Sleep Medicine 14 (2013) 1272–1276

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Sleep Medicine journal homepage: www.elsevier.com/locate/sleep

Original Article

Increased plasma level of tumor necrosis factor a in patients with narcolepsy in Taiwan Yun-Hsiang Chen a,1, Yu-Shu Huang b,1, Chia-Hsiang Chen c,⇑ a

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan Department of Child Psychiatry and Sleep Center, Chung Gung Memorial Hospital, Linkou Medical Center, Chang Gung University College of Medicine, Taoyuan, Taiwan c Department of Psychiatry, Chang Gung Memorial Hospital, Linkou Medical Center, Chang Gung University College of Medicine, Taoyuan, Taiwan b

a r t i c l e

i n f o

Article history: Received 6 March 2013 Received in revised form 29 April 2013 Accepted 30 April 2013 Available online 20 September 2013 Keywords: Narcolepsy Tumor necrosis factor a Inflammation Cataplexy Pathogenesis Association

a b s t r a c t Background: Narcolepsy is a neuropsychiatric disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and abnormal rapid eye movement (REM) sleep. Tumor necrosis factor a (TNF a) and its cognate receptors have been reported to be involved in the pathophysiology of narcolepsy in addition to the HLA antigen system. Our study aimed to determine if the TNF-a system was associated with narcolepsy in our patients. Methods: We first measured the plasma level of TNF a in 56 narcoleptic patients and 53 control subjects using a highly sensitive enzyme-linked immunosorbent assay. We next determined the genotype of three single nucleotide polymorphisms (SNPs) (T-1031C, C-863A, and C-857T) at the promoter region of the TNF-a gene and one missense SNP (T587G, M196R) at the exon 6 of the tumor necrosis factor receptor 2 gene, TNFR2, in a sample of 75 narcoleptic patients and 201 control subjects by direct sequencing analysis. Results: We found a significant elevation of plasma level of TNF a in patients with narcolepsy compared with the control subjects (4.64 pg/mL vs 1.06 pg/mL; P = .0013). However, we did not find significant differences between these two groups in the allelic and genotypic distributions of the investigated polymorphisms. Conclusions: Our study suggests that an increased TNF-a level was associated with narcolepsy in our patients, and that chronic inflammation due to various factors might have led to the increased TNF-a levels found in our patients. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Narcolepsy is a chronic disabling sleep disorder that begins in adolescence and young adulthood and persists throughout an individual’s lifetime. It is characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and abnormal rapid eye movement (REM) sleep. The prevalence of narcolepsy with cataplexy varies in different ethnic groups, ranging from 0.002% to 0.18% [1–5]. Recently, an increased incidence of narcolepsy associated with the H1N1 vaccination pandemic was observed in Finland, Denmark, and Sweden [6–8], and an increased narcolepsy onset following the 2009 H1N1 pandemic in China also was noted [9]. Several lines of study indicate that narcolepsy is a complex disorder resulting from interactions between multiple predisposing ⇑ Corresponding author. Address: Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, 5 Fushing St, Kweishan, Taoyuan 33300, Taiwan. Tel.: +886 3 3281200x2439; fax: +886 3 2380267. E-mail address: [email protected] (C.-H. Chen). 1 These authors contributed equally as first author. 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.04.030

genetic factors and environmental factors. It is well-documented that the HLA-DQB1⁄06:02 allele is associated with narcolepsy across different ethnic groups, especially in patients with the presence of cataplexy, indicating the involvement of an HLA-mediated immune response in the pathogenesis of narcolepsy [10,11]. The immunologic aspect of narcolepsy was further supported by the discovery of its genetic association with the T-cell receptor gene [12,13]. Researchers proposed that an aberrant immune response may lead to the loss of the hypocretin neurons in the hypothalamus and the low hypocretin level in the cerebrospinal fluid of narcoleptic patients [14]. Tumor necrosis factor (TNF a) is a proinflammatory cytokine with the primary function of fighting against infectious diseases. Accumulating evidence has shown that TNF a has multiple functions and is involved in many biologic activities and human diseases including sleep disorders [15,16]. TNF a has been shown to act as a neuromodulator to regulate sleep–wake behavior and daytime sleepiness [17–19]. An elevated plasma level of TNF a has been observed in patients with sleep apnea and narcolepsy [20,21], but other studies could not confirm these results [22,23]. One study reported an elevated plasma level of soluble TNF-a

