Secreted Frizzled-Related Protein 5 (SFRP5) in Patients with Obstructive Sleep Apnea

Dongmei Zhang, Rong Huang＊, Yi Xiao, Fengying Gong,Xu Zhong, Jinmei Luo

1Department of Respiratory Medicine,2Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

Secreted Frizzled-Related Protein 5 (SFRP5) in Patients with Obstructive Sleep Apnea

Dongmei Zhang1, Rong Huang1＊, Yi Xiao1, Fengying Gong2,Xu Zhong1, Jinmei Luo1

1Department of Respiratory Medicine,2Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

secreted frizzled-related protein 5 (SFRP5); obstructive sleep apnea (OSA); obesity

A S a common chronic disease, obstructive sleep apnea (OSA) has a fairly high prevalence, which is currently estimated to be about 14% for adult men and 5% for adult women in general population.1OSA is characterized by repetitive collapse of upper airway, recurrent hypoxia, frequent arousals and fragmented sleeping during night. These physiologic disruptions in OSA may result in long-term sequelae, such as hypertension, cardiovascular morbidities, decrements in cognitive function and mood, reduced quality of life, and premature death.

As the most significant risk factor for OSA, obesity often relates to a low-grade inflammatory state in adipose tissue. Adipose tissue secretes a variety of cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6),adiponectin, apelin, leptin and omentin. Research has indicated that all the above cytokines have association with OSA.2-6Secreted frizzled-related protein 5 (SFRP5) is a recently described adipokine, which has the effects of antiinflammation and reducing insulin resistance.7SFRP5 expression is increased in mouse white adipose tissue,7but down regulated in the adipose tissue of various obese rodents. It is also increased in the visceral adipose tissue of obese people who have adipose tissue inflammation and insulin resistance.8SFRP5 deficiency exacerbates obesityinduced adipose tissue inflammation and metabolic dysfunction through activation of JNK1 signaling pathway7that has been proven to play a role in regulating insulin resistance and inflammation.9-11By preventing Wnt protein from binding to its receptor, which negatively regulates adipogenesis, SFRP5 might be involved in the regulation of lipid metabolism.12Decreased SFRP5 level may also contribute to the pathogenesis of coronary artery disease(CAD).13OSA is closely associated with obesity, insulin resistance and inflammation, and CAD is one of the most common complications of OSA. This study evaluated the level of plasma SFRP5 in over-weighted or obese (body mass index, BMI ＞ 24 kg/m2) OSA patients, aiming at to explore the potential association of SFRP5 with sleeping characteristics and biochemical parameters,including serum glucose, hypersensitive C-reactive protein,total-cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides.

MATERIALS AND METHODS

Study design and the subjects

This is a prospective study conducted at the Peking Union Medical College Hospital over the period from June 2012 to January 2014. This study was approved by the Ethics Committee of the institutional review board at Peking Union Medical College Hospital (protocol number ZS-1107),and written informed consents were obtained from all participants.

The subjects were recruited from male patients who were referred to sleep center for polysomnography (PSG)assessment because of habitual snoring. The Healthy controls were recruited from male subjects who came to the screening center of our hospital for health check-up.The age of the subjects to be enrolled should under 70 years old.

All candidates underwent detailed clinical examinations and filled out questionnaires of sleep habits, diseases history, and the Epworth Sleepiness Scale (ESS). Those healthy controls with a BMI ＞24Kg/m2and those accompanied with craniofacial anatomical anomalies, history of upper and/or lower airway surgery, significant neuromuscular diseases,renal diseases, endocrine diseases including diabetes,heart failure, any acute infectious processes, inflammatory or autoimmune diseases, intake of corticosteroids, cancer,chronic renal dysfunction or liver dysfunction were excluded from the enrollment.

