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The early prediction of atherosclerosis (AS) is important in the management of obstructive sleep apnea patients (OSA). MicroRNA (miRNA) plays a vital role in the evolution of OSA and AS. Its differential expression may therefore serve as a diagnostic and prognostic biomarker of AS in OSA. The aim of this study was to identify specific serum miRNAs that could serve as a novel screening signature of AS in OSA patients. The specificity and sensitivity of these miRNAs in the early diagnosis of AS in OSA patients were then determined. The 128 participants in this study underwent maximum carotid intima-media thickness (CIMT) measurements and polysomnography and were divided into 4 groups: 27 healthy volunteers with normal max-CIMT, 31 healthy volunteers with increased max-CIMT, 35 OSA patients with normal max-CIMT, and 35 OSA patients with iCIMT. MiRNA was extracted from the 12 participants’ serum (3 participants each groups) and used to establish miRNA libraries for deep sequencing. A total of 116 participants were quantified by qRT- PCR. Correlations between differential expression of miRNAs and CIMT were assessed using the Spearman correlation coefficient. Our study was approved by the Ethics Committee of our hospital and was conducted in line with the Helsinki Declaration. MiR-664a-3p expression was quantified by qRT-PCR. Correlations between miR-664a-3p expression and CIMT were assessed using the Spearman correlation coefficient. The results showed that the miR-664a-3p was downregulated in the OSA, OSA with iCMIT, and nCIMT groups compared with the control group. The demonstrated potential of circulating miR-664a-3p as a noninvasive marker of AS in essential OSA patients should be confirmed in further studies. Abbreviations: AHI = Apnea Hyponea Index, AS = atherosclerosis, CIH = chronic intermittent hypoxia, HIF-1b = hypoxia- inducible factor-1b, iCIMT = increased max-CIMT, LOS = lowest oxygen saturation, miRNA = MicroRNA, OSA = obstructive sleep apnea, PSG = polysomnography, SD = standard deviation. Keywords: atherosclerosis, microRNA, miR-664a-3p, obstructive sleep apnea characteristics of the disease, which include systemic inflammation, 1. Introduction [7,8] oxidative stress, and vascular endothelial dysfunction. All of [1] Obstructive sleep apnea (OSA) is a common chronic sleep disorder these features have also been identified in the pathogenesis and whose pathogenesis and complications have been extensively pathophysiology of atherosclerosis (AS). Consequently, OSA may investigated. It is characterized by recurrent episodes of complete [9,10] be an independent risk factor for AS. AS is not only a lipid or partial airway obstruction, which can lead to apnea or hypopnea. deposition disease but is also associated with broader disorders of OSA is associated with several serious diseases, including [11,12] lipid metabolism. In patients with OSA, the incidence of cardiovascular disease, hypertension, diabetes, and metabolic cardiovascular events increases significantly with increasing OSA [2–6] syndrome. These have been attributed to the additional [13] severity and progression. Thus, OSA seems to play an important role in the development and progression of AS. MicroRNA (miRNA) regulates inflammation, oxidative stress, Editor: Giuseppe Insalaco. hypoxia, and lipid metabolic disorders. In a mouse model of This work was supported by The Public Development and Reform Pilot Project of intermittent hypoxia, chronic intermittent hypopnea was shown to Beijing Municipal medical research Institute [grant numbers: 2016-4], Beijing [14] Municipal Administration of Hospitals Clinical Medicine Development of Special alter miRNA expression and the endothelium. Thus, miRNA Funding Support [grant numbers: ZYLX201605], and National Natural Science may play an important role in the development of OSA and AS. Its Fundation of China [grant numbers: 81470567]. differential expression in OSA may therefore be a useful biomarker The authors have no conflicts of interest to disclose. to diagnose the risk of AS in OSA patients. The present study Department of Otolaryngology, Beijing AnZhen Hospital, Capital Medical investigated the differential expression of miRNA in OSA as a University, Beijing, China. biomarker of AS development. It also presents a novel view of the Correspondence: Yongxiang Wei, Beijing AnZhen Hospital, No. 2 Anzhen Road, mechanism underlying the association of AS and OSA. Beijing 100029, China (e-mail: anzhenent@163.com). Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. 