients with different severity and controls, and between continuous positive airway pressure (CPAP) and non-CPAP interventions for OSA patients. Using published GWAS summary statistics, we conducted a bidirectional two-sample Mendelian Randomization (MR) to estimate the causal relationships between CRP and TNF-alpha levels and OSA risk. Effect estimates were evaluated using inverse-variance weighted (MN) as primary method, and several other MR methods as sensitivity analysis. Results: Both TNF-alpha (WMD [95%CI]= 5.86 [4.80-6.93] pg/ml, p < .00001) and CRP (WMD [95%CI] = 2.66 [2.15-3.17] mg/L, p < .00001), showed a significant increase in OSA patients compared with controls and this increasing trend was associated with OSA severity. Besides, compared to blank control (non-CPAP), CPAP treatment can reduce high TNF-alpha (WMD [95%CI] = -4.44 [-4.81, -4.07]pg/ml, p < .00001) and CRP (WMD [95%CI] = -0.91 [-1.65, -0.17] mg/l, p = .02) in OSA. Moreover, the primary MR analysis by IVW showed that OSA was the genetically predicted cause of elevated CRP (estimate: 0.095; 95% CI, [0.010-0.179]; p = .029) using six SNPs as the instrument variable, which were repeated by weighted median (estimate: 0.053; 95% CI, [0.007, 0.100]; p = .024) and MR RAPS (estimate: 0.109; 95% CI, [0.079, 0.140]; p = 1.98x10(-12)). Besides, the causal effect from elevated CRP on increased OSA risk was almost significant by IVW (OR:1.053; 95% CI, [1.000, 1.111]; p = .053). However, there were no causal associations between TNF-alpha and OSA from both directions. Conclusions: Increased CRP and TNF-alpha were associated with OSA severity and sensible to CPAP treatment. Also, OSA had a suggestive causal effect on elevated CRP.