Once enrolled, participants underwent PSG. Candidates who had apnea–hypopnea Index (AHI) ≥ 5 /h, accompanied with daytime somnolence were diagnosed as OSA, and enrolled in the study group; candidates who had AHI ＜ 5/h and BMI ＞ 24 kg/m2were enrolled in the overweight group. Patients with severe OSA were further treated with nasal continuous positive airway pressure (nCPAP) titration(Autoset? CS, ResMed, M?nchengladbach, Germany) under the monitoring of PSG at the second night. The therapy was considered effective if the subjects used nCPAP for at least 4 hours during sleeping, and AHI ＜ 10 /h or decreased by 75% from the baseline. For the patients whose therapy was effective, plasma SFRP5 examination was performed the next morning for comparison.

Polysomnography

All subjects had a standard full night polysomnography by an experienced technician in the sleep laboratory. They were monitored for 8 hours continuously (from 10 pm to 6 am) using a 60-channel polysomnography (Embla N7000,Natus Medical Incorporated, USA). Electroencephalography,electrooculography, and chin electromyography were recorded with surface electrodes according to standard methods. Airflow was monitored by nasal pressure. Thoracic and abdominal movements were assessed by respiratory inductive plethysmography that was recorded by belts connected to transducers. The night recording of pulse oxygen saturation (SpO2) was continuously acquired by a finger-attached oximeter. Electrocardiography and sleep positions were also noted. Apnea was defined as a cessation of airflow lasting for at least 10 seconds.Hypopnea was defined as a reduction of airflow over 30%and lasting for over 10 seconds, accompanied by a decrease of SpO2by 3% or arousals. Oxyhemoglobin desaturation was described as the percentage of sleep time with SpO2less than 90% in total sleep time (TST). The sleep records were scored based on standardized criteria by the American Academy of Sleep Medicine.14The ESS was applied to assess daytime sleepiness for all enrolled subjects.

Laboratory assessment

In the early morning (between 6 am and 7 am) after PSG,blood samples were drawn for SFRP5 examination and biochemical analysis. Blood samples were put into EDTA vacutainer tubes and immediately centrifuged at 3000 rpm/4°C for 10 minutes. Then, the samples were cryopreserved at ?80°C until being tested. Biochemical examinations, including glucose, total-cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and hypersensitive C-reactive protein (hsCRP), were performed by an auto biochemistry instrument (Hitachi 7060, Tokyo, Japan). Plasma concentration of SFRP5 was measured with a commercial enzymelinked immunosorbent assay kit (Human ELISA, Wuhan USCN Science Co Ltd, China) according to the manufacturer’s instruction; and the intra-assay and inter-assay coefficients of variation were 10% and 12%, respectively.SFRP5 examination of all samples was performed at the same time to avoid procedural variations. The operators were blind to the identifications of the subjects during laboratory assessments.

Statistical analysis

Analysis was performed with SPSS 21.0 (Chicago, Illinois,USA) and GraphPad Prism 6.02 (GraphPad Software Inc.La Jolla, USA). The distribution of quantitative variables was assessed by Kolmogorov-Smirnov’s test of normality.Normally distributed variables were expressed as mean ±standard deviation; and non-normal ones were reported as median and quartiles. The differences of normally distributed clinical characteristics, PSG parameters, and biochemical concentrations among the groups were compared using one-way ANOVA. Bonferroni Post-Hoc test was performed for pairwise comparison. Pearson’s correlation was used to investigate the correlations between variables and SFRP5.Paired t-test was performed to compare the SFRP5 levels between the pre- and post-nCPAP treatment. Statistical significance was defined at two-sided if P value＜ 0.05.

RESULTS

Subjects characteristics and sleep metrics

A total of 68 subjects were prospectively enrolled, with 10 subjects in the healthy control (HC) group, 20 in the overweight (OW) control group and 38 in the OSA group.The detailed anthropometric and metabolic data were listed in Table 1. No significant difference in the age was observed among the three groups. The BMI, neck circumference (NC) and abdominal circumference (AC)of the OW group were significantly higher than those of HC group, but not significantly different from those of OSA group. The HDL cholesterol was lower in both OW and OSA groups as compared to the healthy controls.No differences were observed regarding total cholestoral(TC), triacylglycerol (TG), low densify lipoprotein (LDL)and hsCRP.

