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Psychosomatic Medicine 69:756-761 (2007)
© 2007 American Psychosomatic Society

ORIGINAL ARTICLES

C-reactive protein Levels and Sleep Disturbances: Observations Based on The Northern Finland 1966 Birth Cohort Study

Timo Liukkonen, MD, Pirkko Räsänen, MD, PhD, Aimo Ruokonen, MD, PhD, Jaana Laitinen, PhD, Jari Jokelainen, MSc, Maija Leinonen, PhD, V. Benno Meyer-Rochow, PhD, DSc and Markku Timonen, MD, PhD

From the Department of Psychiatry (T.L), Savonlinna Central Hospital, Savonlinna, Finland; Department of Public Health Science and General Practice (T.L., J.J., M.T.), University of Oulu, Oulu, Finland; Department of Psychiatry (P.R.), University of Oulu, Oulu, Finland; Department of Psychiatry (P.R.), Oulu University Hospital, Oulu, Finland; Department of Clinical Chemistry (A.R.), University of Oulu, Oulu, Finland; Finnish Institute of Occupational Health (J.L.), Promotion of Work Ability and Health Team, Oulu, Finland; Unit of General Practice (J.J.), Oulu University Hospital, Oulu, Finland; National Public Health Institute (M.L.), Oulu, Finland; School of Engineering and Science (V.B.M.-R.), Jacobs University (formerly known as International University Bremen), Bremen, Germany; Department of Physiology (V.B.M.-R.), University of Oulu, Oulu, Finland.

Address correspondence and reprint requests to Timo Liukkonen, Department of Psychiatry, Savonlinna Central Hospital Keskussairaalantie 6, FIN-57120 Savonlinna, Finland. E-mail: liukkonen.timo{at}dnainternet.net


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: To investigate whether sleep disturbances are associated with C-reactive protein (CRP) levels at the population level. Elevated CRP levels have been found to accompany sleep disturbances, but evidence so far comes only from limited clinical and experimental studies; epidemiological studies are lacking.

Methods: We utilized the Northern Finland 1966 Birth Cohort, whose participants have been followed up to the age of 31 years. The hs-enzyme immunoassay method was used to measure highly sensitive-CRP (hs-CRP) concentrations (4011 participants). Self-reported sleep disturbances were ranked from 1 (no problem) to 5 (severe disturbances).

Results: Multivariate analyses, after adjusting for confounders, revealed that hs-CRP levels in men in the sleep disturbance category "moderate, considerable and severe" (i.e., self-reported sleep disturbances rated 3, 4, or 5), were >18% (18.2%, 95% Confidence Interval 3.0% to 36.3%) higher than those in men with "no" sleep disturbance. In women, hs-CRP levels did not significantly differ between different sleep disturbance categories.

Conclusions: Our results support the hypothesis that moderate-to-severe sleep disturbances in men are associated with slightly increased CRP levels at the epidemiological level. Further investigations are called for to see whether our results can be replicated in other databases.

Key Words: C-reactive protein • inflammation • sleep • sleep disturbances

Abbreviations: CRP = C-reactive protein; IL-6 = interleukin-6; EIA = enzyme immunoassay; Hs-CRP = highly sensitive C-reactive protein; HSCL-25 = Hopkins Symptom Checklist-25.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
There is a growing body of evidence, based on animal models (1) and also observations in humans (2–5), that suggests that sleep disturbance and impaired physical well-being are connected. Reduced sleep durations have been associated with increased risks of developing cardiovascular disorders (2,6,7) and Type 2 diabetes (2,8,9), whereas low-grade inflammation has been assumed to be an underlying mechanism for these disorders (10–12).

Several studies have reported associations between sleep latency, sleep restriction or impaired night time sleep, and elevated levels of interleukin-6 (IL-6) (13–17), which is thought to regulate C-reactive protein (CRP) production. When compared with IL-6, CRP-level is, however, known to be more stable across 24 hours and for that reason may reflect more accurately the state of inflammation (18). In two different experiments, based on 10 participants each, it was shown that partial (4.2 hours of night time sleep) as well as total (continuous 88 hours) sleep restriction caused an elevation of CRP concentrations (19). Larkin et al. also found CRP levels to be associated negatively with sleep duration in a study with 143 adolescent patients suffering from sleep disordered breathing (20). Very recently, McDade et al. found sleep latency to be independently associated with elevated CRP in among 188 participants, aged 52 to 72 years (21).

