C-reactive Protein and Risk of OSA in Four US Cohorts

Published:January 30, 2021DOI:


      Individuals with OSA have elevated levels of inflammatory markers, but no prospective study has examined the role of inflammation in the development of OSA.

      Research Question

      Is C-reactive protein (CRP) prospectively associated with risk of developing OSA?

      Study Design and Methods

      We followed 1,882 women from the Nurses’ Health Study (NHS) (2002-2012), 3,854 women from Nurses’ Health Study II (NHSII) (1995-2013), 3,075 men from the Health Professionals Follow-up Study (HPFS) (1996-2012), and 1,919 women and men from the Multi-Ethnic Study of Atherosclerosis (MESA) (2000-2012) who did not have diagnosed OSA at baseline and for whom CRP levels were available. In NHS/NHSII/HPFS, physician-diagnosed OSA was self-reported. In MESA, at-home polysomnography was performed and OSA was identified as an apnea-hypopnea index ≥ 30. Logistic regression was used to estimate the OR for OSA risk according to baseline CRP level, adjusted for multiple inflammation-related factors.


      After multivariable adjustment not including BMI, the pooled OR for OSA risk per doubling of baseline CRP level was 1.24 (95% CI, 1.18-1.30). Additional adjustment for BMI substantially attenuated the association (pooled OR, 1.07; 95% CI, 1.01-1.12). The fully adjusted association was consistently stronger in individuals < 55 vs ≥ 55 years of age (P interaction = .01), in individuals with BMI < 25 vs ≥ 25 kg/m2 (P interaction = .02), and in pre- vs postmenopausal women (P interaction = .002). CRP was more strongly associated with risk of OSA associated with excessive daytime sleepiness, high airway collapsibility, and low arousal threshold (P heterogeneity < .05).


      Higher CRP was prospectively associated with increased OSA risk, particularly among younger individuals, underweight/normal-weight individuals, or premenopausal women. The differential associations by OSA phenotype/endotype suggest possible mechanisms through which inflammation operates to modulate OSA risk. Given our reliance on a single CRP level measured a decade before OSA assessment, future studies with repeated CRP measurements are warranted to confirm these prospective associations.

      Key Words


      AHI (apnea-hypopnea index), CRP (C-reactive protein), CV (coefficient of variation), EDS (excessive daytime sleepiness), HPFS (Health Professionals Follow-up Study), MESA (Multi-Ethnic Study of Atherosclerosis), NHS (Nurses’ Health Study), NHSII (Nurses’ Health Study II), SNS (sympathetic nervous system)
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      Linked Article

      • Relationship Between C-reactive Protein and Risk of OSA in the Framework of Causal Inference
        CHESTVol. 159Issue 6
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          I read with great interest the study by Huang et al1 published in this issue of CHEST that showed consistently that C-reactive protein (CRP) was associated with increased risk of OSA. The authors tried to secure causal association between CRP and OSA by using multiple statistical methods such as multivariable regression model, sensitivity analysis, and interaction. However, some assumptions may not hold in the use of regression models. By adjusting for confounders in a logistic regression model, the authors assume that obesity and other covariates are on the backdoor path that creates spurious correlations between CRP and OSA that are driven solely by fluctuations in the obesity/BMI variable.
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      • Response
        CHESTVol. 159Issue 6
        • Preview
          We thank Dr Ye for the insightful comments on the relationship between C-reactive protein and risk of OSA.1 We agree that overweight/obesity is a strong confounder for this association, which is expected, given that overweight/obesity is a potent risk factor for both inflammation and OSA risk. However, this does not preclude a role of inflammation in OSA development. In addition to BMI adjustment, we used stratification as another way to assess confounding by obesity. We observed stronger associations among participants with BMI <25 kg/m2 vs BMI ≥25 kg/m2, after adjusting for BMI continuously within each BMI stratum.
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