Most of the subjects in the OSA group exhibited severe degree of obstructive sleep apnea. The AHI was significantly higher in OSA group [median 58.70 (36.63, 71.15)] than in OW group [median 2.00 (0.75, 2.78)] and HC group[median 0.55 (0.08, 1.50)] (both P＜ 0.001). The SpO2and minimum SpO2were significantly lower in OSA group than in HC and OW group, and the percentage of sleeping time with SpO2below 90% in OSA group was also significantly higher compared to HC and OW group.

OSA group had longer light sleep time (LST, stage N1 and N2) than the HC and the OW group (F=7.56, P=0.001),and had significantly less slow-wave sleep time (SWS,stage N3) than HC and OW controls (F=15.72, P＜0.001),whereas no significant difference was observed in either the time of rapid eye movement (REM) or non-rapid eye movement (NREM) between the OSA group and the HC group.

ESS of OSA patients [median 10.50 (6.75, 13.00)] was significantly higher than that of the HC group [median 5.50(2.75, 10.00)] (Z=-2.46, P=0.014), also higher than that of OW controls [median 9.00 (5.25, 11.00)] but not reaching a statistical significance (Z=-1.68, P= 0.093).

SFRP5 levels and correlations with characteristics of OSA patients

The plasma SFPR5 levels did not have significant difference among the HC, OW and OSA group (3.15 ± 2.25 ng/mL vs.3.51±2.14 ng/mL vs. 4.72±3.20 ng/mL, F=1.932, P=0.153)(Fig. 1). Analysis of co-variance adjusted for the covariates of age and BMI did not find any difference either. We further divided OSA into subgroups of mild-moderate (mOSA,5/h≤AHI＜30/h) and severe OSA (sOSA, AHI≥30/h), and there was still no difference of SFPR5 among the three groups (F=1.411, P=0.248) (Fig. 2).

In OSA patients, the SFRP5 level significantly correlated with the lipid profile. Specifically, a positive correlation was shown with triglyceride (TC) (r=0.447, P=0.005), while negative correlations were found with HDL-cholesterol (r=–0.478, P=0.002) and LDL-cholesterol (r=–0.472, P=0.003).No correlation was observed between the plasma SFRP5 level and sleep parameters, including ESS, AHI, average SpO2, minimum SpO2, or time spent in SpO2＜90%.Anthropometric parameters, i.e. age, NC, WC and BMI in OSA patients did not show any significant association with the SFRP5 level as well (Table 2).

Plasma SFRP5 levels before and after nCPAP therapy

In the 25 patients with severe OSA, 5 refused to have nCPAP therapy, and 8 failed their first overnight nCPAP titration. In the 12 patients who successfully completed nCPAP titration,the plasma SFRP5 level measured the next morning (mean 4.04 ± 2.20 ng/mL) was not significantly different from that before the treatment (mean 4.77±2.19 ng/mL, t=1.557,P=0.148) (Fig. 3). In contrast, AHI dramatically dropped from 62.35 (58.18, 74.90)/h before the treatment to 7.00 (3.03,9.28)/h after the treatment (Z=?3.059, P=0.002), and the minimum SpO2was elevated from 70.83%±14.97% to 89.25%±3.89% accordingly (t=?4.926, P＜0.001).

Table 1. Comparison of baseline clinical, biochemical and polysomnographic characteristics of the study subject §

Figure 1. Comparison of plasma SFRP5 levels among the group of OSA, OW and HC.

Figure 2. Comparison of plasma SFRP5 levels among the group of mOSA, sOSA, HC and OW.

