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

Minhan Yi; Wangcheng Zhao; Yun Tan; Quanming Fei; Kun Liu; Ziliang Chen; Yuan Zhang

doi:10.1080/07853890.2022.2081873

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

Ann Med. 2022 Dec;54(1):1578-1589. doi: 10.1080/07853890.2022.2081873.

Authors

Minhan Yi^{1

2

3}, Wangcheng Zhao^{1

3

4}, Yun Tan^{1

2

3}, Quanming Fei^{1

3

4}, Kun Liu², Ziliang Chen⁵, Yuan Zhang^{1

3}

Affiliations

¹ Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
² School of Life Sciences, Central South University, Changsha, China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁴ Xiangya School of Medicine, Central South University, Changsha, China.
⁵ School of Computer Science and Engineering, Central South University, Changsha, China.

Abstract

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, 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-α (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-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.

Keywords: CPAP; CRP; Mendelian Randomization; Obstructive sleep apnea; TNF-α.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

C-Reactive Protein / metabolism
Continuous Positive Airway Pressure / methods
Humans
Inflammation
Sleep Apnea, Obstructive* / genetics
Sleep Apnea, Obstructive* / therapy
Tumor Necrosis Factor-alpha* / genetics

Substances

Tumor Necrosis Factor-alpha
C-Reactive Protein

Grants and funding

This research was supported by the National Natural Science Foundation of China [No. 82001357] the Hunan Provincial Natural Science Foundation of China [No. 2020JJ5951, No. 2021JJ80079], the Youth Science Foundation of Xiangya Hospital [No. 2019Q17], the Degree & Postgraduate Education Reform Project of Central South University [No. 2021YJSKSA10], the Undergraduate Education Reform Project of Central South University [No. 2021CG065, No. 2021CG068] and the Research Project of Laboratory Construction and Management of Central South University [No. 202120].