To the best of our knowledge, there is no large population-based study that investigates, at epidemiological level, whether sleep disturbance is associated with CRP levels. In the present study, we used the highly sensitive (hs) enzyme immunoassay (EIA) method and applied it to the measurement of CRP concentrations to investigate whether sleep disturbances, with regard to the general population birth cohort database, are associated with increased levels of hs-CRP.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Study Design
We used data from the large and genetically homogeneous Northern Finland 1966 Birth Cohort. In the two northernmost Finnish provinces, i.e., Oulu and Lapland, 96% of all women (n = 12,068), with an expected date of delivery falling between 1st January and 31st December in 1966, were evaluated. They gave birth to 12,058 live infants. Many biological, socioeconomic, and health conditions as well as living habits and family characteristics of the cohort members were collected from prenatal stages through the age of 31 years. A detailed description of the data has been published earlier (22,23). This study was approved by the Ethics Committee of the Faculty of Medicine, University of Oulu (Finland), and the informed consent was signed by all participants.

Instruments and Measurements
In 1997, as part of the 31-year follow-up survey, 11,541 of the original 12,058 cohort members were available and were sent postal questionnaires. All those who were living in northern Finland or in the capital area were invited to undergo a clinical examination (n = 8463), and 6025 (71.2%) attended (24,25). The question regarding sleep disturbances was addressed by question 5 in 15-D-questionnaire (26), which was included in the postal questionnaires. Sleep disturbance was scaled from 1 to 5, where 1 indicated no problem, 2 slight, 3 moderate, 4 considerable, and 5 severe sleep disturbances. For the purpose of this study, sleep disturbances were assigned to three categories: 1) "no," 2) "slight," and 3) "moderate, considerable, and severe." Hs-CRP-levels were measured from the serum samples, collected during clinical examinations, and assayed immunoenzymometrically (MedixBiochemica, Helsinki, Finland). The sensitivity of the assay was 0.08 mg/l (27).

Initially, hs-CRP concentration was analyzed as continuous variable. We then dichotomized the hs-CRP variable by using a cut-off point of ≥1.0 mg/L, which had earlier been shown to be associated with an elevated risk of another inflammatory associated disorder, namely, cardiovascular disease (10). Consequently hs-CRP levels were judged to have been elevated, when the hs-CRP level was ≥1.0 mg/L (10,28).

Because sleep disturbance is a major symptom of depression and depression is known to be associated with elevated CRP levels (28–31), we excluded participants (n = 1924), who had depressive symptoms according to Hopkins Symptom Checklist-25 (HSCL-25). HSCL-25 was included in the postal questionnaires, as a 25-item shortened version of an originally 90-item questionnaire designed by Derogatis and colleagues (32). A depression subscale containing 13 questions was used to define depression (33). Cohort members recorded their estimate of the severity of their depressive symptoms on a scale ranging from 1 ("not at all") to 4 ("extremely"). Responses were summed and, to generate a depression mean score ranging from 1.0 to 4.0, divided by the number of answered items (32). In the present study, depressive symptoms were defined to be present if the HSCL-25 depression subscale mean score was ≥1.55 (33–35).

Body mass index, current smoking, physical inactivity, socioeconomic status, systolic blood pressure, and dyslipidemia were used as potential confounding variables (Tables 1 and 2) in multivariate analyses because all of them had been shown to be associated with sleep disturbances (35–41) and CRP levels (42–44). Psychiatric hospital treatment was also used as a confounding variable because sleep disturbance is known to occur in severe mental illnesses. Because the use of oral contraceptives in women is known to have an effect on CRP, we also treated oral contraceptive use as a potential confounding variable in females, and we excluded those women who were pregnant (45).