2. Materials and methods This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial 2.1. Study participants and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. All participants were from Beijing AnZhen Hospital, affiliated with Capital Medical University. The 116 participants assessed in the Medicine (2018) 97:6(e9813) study included 24 healthy controls with normal maximum carotid Received: 30 October 2017 / Received in final form: 2 January 2018 / Accepted: 17 January 2018 intima-media thickness (CIMT) (Con), 28 participants with an increased max-CIMT (iCIMT), 32 patients with OSA (OSA), and http://dx.doi.org/10.1097/MD.0000000000009813 1 Li et al. Medicine (2018) 97:6 Medicine 2.5. Statistical analysis 32 with OSA and an increased max-CIMT (OSA with iCIMT). Polysomnography (PSG) was used to measure the severity of OSA Continuous variables were expressed as the mean and standard and hypoxemia. OSA is diagnosed based on the Apnea Hyponea deviation (SD). Categorical variables were expressed as a Index (AHI) index, with OSA defined as >5events/h. The number. The Mann–Whitney U test was used to compare standard is further subdivided into mild (5<AHI 15events/h), differences in serum miRNA expression, determined from the moderate (15<AHI 30events/h), and severe (AHI> 30events/ scatter plots of the log-transformed relative expression levels. h). The diagnostic standard for hypoxemia is based on the lowest Hierarchical cluster analysis (average linkage) was performed oxygen saturation (LOS), which is further subdivided into mild using Cluster software and Treeview. The associations between (0.85 LOS < 0.9), moderate (0.65 LOS < 0.85), and severe miR-664a-3p expression levels and AHI, LOS, and CIMT were (LOS < 0.65). CIMT was measured in all participants using analyzed using the Spearman correlation analysis. All statistical diagnostic Color Doppler ultrasound (Toshiba Aplio 500 analyses were performed using STATA 9.2, and visualized with ultrasound scanner). CIMT was defined as the distance between GraphPad Prism 5.0 software. A P value <.05 was considered to the blood-intimae and media-adventitia interfaces of the arterial indicate statistical significance. wall. The study protocol and criteria were based on current sonographic guidelines. A max-CIMT < 0.9mm was defined as 3. Results normal, a max-CIMT > 0.9mm as intimal thickening, and a [15,16] max-CIMT > 1.3mm as an atherosclerotic plaque. 3.1. Study participants Participants with a history of malignant tumor, ischemic heart The 116 participants in this study included 24 healthy controls disease, hypertension, diabetes mellitus, or chronic renal diseases (Con), 28 patients with an increased maximum carotid intima- were excluded. Our study was approved by the Ethics Committee media thickness (iCIMT), 32 with OSA (OSA), and 32 with OSA of our hospital and was conducted in line with the Helsinki and iCIMT. In all study participants, the carotid artery was Declaration. evaluated ultrasonographically and PSG was performed. The baseline data of the study participants are presented in Table 1. 2.2. MicroRNA expression profiles From the results of Table 1, we could learn that the level of blood Total RNA was extracted from the 12 participants’ serum and lipids in OSA group is significantly more than that in patients of used to establish miRNA libraries for deep sequencing Con group, especially in the level of TC and TG. However, the according to the manufacturer’s protocol. After adapters were level of HDL-c expression in OSA patients is not significantly ligated to the RNA, cDNAs were generated using SuperScript II different from that in patients of Con group. The expression level reverse transcriptase (Life Technologies). PCR amplification of Hcy was not significant in the OSA patients compared with the was followed by sequencing using the Illumina HiSeq 3000 patients of Con group. The expression level of CRP is significant (Illumina) platform. Clean reads acquired after trimming were in OSA patients. Therefore, OSA might cause disorders of blood used for mapping and further analysis. MicroRNA expression lipid levels and the inflammatory response of the body. values were determined for the differential expression analysis using the edgeR tool from Bioconductor. The screening criteria 3.2. Identification of differentially expressed microRNAs used to identify differentially expressed microRNAs were as and hierarchical clustering analysis follows: normalization reads > 50, absolute value of the fold- change > 2, and a P <.05. The P value was then adjusted using Differentially expressed