Y.-H. Chen et al. / Sleep Medicine 14 (2013) 1272–1276

receptor p75 in patients with narcolepsy [22], supporting a functional alteration of the TNF-a system in narcolepsy. Furthermore, several studies revealed a genetic association between the TNF-a system and narcolepsy. For example, a single nucleotide polymorphism (SNP) C-857T at the TNF-a gene promoter region, and a missense SNP at exon 6 of the tumor necrosis factor receptor 2 gene, TNFR2 (T587G that changed the amino acid methionine to arginine at codon 196, M196R), were reported to be associated with narcolepsy [24–27]. Nevertheless, other studies did not find this association [28–30]. Our study aimed to assess the role of TNF a in our patients with narcolepsy. To address this issue, we first measured the plasma level of TNF a, then we genotyped three SNPs (T-1031C, C-863A, and C-857T) located at the promoter of the TNF-a gene, and one SNP (T587G, M196R) located at the coding region of the TNFR2 gene in a sample of patients with narcolepsy and control subjects from Taiwan.

2. Methods 2.1. Subjects All studied subjects were Han Chinese residing in Taiwan. A total of 56 subjects diagnosed with narcolepsy (23 women, 33 men; mean age, 18.6 ± 9.0 years, mean disease duration, 9.9 ± 7.5 years) and 53 (27 women, 26 men; mean age, 49.6 ± 10.7 years) control subjects were enrolled for the measurement of plasma TNF-a level. To exclude the effect of medication on the TNF-a level, only drugnaïve patients were enrolled in our study. Narcoleptic patients were diagnosed based on the International Classification of Sleep Disorders, Second Edition, criteria and divided into two groups: narcolepsy with cataplexy (N+C) (n = 44, 18 women and 26 men; mean age, 17.9 ± 9.1 years; disease duration, 10.2 ± 8.3 years) and narcolepsy without cataplexy (NC) (n = 12, five women and seven men; mean age, 21.5 ± 8.6 years; disease duration, 9.0 ± 4.2 years). All the patients underwent a systematic standardized evaluation based on the international recommendations (International Classification of Sleep Disorders, Second Edition) for the diagnosis of narcolepsy. Patients and their parents filled out the following sleep questionnaires (validated in Mandarin Chinese): the Pediatric Daytime Sleepiness Scale, the Epworth Sleepiness Scale if the patient was old enough to drive, and the Stanford Narcolepsy Questionnaire. They also were asked to fill out sleep diaries for a minimum of 14 successive days and to note the indicators, triggers, and duration of each cataplexy attack in association with four visual analog scales (1–100) that observed daytime sleepiness, the presence of hypnagogic or hypnopompic hallucinations, and sleep paralysis. Each patient had to wear an actigraph unit at home for at least 7 days and for a maximum of 14 days and had to undergo nocturnal polysomnography for a minimum of 7 h. The following variables were monitored during the nocturnal polysomnography: electroencephalography (C3/A2, C4/A1, Fz/A1–A2, and O1/A2), right and left electrooculography, chin and legs electromyography, electrocardiography with a modified V2 lead, nasal cannula pressure transducer, mouth thermistor, chest and abdomen inductive plethysmography bands, neck microphone, and the finger oximetry from which oximetry curve and finger plethysmography were extracted and recorded. The following morning, a multiple sleep latency test consisting of 5- to 20-min naps was administered to each patient at 2-h intervals; the mean sleep latency and presence of a sleep-onset REM period were calculated. At the end of the polysomnographic recordings, patients were submitted to challenges reported by family members to trigger cataplectic attacks that were video-monitored. Family members usually were the ones