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  		TABLE 1. Descriptive Information on Cohort Members of the Northern Finland 1966 Birth Cohort in Relationship to Hs-CRP Categories

 


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  		TABLE 2. Descriptive Information on Cohort Members of the Northern Finland 1966 Birth Cohort in Relationship to Sleep Disturbance Categories

 
The final number of cohort members, for whom complete information was available and who had consented in writing to the use of their collected data for scientific purposes, was 4011 (52.5% males).

Statistical Analysis
Distributions of continuous variables were expressed as mean ± standard deviation and medians (interquartile range), and regarding categorical variables as proportions. Comparisons of continuous variables across categories of sleep disturbances ("no," "slight," "moderate, considerable, and severe") and hs-CRP levels were based on the Kruskal-Wallis test and carried out pair-wise using the Wilcoxon Rank-Sum test. The main analyses to investigate the impact of sleep disturbance on hs-CRP levels were carried out in two ways. Primarily, a robust regression analysis was conducted to minimize the effect of the outliers and influential data points in multivariate analyses, given that the results of robust regression are much less sensitive to outliers than those of the more familiar ordinary least squares regression. In multivariate analyses, logarithmically transformed hs-CRP values were used (log [hs – CRP + 1]) (46,47). Multivariate models were adjusted for body mass index, current smoking, physical inactivity, socioeconomic status, systolic blood pressure, psychiatric hospital treatment, dyslipidemia, and oral contraceptive use in women.

Secondly, multivariate log-binomial regression analyses (a generalized linear model with a logarithmic link function and binomial distribution of the residual) was used to examine the association between elevated hs-CRP-levels and sleep disturbances after adjusting for the above-mentioned confounders. Logistic regression analysis, which is commonly used for modeling binary outcome, was rejected because of its substantial overestimation of the risk ratio in situations of common outcomes (48). A p < .05 was considered statistically significant. The statistical analyses were performed with SAS, version 9.1.


   RESULTS
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Median hs-CRP levels in men for sleep disturbance categories "no," "slight," and "moderate, considerable, and severe" were 0.6, 0.7, and 1.0 (p < .038), respectively. In women, the corresponding medians were 0.8, 0.8, and 0.9 (p = .950). In men, based on pair-wise comparisons, the category "no" differed significantly from the category "moderate, considerable, and severe" (p < .001), but the categories "no" and "slight" did not differ statistically significantly from each other (p = .403). In multivariate analyses, after adjusting for confounders, the hs-CRP levels in men with "moderate, considerable, and severe" sleep disturbances were >18% (18.2%, 95% Confidence Interval (CI) 3.0% to 36.3%) higher than those in men with "no" sleep disturbance.

Elevated hs-CRP values (hs-CRP ≥1.0 mg/L) were found in 35.88% of the men and 44.42% of the women. In the categories of "no," "slight," and "moderate, considerable, and severe" sleep disturbance, respective hs-CRP-levels were elevated in 35.39%, 35.86%, and 56.41% of the men (p = .03), and 44.15%, 44.82%, and 48.65% of the women (p = .84).

Compared with men with "no" sleep disturbances, those with "moderate, considerable, and severe" sleep disturbances had a statistically significantly increased chance of having elevated hs-CRP values as high as 1.6-fold (relative risk (RR) = 1.60; 95% CI = 1.22–2.11). "Slight" sleep disturbances in men, and any level of sleep disturbance in women, did not result in significant increases of elevated hs-CRP levels. After adjusting for potential confounding variables, the corresponding risk ratio for "moderate, considerable, and severe" sleep disturbances remained statistically significant in men (adjusted RR = 1.30; 95% CI = 1.05–1.61).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
To the best of our knowledge, this was the first study in which the association between hs-CRP levels and sleep disturbances was investigated at epidemiological level. Our main finding, based on data of our genetically homogeneous and prospectively followed general population birth cohort, was that, after adjusting for confounders, the hs-CRP level was about 18% higher in men with "moderate, considerable, and severe" sleep disturbances than in men without sleeping disturbances. What seems noteworthy of our data is that, after dichotomizing the hs-CRP variable by using the cut-off point (1.0 mg/L)—that had previously been recommended in assessing the risk for cardiovascular disease (10)—the majority of those with "no" and "slight" sleep disturbances had hs-CRP levels <1.0 mg/L. In addition, after adjusting for potential confounding variables, "moderate, considerable, and severe" sleep disturbances increased the risk of elevated CRP level (hs-CRP ≥1.0 mg/L) nearly 1.3-fold in men, but not in women. This finding of elevated CRP levels in connection with sleep disturbances in males is generally in line with earlier findings (19–21).