Table 2. Correlations between the SFRP5 level and clinical, biochemical and sleep characteristics of OSA patients (n=38)

Figure 3. Plasma SFRP5 levels of the 12 OSA patients at the baseline and after overnight nCPAP treatment.

DISCUSSION

This study aimed to evaluate the potential association of plasma SFRP5 of OSA patients with sleep metrics and metabolic parameters. To our best knowledge, this is the first study investigating the SFRP5 level in OSA patients.In this study, no significant difference in the SFRP5 level was detected among patients with OSA, overweight subjects and healthy controls. This result indicated that, in nondiabetic obese subjects, the occurrence of sleep apnea might not be associated with the plasma SFRP5 concentration.The nCPAP treatment did not make a significant change in the plasma SFRP5 level in our study.

In this study, no correlation was observed between the SFRP5 level and the sleep parameters (Sp02, Nadir SpO2and SLT 90%) in OSA patients, even in the patients with severe OSA. Studies had shown that sleep disturbance regulates endocrine and metabolic function by affecting the activity of the hypothalamic-pituitary-adrenal and growth axis;15,16SFRP5 expression was reduced in metabolic dysfunction mouse models; and it were transiently upregulated after 12 weeks of high fat and high sucrose diet in the mice with adipocytes inflammation.7Hu WJ et al found SFRP5 in circulation was regulated by glucose and liraglutide in humans;12in Schulte DM’s trail, SFRP5 concentration also significantly increased after 1 month caloric-limited diet in obese patients.17Accordingly, it is assumed that SFRP5 is regulated by glucose and insulin levels, but not by the hypothalamic-pituitary-adrenal axis.

The data in our study showed that, plasm SFRP5 positively correlated with the triglycerides level, and was negatively associated with LDL-cholesterol and HDL-cholesterol levels. Molecularly, SFRP5 has been shown to bind and antagonize Wnt5a signaling by sequestering Wnt protein in the extracellular space and preventing it from binding to their receptors,18,19and to block Wnt5a-induced JNK1 activation. Canonical Wnt signaling represses adipogenesis and maintains preadipocytes in an undifferentiated state.20We assume that SFRP5 may be involved in the regulation of lipid metabolism, and it is dyslipidemia, instead of sleep apnea, that determines the plasma SFRP5 level in this clinical condition.

However, the relationship between the SFRP5 level and the lipid profile is still controversial. In a trail of general population that included newly diagnosed type 2 diabetic patients with impaired glucose tolerance, SFRP5 was reported negatively correlated with triglycerides, positively correlated with HDL-cholesterol, and not correlated with LDL-cholesterol level.12Thus, the role of SFRP5 in lipid metabolism remains elusive, and more investigation is needed to clarify whether SFRP5 is a linking marker for insulin resistance, obesity and dyslipidemia.

The relationship between SFRP5 and obesity has been controversial as well. In an animal study, SFRP5 expression was reduced in obese leptin-deficient (ob/ob) mice and Zucker diabetic fatty rats.7Clinical studies in adult with impaired glucose tolerance and type 2 diabetes mellitus(T2DM) demonstrated that the plasma SFRP5 level was negatively correlated with BMI, waist-hip rate (WHR) and homeostasis model assessment of insulin resistance(HOMA-IR).12,13Study in obese children with metabolic syndrome also reported the similar result; addi-tionally,SFRP5 increased after weight loss.21However, our study did not find any association between the SFRP5 level and variables of obesity. Our result was in consistency with the observation of Schulte,17whose study found that circulating SFRP5 concentration was not influenced by obesity.The disparities among studies are likely due to the differences in clinical characteristics of the samples of the studies. The BMI of the subjects in our study was in a narrow range; the majority of subjects were overweight rather than obese; besides, the blood glucose measurements in our study were mostly normal.