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to interact with the subjects in the attempt to trigger cataplectic attacks. Subjects receiving routine medical examinations at the Department of Family Medicine of a medical center were recruited as control subjects. The mental status of the control subjects was screened by a senior psychiatrist. Individuals with major psychiatric disorders were excluded. In the genetic association study of the TNF-a promoter and the TNFR2 gene with narcolepsy, the sample size was increased to 75 patients (53 N+C patients and 22 NC patients) and 201 controls. The study was approved by the institutional review board and written informed consent was obtained from each subject after the procedures were fully explained. Peripheral blood was collected from each subject with ethylenediaminetetraacetic acid as an anticoagulant. 2.2. Measurement of TNF a The plasma concentration of TNF a was measured using commercial highly sensitive enzyme-linked immunosorbent assay kits (R&D Systems, Minneapolis, MN, USA.), according to the manufacturer’s instructions. Absorbance was measured using a microtiter plate reader at a wavelength of 490 nm and corrected for optical imperfections in the plate by subtracting values read at 650 nm. The range of the standard curve concentrations was 0.12–32 pg/ mL and the minimum detectable concentration was 0.04 pg/mL. The average intra- and interassay coefficients of variation were 5.3% and 8.4%, respectively. Each assay was performed in duplicate. 2.3. Genotyping Genomic DNA was prepared from peripheral white blood cells using genomic DNA Purification kits (Gentra systems, Minneapolis, Minnesota, USA), according to the directions provided by the manufacturer. An amplicon of 325 bp containing three SNPs at the promoter region of the TNF-a gene was polymerase chain reaction (PCR) amplified using the forward primer (50 -gaggccgccagactgctgcag-30 ) and the reverse primer (50 -ccccagtgtgtggccatatcttcttt-30 ), while an amplicon of 242 bp containing the SNP at exon 6 of the TNFR2 gene was PCR amplified using the forward primer (50 actctcctatcctgcctgct-30 ) and the reverse primer (50 -ttctggagttggctg cgtgt-30 ). Amplification conditions generally were optimized by adjusting annealing temperatures to produce a single amplicon with a desired fragment size in 30 cycles of reactions. Genotypes were determined by sequencing the PCR products using BigDye Terminator V3.1 Cycle Sequencing kits on an ABI 3730 autosequencer (Perkin-Elmer Applied Biosystems, Foster City, CA) according to manufacturer’s instructions. 2.4. Statistical analysis For comparison of group means of the TNF-a level between the subject and control subject groups, the Student t test was used. The v2 test was used to assess the difference in allelic and genotypic frequencies between the two groups. Pearson product moment correlation coefficients were calculated to test associations between plasma TNF-a concentrations and age. A P value of less than .05 was considered as statistically significant. All statistical assessments were performed using GraphPad Prism 5.0 version software. 3. Results 3.1. Plasma TNF-a level The mean plasma TNF-a concentration was significantly elevated in N+C subjects compared with the control group (4.64 pg/

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Table 1 Plasma tumor necrosis factor-a level in subjects with narcolepsy and healthy control subjects.

n TNF a P value

Narcolepsy

N+C

NC

Controls

56 4.64 ± 1.06 .0013a

44 5.32 ± 1.30 .0006a, .2107b

12 2.13 ± 0.30 0.0210a

53 1.06 ± 0.21

Abbreviations: N+C, narcolepsy with cataplexy; NC, narcolepsy without cataplexy; TNF a, tumor necrosis factor-a. n indicates subject numbers. The plasma level of TNF a is presented as picograms per milliliter and data are given as mean ± standard error of the mean. A P value of less than .05 is considered statistically significant. a vs control subjects. b vs narcolepsycataplexy.

Fig. 1. Cumulative percentage of tumor necrosis factor a plasma levels in narcoleptic patients and healthy control subjects.

mL vs 1.06 pg/mL; P = .0013) (Table 1). When the subjects were divided into N+C and NC subject groups, the mean plasma TNF-a levels in both groups was significantly higher (P = .0006 and P = .021, respectively) than in the controls. The narcolepsy subjects were significantly younger than the control subjects (18.6 vs 49.6 y; t = 16.4; df = 107; P < .0001). However, the TNF-a level was not correlated with the age in the narcolepsy (r = 0.15; P = .28) or control (r = 0.13; P = .34) group. The association between plasma TNF-a concentration and narcolepsy was graded as shown in Fig. 1. Narcoleptic subjects whose plasma TNF-a level was beyond that of the 70th percentile of healthy control subjects had an odds ratio of 7.6 (P < .0001; 95% confidence interval, 3.3–18.0), while those whose level was beyond that of the 87th percentile had an increased odds ratio of 12.8 (P < .0001; 95% confidence interval, 4.9–33.7). 3.2. Genetic analysis The allelic and genotypic frequencies of three SNPs (T-1031C, C863A, and C-857T) located at the TNF-a promoter and one missense SNP (T587G, M196R) in 75 patients and 201 control subjects were analyzed (Table 2). The genotype distributions of these SNPs were in Hardy–Weinberg equilibrium (P > .05) for both the subject and control subject groups. There were no significant differences in the allelic and genotypic frequencies of these SNPs between the two groups. When the subjects were divided into two groups based on the presence or absence of cataplexy, neither group showed a significant difference in the allelic and genotypic frequencies of these SNPs compared with the control subjects. Because the combination of the TNF a (857T) and TNFR2-196R alleles was demon-

strated to be significantly associated with narcolepsy in a previous study [25], we further examined this association in our samples. No intergenic interaction of these two SNPs with narcolepsy was noted (Table 3).