microRNAs were identified after pre- the Benjamini–Hochberg method to generate the false discovery processing of the sequencing results and an evaluation of the rate (FDR). microRNA expression profiles (FDR <0.05 and jlog2FCj ≥1). Hierarchical clustering analysis was used to illustrate the differential expression of microRNAs between the 4 groups 2.3. Hierarchical clustering analysis of differentially (Fig. 1). A comparison of the OSA and control groups revealed expressed microRNAs To determine the sample specificity of differentially expressed Table 1 microRNAs, supervised hierarchical clustering was conducted Characteristics of the study participants. based on the Euclidean distance of microRNAs in samples using Con (n= 24) OSA (n= 32) OSA+ iCIMT (n= 32) iCIMT (n= 28) the Pheatmap package. Gender (M/F) 11/13 27/3 26/4 17/7 ∗ ∗ ,† ,† Age, y 43.17± 14.83 42.07± 9.84 50.28± 11.83 53.54± 14.16 BMI, kg/m 22.33± 3.49 24.10± 4.46 26.82± 2.95 24.50± 3.27 2.4. RT-qPCR assay SBP, mm Hg 114.13± 15.41 126.44± 9.96 125.65± 11.89 121.75± 10.57 DBP, mm Hg 72.25± 9.62 80.00± 7.23 80.24± 8.16 77.4± 10.58 A total of 116 participants (24 Con, 28 iCIMT, 32 OSA, 32 OSA ∗ ∗ ∗ † ,† ,† TC, mmol/L 4.26± 0.88 4.57± 0.67 5.21± 1.22 5.0± 1.12 ∗ ∗ ∗ +iCIMT) were quantified by qRT-PCR. From each fasting † ,† ,† TG, mmol/L 1.11± 0.73 1.62± 0.67 1.84± 1.03 1.94± 1.92 † ,† participant, 2 mL of whole blood was collected in anticoagulant HDL-c, mmol/L 1.26± 0.33 1.3± 1.13 1.17± 0.25 1.94± 1.92 ∗ ∗ ∗ † ,† ,† LDL-c, mmol/L 2.56± 0.81 2.89± 0.58 3.32± 1.00 1.19± 0.32 tubes. Total RNA was extracted using Trizol as previously ∗ ∗ ∗ † ,† AHI, n/h 2.58± 1.36 47.44± 24.64 48.41± 28.44 2.59± 1.30 ∗ ∗ ∗ † ,† described. The miRNAs were reverse-transcribed with the LSL, % 87.93± 16.95 75.20± 12.17 73.14± 13.30 91.92± 1.91 ∗ ∗ ,† ,† Max-IMT, mm 0.88± 0.05 0.86± 0.07 1.27± 0.15 1.24± 0.14 TaqMan microRNA reverse transcription kit (Invitrogen, CA) ,† Hcy, mmol/L 11.81± 4.62 11.66± 9.19 13.64± 12.29 11.71± 5.32 ∗ ∗ according to the manufacturer’s instructions. The miRNA-specifc † ,† † CRP, mmol/L 2.50± 1.16 3.93± 4.60 6.00± 10.58 2.99± 4.07 TaqMan microRNA assay (Invitrogen) was used to measure Continuous and categorical variables are expressed as the mean± SEM or the number of participants, serum miRNA expression. The data were processed using the 2 respectively. DDCT method as previously described. For the analysis of miRNA DBP = diastolic blood pressure; SBP = systolic blood pressure. expression levels, both an internal reference (U6) and an external Different from Con (P< .05). normalization using cel-miR-39 were applied. Different from OSA group (P< .05). 2 Li et al. Medicine (2018) 97:6 www.md-journal.com Figure 1. Hierarchical clustering analysis of differentially expressed microRNAs (miRNAs). High-level miRNA expression is shown in red, and low-level miRNA expression in blue. Con = healthy individuals, iCIMT = healthy individuals with an increased maximum carotid intima-media thickness, OSA = obstructive sleep apnea sample. 104 differentially expressed miRNAs (OSA/Con) potentially +iCIMT and Con (OSA+iCIMT /Con) groups, 100 differentially related to OSA. In a comparison of the iCIMT and Con (iCIMT/ expressed miRNAs potentially related to OSA or AS. The Con) groups, 54 differentially expressed miRNAs potentially intersection graph showed the miRNAs that might serve as related to AS were identified, and in a comparison of the OSA screening signature of AS in OSA patients (Fig. 2). 3 Li et al. Medicine (2018) 97:6 Medicine (r=0.318, P<.01), max-CIMT (r=0.235, P<.05; Table 2). In addition, the AHI correlated positively with LOS (r= 0.865, P<.01), and the total cholesterol (TC) level with OSA and AS: AHI (r=0.204, P<.05), LOS (r= 0.236, P<.05), and max- CIMT (r=0.250, P<.01). The TG level correlated significantly with OSA, AHI (r=0.345, P<.01), and LOS (r= 0.312, P<.01; Table 2). 4. Discussion This study investigated the well-established close association of OSA with AS, by examining the differences in candidate miRNA expression. After identifying miR-664a-3p as a candidate biomarker of AS in OSA, we showed its expression was significantly higher in patients in the OSA, iCIMT, and OSA with iCIMT groups than in healthy controls (Fig. 1). We further demonstrated that miR-664a-3p expression is associated with AHI, LOS, and max-CIMT (Table 2). AS is one of the most important and serious complications of Figure 2. Intersection graph shows candidate screening signature miRNAs of OSA. In OSA and non-OSA patients, it can lead to coronary atherosclerosis in patients with obstructive