However, we did not find an association between CRP levels and sleep disturbance in young women. Our data were based on participants 31 years of age and, therefore, included the premenopausal women. Earlier studies on this topic had included either adolescent (20) or peri- and postmenopausal participants (21). Thus, the different hormonal milieu of differently aged women could be one possible explanation why our study, in contrast to those of others, did not reveal an association between CRP levels and sleep disturbance in women. An association between a supposedly "inflammation-associated state," i.e., depression, and elevated CRP levels has been reported in men and elderly women, but not premenopausal women (28,30,49). Hormonal milieu changes across lifetime were held responsible for this (28,30). Although oral contraceptive use was controlled in our study, there is also the possibility that changes in the menstrual cycle have made it harder or impossible to find the association in the young women of our study.

To interpret our findings, some limitations need to be considered. First, measurements of hs-CRP were based on one-time measurements, but short-term fluctuations of CRP levels are known to be infrequent (50). Nevertheless, additional markers of inflammation could have been useful in validating the finding. Second, it is possible that some other unknown factor could have caused the observed elevation of CRP levels. This possibility, however, is seen as extremely unlikely due to the relatively young study population, and consequently low incidence of possible somatic diseases and use of medication putatively affecting CRP levels. It is noteworthy that the number of confounders taken into account did not change the result. Third, it is possible that sleep disturbance could have been one of the symptoms of depression, and that the association would have been principally a reflection of the association between depression and elevated CRP levels. On the other hand, the HSCL-25 subscale has been found to be a valid tool for the identification of depressive symptoms and a supposedly reliable instrument for excluding depressive participants (51). Also, it is notable that the evaluation of sleep disturbance was based on only one question, and that subjective sleep quality does not always correlate with objective sleep quality. Finally, it is important to point out that our study was of a cross-sectional nature and therefore causalities were not meant to be investigated. Nevertheless, in experimental studies (19), sleep restriction has recently been shown to cause an elevation of CRP level. It is also possible that sleep disturbance is due to elevated IL-6 because the latter has been shown to alter significantly sleep architecture, so that an elevated CRP value could be a consequence of elevated IL-6 (52).

The strengths of our study were that our data were based on a genetically homogeneous birth cohort, although CRP levels are known to differ significantly between races (53). All of the cohort participants were white. In addition, the hs-EIA method allowed us to conduct well-aimed measurements of the CRP levels. Finally, 15-D has been shown to be a valid measure of health-related aspects of the quality of life (26).

In sum, our novel findings were that moderate-to-severe sleep disturbances in men might be associated with increased levels of hs-CRP at epidemiological level and also that men without sleep disturbances tended to have hs-CRP levels <1.0 mg/L. However, our findings should be replicated and, if confirmed, would contribute to deepen our understanding of risk factors in the context of the pathophysiological backgrounds of cardiac diseases and diabetes, because both of the latter are known to be associated with low-grade inflammation and sleep disturbance. If sleep disturbances actually cause elevations of inflammation markers at epidemiological level, this would be of considerable public health concern. It would furthermore underscore the importance of detecting, monitoring, and treating sleep disturbances.


   NOTES
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
Received for publication December 18, 2006; revision received May 21, 2007.

This study was supported by grants from Finnish Psychiatric Association (T.L.).

DOI:10.1097/PSY.0b013e318157cb96


   REFERENCES
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 INTRODUCTION
 METHODS
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 DISCUSSION
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 REFERENCES
 

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Psychosom Med, May 1, 2009; 71(4): 423 - 430.
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