The study of Rulifson IC et al on obese mice had a promising result,22which showed that over-expression of SFRP5 elevated glucose intolerance, and anti-SFRP5 monoclonal antibody therapy improved glucose tolerance. An inverse association of serum SFRP5 with β-cell function was also observed in human.23These results suggest that SFRP5 is probably a potential target for the treatment of diabetes. However, knowledge on the role of SFRP5 in metabolic disease is still limited. More studies are needed to determine the effect of SFRP5 on obesity-related abnormalities.

There are several limitations in the present study. The sample of the study was small, and we only measured blood glucose, but did not assess insulin and HOMA-IR.There were studies reporting that SFRP5-deficient mice with impaired insulin sensitivity had normal glucose tolerance even on a regular diet, and OSA promoted the onset and progression of diabetes.24,25Since it was based on nondiabetic OSA patients, our study did not demonstrate a correlation between SFRP5 and FBG. Further clinical research with a larger sample that involves patients of sleep apnea, T2DM, and healthy controls is warranted to clarify the relationship between SFRP5 and OSA, and that whether SFPR5, combined with other parameters, could be used in predicting T2DM as a complication of OSA.

In conclusion, plasma SFRP5 of nondiabetic OSA patients did not differ from that of healthy controls. The SFRP5 level was associated with the lipid profile (triglyceride, LDL-cholesterol and HDL-cholesterol levels) in nondiabetic OSA patients; but no association between the SFRP5 level and the sleep parameters was found.

The authors thank Hui Pan and Huijuan Zhu at Department of Endocrinology, Peking Union Medical College Hospital for their guidance in the measurement of SFRP5.

Statement of conflict of interests

The authors have no conflicts of interest to disclose.

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ObjectiveObstructive sleep apnea (OSA) is closely related to obesity, insulin resistance and inflammation. Secreted frizzled-related protein 5 (SFRP5) is a recently discovered adipokine. It is involved in insulin resistance and inflammation in obesity. This study aimed at evaluating the association between SFRP5 and sleeping characteristics as well as biochemical parameters of OSA patients.

MethodsThis was a prospective case control study. Nondiabetic OSA patients and controls were consecutively recruited and divided into three groups: OSA group, apnea–hypopnea Index (AHI)≥5/h; healthy controls with normal body mass index (BMI); obese controls without OSA, and BMI ＞ 24.0 kg/m2. All participants underwent polysomnography (PSG). Plasma SFRP5 was examined using enzyme-linked immunosorbent assay(ELISA). Blood biochemical examinations, including fasting blood glucose (FBG), lipid profile, hypersensitive C-reactive protein (hsCRP), were performed early in the morning after PSG. Patients with severe OSA were treated with nasal continuous positive airway pressure (nCPAP), and plasma SFRP5 was repeatedly measured for comparison.

ResultsSixty-eight subjects were enrolled in the study, including 38 patients of OSA, whose medium AHI was 58.70 /h (36.63, 71.15), 20 obese controls, and 10 healthy controls. The plasma SFRP5 level of OSA patients was not significantly different from that of healthy controls or obese controls. In OSA patients, SFRP5 level correlated positively with triglyceride level (r=0.447,P=0.005) and negatively with LDL-cholesterol level and HDL-cholesterol level (r=?0.472 andP=0.003;r=?0.478 andP=0.002; respectively). SFRP5 level was not found correlating with FBG, AHI, or any of nocturnal hypoxia parameters. After overnight nCPAP treatment, plasma SFRP5 levels of OSA patients did not change significantly (t=1.557, P= 0.148) compared to that of pretreatment.

ConclusionsIn nondiabetic OSA patients, plasma SFRP5 is associated with the lipid profile. However,no correlation was observed between SFRP5 and FBG or sleep parameters. The SFRP5 level of OSA patients did not differ from that of non-OSA individuals in our study.

10.24920/J1001-9294.2017.034

March 7, 2017.

＊Corresponding author Tel: 86-10-69155037; E-mail: huangrong0212@163.com