sleep apnea (OSA). heart disease, stroke, and peripheral vascular disease. These serious complications are not only life-threatening, they also impose large familial, societal, and economic burdens. The early ability to predict the risk of AS in OSA patients would 3.3. Significant differential expression of miRNAs avoid many of the serious complications of this disease. The candidate miRNAs were further examined by RT-qPCR in a Echocardiography is used in the clinical and differential training sample and a validation set (24 Con, 28 iCIMT, 32 OSA, diagnosis of AS, and PSG to measure the severity of OSA and 32 OSA with iCIMT). As shown in Figure 2, 3 miRNAs, and related hypoxemia. Additional tools are a determination of miR-664a-3p, miR-365a-3p, and miR-1269a, downregulated in CIMT, to assess the severity of AS, and measurements of AHI the serum samples of Cont versus OSA, iCIMT, and OSA+iCIMT and LOS to evaluate the severity of OSA. We identified a groups were identified. Of these, only the expression of miR- significant correlation between serum mir-664a-3p expression 664a-3p was consistent with the results of earlier experiments and AHI (r= 0.314, P<0.01), LOS (r=0.318, P<0.01), and (Fig. 3). The other 2 miRNAs were ruled out based on the max-CIMT (r= 0.235, P<.05) (Table 2). In addition, AHI inconsistent results with previous experiments (miR-365a-3p) or correlated positively with LOS (r= 0.865, P<.01). The TC their low-level expression (miR-1269a). level correlated significantly with OSA and AS, based on the AHI (r=0.204, P<.05), LOS (r= 0.236, P<.05), and max- 3.4. Association of miR-664a-3p expression levels with the CIMT (r=0.250, P<.01), and the TG level with OSA, based AHI, LOS, and CIMT on the AHI (r=0.345, P<.01) and LOS (r= 0.312, P<.01). Consistent with previous studies, our results suggest that OSA Our study showed that the expression level of miR-664a-3p influences lipid metabolism. correlated significantly with AHI (r= 0.314, P<.01), LOS Figure 3. The relative expression levels of miRNAs in 4 groups. Serum miRNA expression: log2 (miRNA/miR-39). The horizontal lines indicate the mean. P values were generated in a Mann–Whitney U test; P<.05 was considered to indicate statistical significance. 4 Li et al. Medicine (2018) 97:6 www.md-journal.com Table 2 Correlations between circulating microRNAs critical to atherosclerosis and clinical parameters. Correlations AHI LSL MaxIMT miR664a3p Spearman’s rho † † AHI correlation coefficient 1.000 .865 0.154 0.314 Sig. (2-tailed) 0.000 0.099 0.001 † † LSL correlation coefficient 0.865 1.000 0.107 0.318 Sig. (2-tailed) 0.000 0.254 0.001 MaxIMT correlation coefficient 0.154 0.107 1.000 0.235 Sig. (2-tailed) 0.099 0.254 0.011 ∗ ∗ TC correlation coefficient 0.204 0.236 0.250 0.057 Sig. (2-tailed) 0.028 0.011 0.007 0.546 † † TG correlation coefficient 0.354 0.312 0.130 0.076 Sig. (2-tailed) 0.000 0.001 0.163 0.419 HDLc correlation coefficient 0.169 0.152 0.105 0.006 Sig. (2-tailed) 0.070 0.103 0.260 0.953 † † LDLc correlation coefficient 0.313 0.342 0.128 0.081 Sig. (2-tailed) 0.001 0.000 0.169 0.389 CRP correlation coefficient 0.092 0.082 0.081 0.012 Sig. (2-tailed) 0.327 0.381 0.390 0.899 † † HCY correlation coefficient 0.282 0.240 0.125 0.026 Sig. (2-tailed) 0.002 0.010 0.182 0.784 † † miR664a3p correlation coefficient 0.314 0.318 0.235 1.000 Sig. (2-tailed) 0.001 0.001 0.011 NA= not applicable, P= sig. (2-tailed), R= correlation coefficient. Correlation is significant at the .05 level (2-tailed). Correlation is significant at the .01 level (2-tailed). Human plasma or serum may contain specific miRNAs that needed to explore the functions of miR-664a-3p in OSA patients can serve as biomarkers of disease, and therefore an early and its relation to AS. warning of, for example, cardiovascular disease or target organ [17–24] damage. Our study demonstrated that patients in the OSA 5. Conclusions and OSA with iCIMT groups had significantly higher levels of miR-664a-3p expression than healthy controls. This result In summary, our study demonstrated the positive association of suggested the utility of miR-664a-3p as a marker of AS in miR-664a-3p levels with AHI, LOS, and CIMT and thus its OSA patients. In fact, both the role and mechanism of miR-664 in possible role in the pathogenesis of AS in OSA patients and as a [25–28] disease have been investigated in several studies. noninvasive marker of these related conditions. 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Medicine – Wolters Kluwer Health
Published: Feb 1, 2018
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