4. Discussion In our study, we found that the plasma level of TNF a in drugnaïve subjects with narcolepsy was significantly higher than that in the control subjects, especially in N+C subjects. Our finding is in line with previous studies [20,21], supporting the involvement of elevated TNF a in the pathophysiology of narcolepsy. N+C subjects tended to be have higher plasma TNF-a levels than NC subjects, but the difference did not reach statistical significance (5.32 vs 2.13 pg/mL; P = .21), which might be due to the small sample size in our study. Further investigation with a larger sample size is required to verify our preliminary observation. Various factors, including age, body mass index (BMI), and medication have been noted to influence the circulating TNF-a level [20,31]. We did not consider the effect of medication, as we recruited medication-free subjects in our study. The circulating TNF-a level has been well-documented to be positively correlated with age in various studies [31–34]. However, given that our patients were significantly younger than the controls (18.6 vs 49.6 years), one would expect our subjects to have decreased plasma TNF-a levels. Therefore, it is unlikely that age-related factors are responsible for the elevated TNF-a plasma levels in our subjects. We were not able to obtain blood samples from children and young adolescents as age-matched controls due to ethical consideration and human subject protection, which is a limitation of our study. Because the BMI data of our control subjects were not recorded, we were not able to analyze the correlation of BMI and TNF-a levels. The average BMI in the subject group was 23.7 ± 5.7 kg/m2, and there was no correlation between BMI and TNF-a levels (r = 0.036; P = .83). Thus the increased TNF-a levels in the narcolepsy subjects was not related to their BMI in our study. One possible cause of the elevated TNF-a plasma level in the narcoleptic subjects could be due to the genetic polymorphism at the promoter region. Several SNPs at the promoter region of the TNF-a gene have been reported to be associated with the expression of TNF a [35–40]. In our study, we resequenced an amplicon of 325 bp at the promoter region of the TNF-a gene that contains three SNPs including the SNP C-857T, which has been shown to be associated with TNF-a gene expression and narcolepsy [24,26]. However, we were not able to find a significant association of these three promoter SNPs with narcolepsy in our sample. The results indicated that the elevated plasma levels of TNF a in our subjects were unlikely to be due to the promoter genetic polymorphisms of the TNF a gene. One study reported an elevated plasma level of soluble TNF receptor 2 in narcoleptic patients [22], and the 196R of the TNFR2 gene was found to be associated with narcolepsy in a Japanese population [27]. In our study, we did not detect the genetic association of the 196R of the TNFR2 gene with narcolepsy in our subjects. Furthermore, we could not replicate the finding as reported by Hohjoh et al. [27] that the combination of TNFR2-196R and TNF a (857T) alleles was associated with narcolepsy [27]. This discrepancy may be partly due to our small sample size. A growing body of evidence suggests that the central nervous system (CNS) and the immune system influence each other through a variety of mediators, including cytokines, chemokines, hormones, and neurotransmitters [41–43]. In particular, cytokines were initially thought to be produced solely by immune cells to regulate the immune system; however, it was more recently

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Table 2 Allelic and genotypic frequencies of the polymorphisms in the tumor necrosis factor-a promoter and the tumor necrosis factor receptor 2 gene, TNFR2, in the subject and control subject groups. Locus

Group

n

TNF-a T-1031C Narcolepsy N+C NC Control

75 52 23 198

TNF-a C-863A Narcolepsy N+C NC Control

75 52 23 201

Narcolepsy N+C NC Control

75 53 22 201

Narcolepsy N+C NC Control

75 52 23 200

TNF-a C-857T

TNFR2 T587G

Genotype

P value

TT

TC

CC

54 (72%) 36 (69%) 18 (78%) 130 (66%)

19 (25%) 15 (29%) 4 (17%) 58 (29%)

2 (3%) 1 (2%) 1 (4%) 10 (5%)

CC

CA

AA

56 (75%) 38 (73%) 18 (78%) 139 (69%)

