阻塞性睡眠呼吸暂停与 CRP 和 TNF-α 蛋白水平升高之间的因果关系。
The causal relationships between obstructive sleep apnea and elevated CRP and TNF-α protein levels.
机构信息
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
School of Life Sciences, Central South University, Changsha, China.
出版信息
Ann Med. 2022 Dec;54(1):1578-1589. doi: 10.1080/07853890.2022.2081873.
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-α) levels andOSA.
METHODS
Pooled analysis was conducted to compare the expression differences of CRP and TNF-α 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-α levels and OSA risk. Effect estimates were evaluated using inverse-variance weighted (IVW) as primary method, and several other MR methods as sensitivity analysis.
RESULTS
Both TNF-α (WMD [95%CI] = 5.86 [4.80-6.93] pg/ml, < .00001) and CRP (WMD [95%CI] = 2.66 [2.15-3.17] mg/L, < .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-α (WMD [95%CI]= -4.44 [-4.81, -4.07]pg/ml, < .00001) and CRP (WMD [95%CI]= -0.91 [-1.65, -0.17] mg/l, = .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]; = .029) using six SNPs as the instrument variable, which were repeated by weighted median (estimate: 0.053; 95% CI, [0.007, 0.100]; =.024) and MR RAPS (estimate: 0.109; 95% CI, [0.079, 0.140]; = 1.98x10). 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]; = .053). However, there were no causal associations between TNF-α and OSA from both directions.
CONCLUSIONS
Increased CRP and TNF-α were associated with OSA severity and sensible to CPAP treatment. Also, OSA had a suggestive causal effect on elevated CRP.
背景
阻塞性睡眠呼吸暂停（OSA）与炎症密切相关。本研究旨在评估 C 反应蛋白（CRP）和肿瘤坏死因子-α（TNF-α）水平与 OSA 之间的关联和因果关系。
方法
对比较 OSA 患者与对照组之间、CPAP 与非 CPAP 干预治疗 OSA 患者之间 CRP 和 TNF-α 表达差异的研究进行汇总分析。使用已发表的 GWAS 汇总统计数据，我们进行了双向两样本 Mendelian Randomization（MR），以估计 CRP 和 TNF-α 水平与 OSA 风险之间的因果关系。使用逆方差加权（IVW）作为主要方法，以及其他几种 MR 方法作为敏感性分析，评估效应估计值。
结果
与对照组相比，TNF-α（WMD [95%CI] = 5.86 [4.80-6.93] pg/ml， < .00001）和 CRP（WMD [95%CI] = 2.66 [2.15-3.17] mg/L， < .00001）在 OSA 患者中均显著升高，且这种升高趋势与 OSA 严重程度相关。此外，与空白对照（非 CPAP）相比，CPAP 治疗可降低 TNF-α（WMD [95%CI]= -4.44 [-4.81, -4.07] pg/ml， < .00001）和 CRP（WMD [95%CI]= -0.91 [-1.65, -0.17] mg/L， = .02）在 OSA 中的水平。此外，通过 IVW 进行的主要 MR 分析表明，CRP 升高的遗传预测原因是 OSA（估计值：0.095；95%CI，[0.010-0.179]； = .029），使用六个 SNP 作为工具变量，加权中位数（估计值：0.053；95%CI，[0.007, 0.100]； = .024）和 MR RAPS（估计值：0.109；95%CI，[0.079, 0.140]； = 1.98x10）可重复检测到。此外，通过 IVW，CRP 升高对 OSA 风险增加的因果效应几乎具有统计学意义（OR：1.053；95%CI，[1.000, 1.111]； = .053）。然而，从两个方向来看，TNF-α 与 OSA 之间均无因果关系。
结论
升高的 CRP 和 TNF-α 与 OSA 严重程度相关，且对 CPAP 治疗敏感。此外，OSA 对 CRP 升高有提示性的因果影响。
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