18 (24%) 13 (25%) 5 (22%) 55 (27%)

1 1 0 7

CC

CT

TT

48 (64%) 31 (58%) 17 (77%) 141 (70%)

25 (33%) 20 (38%) 5 (23%) 57 (28%)

2 2 0 3

TT

TG

GG

51 (68%) 37 (71%) 14 (61%) 135 (68%)

23 (31%) 15 (29%) 8 (35%) 61 (31%)

1 0 1 4

(1%) (2%) (0%) (3%)

(3%) (4%) (0%) (1%)

(1%) (0%) (4%) (2%)

.51 .61 .46

.51 .78 .52

.56 .21 .71

.93 .56 .68

Allele

P value

T

C

127 (85%) 87 (84%) 40 (87%) 318 (80%)

23 (15%) 17 (16%) 6 (13%) 78 (20%)

C

A

130 (87%) 89 (86%) 41 (89%) 333 (83%)

20 (13%) 15 (14%) 5 (11%) 69 (17%)

C

T

121 (81%) 82 (77%) 39 (89%) 339 (84%)

29 (19%) 24 (23%) 5 (11%) 63 (16%)

T

G

125 (83%) 89 (86%) 36 (78%) 331 (83%)

25 15 10 69

(17%) (14%) (22%) (17%)

.24 .44 .28

.28 .50 .37

.30 .09 .45

.87 .49 .45

Abbreviations: TNF a, tumor necrosis factor a; N+C, narcolepsy with cataplexy; NC, narcolepsy without cataplexy; n, number of subjects. Table 3 Relationship of tumor necrosis factor a (857T) and tumor necrosis factor receptor 2-196R alleles with susceptibility to narcolepsy. Allele combination

Narcolepsy subjects n = 75

Control subjects n = 198

TNF a (857T) and TNFR2-196Ra

6 (8.0%)

19 (9.6%)

Other combinations

69 (92.0%)

179 (90.4%)

OR (95% CI)

P value

0.82 (0.31–2.14)

.81

Abbreviations: OR, odds ratio; CI, confidence interval; n, number of patients; TNF a, tumor necrosis factor a. a Subjects carrying both TNF a (857T) and TNFR2-196R alleles.

revealed that cytokines and their corresponding receptors also were expressed by and act on most cell types in the CNS [41,43,44]. Several cytokines have been found to be involved in physiologic sleep regulation and synaptic plasticity [45,46]. Regarding the act of sleep regulation, IL-1b and TNF a are the most extensively studied cytokines. In every tested animal species, injection of either IL-1b or TNF a or the induction of endogenous synthesis of these cytokines by microbial substances promoted sleep and enhanced the amount of time spent in non-REM sleep, though inactivation of these cytokines inhibited spontaneous sleep and reduced non-REM sleep [47–50]. Therefore, the elevated TNF-a plasma levels observed in our study and in other studies [20,21] may partially explain the appearance of sudden irresistible sleepiness in patients with narcolepsy. We speculate that there would be several causes of elevated TNF-a plasma levels in narcolepsy patients, as suggested by various studies. These causes would include microbe infection, such as influenza virus infection [9] and streptococcal infection [51], an aberrant immune reaction due to vaccination [6–8], an autoimmune response [52], and other unidentified factors. In light of the fact that cytokines can be produced in several brain sites [53,54], it should be noted that peripheral cytokine levels may not precisely reflect the immune status in the CNS; and thus, exploring the TNF-a level in the cerebrospinal fluid may improve our understanding of the immune-related pathogenesis of narcolepsy.

5. Conclusion We observed an elevated TNF-a plasma level in narcoleptic patients compared with healthy control subjects, suggesting that the

functional abnormality of the TNF-a cytokine system may be involved in the development of narcolepsy. However, a genetic association with narcolepsy was not detected in our population for the previously reported polymorphisms in the TNFR2 gene and the promoter region of the TNF-a gene. The underlying mechanism of the increased expression of TNF a in patients with narcolepsy is still not clear. It will be interesting to determine if the TNF-a elevation in patients contributes to the development of narcolepsy or if it merely is an outcome of the disease, which will require further investigation to gain a clear understanding. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.04.030.

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Increased plasma level of tumor necrosis factor α in patients with narcolepsy in Taiwan.

Narcolepsy is a neuropsychiatric disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and abnormal rapid eye ...
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