Download Preprohypocretin Polymorphisms in Parkinson Disease

Preprohypocretin Polymorphisms in Parkinson Disease Patients Reporting “Sleep
Attacks”
Ida Rissling, MD1; Yvonne Körner, MSc3; Frank Geller, MSc3; Karin Stiasny-Kolster, MD1; Wolfgang H. Oertel, MD1; J. Carsten Möller, MD1
1
Department of Neurology and 2Institute of Medical Biometry and Epidemiology, Philipps-University Marburg, Germany; 3Center for Traffic Sciences,
Department of Psychology, Julius-Maximilians-University Würzburg, Germany
ease patients with sudden onset of sleep. Statistical analysis showed that
there were significant differences in the genotype (P = .024) and allele
(P = .018) distribution between both groups. For heterozygous and homozygous carriers of allele T, the genotype relative-risk estimates for the
presence of sudden onset of sleep were 2.01 (95% confidence interval:
0.76-5.34) and 2.81 (95% confidence interval: 1.09-7.25), respectively.
Conclusions: Our results show a significant association between the (909T/C) preprohypocretin polymorphism and sudden onset of sleep in
Parkinson disease. However, we could not demonstrate any interaction
between the Taq IA and (-909T/C) polymorphisms with respect to the occurrence of sudden onset of sleep, suggesting that multiple genetic factors may contribute to the pathogenesis of this phenomenon.
Keywords: Dopamine receptor, polymorphism, sudden onset of sleep,
Parkinson disease, narcolepsy, preprohypocretin, hypocretin (HCRT),
orexin
Citation: Rissling I; Körner Y; Geller F et al. Preprohypocretin polymorphisms in parkinson disease patients reporting “sleep attacks”. SLEEP
2005;28(7): 871-875.
Study Objectives: Previously, we found a significant association between
the dopamine D2 receptor gene polymorphism Taq IA and sudden onset of
sleep in patients with Parkinson disease. Here we evaluated the association between the preprohypocretin (-909T/C), (-22C/T), and (-20C/A) polymorphisms and sudden onset of sleep in the same population of patients
with Parkinson disease.
Design: We conducted an association study analyzing the distribution of
preprohypocretin polymorphisms in Germanic, caucasian Parkinson disease patients with and without sudden onset of sleep, matched according
to drug therapy, disease duration, sex, and age.
Setting: Movement disorders section at a university hospital.
Participants: 132 Parkinson disease patients with sudden onset of sleep
and 132 Parkinson disease patients without sudden onset of sleep.
Interventions: Blood samples were taken from each participant and used
for DNA extraction. Polymorphisms were analyzed by established polymerase chain reaction protocols or direct sequencing.
Measurements and Results: The variant allele T of the (-909T/C) preprohypocretin polymorphism was more commonly found in Parkinson dis-
study investigating the distribution of previously identified polymorphisms in the family of dopamine D2-receptor genes (DRD2,
DRD3, DRD4) in PD patients with and without sudden onset of
sleep, daytime sleepiness, or both sudden onset of sleep and daytime sleepiness. We could show a significant association between
the DRD2 receptor gene polymorphism Taq IA and SOS in PD.1
Narcolepsy is characterized by excessive daytime sleepiness,
cataplexy, hypnagogic hallucinations, and sleep paralysis and
usually begins during adolescence.9 Hypocretins play a major
role in the pathophysiology of narcolepsy.10 Human narcolepsy
is probably caused by deficient hypocretin neurotransmission in
the lateral hypothalamus.11 Animal models have shown narcolepsy syndromes to be caused by mutations in the hypocretinergic
system.12 In humans, hypocretin-1 is almost undetectable in the
cerebrospinal fluid (CSF),10 and the pathogenesis of narcolepsy
appears to be multifactorial and triggered by genetic and environmental factors. Neuropathologic studies have demonstrated an
almost complete loss of hypocretin mRNA and peptides in human
narcoleptic brains.13 A possible link between the dopaminergic
and hypocretinergic system with respect to sleep-wake regulation
has been suggested by the recent observations that the catecholO-methyltransferase (COMT) genotype is significantly associated
with daytime sleepiness in patients with PD and narcolepsy.14,15
We therefore hypothesized that the hypocretin system may also be
involved in the pathogenesis of SOS in PD and investigated the
distribution of the previously described preprohypocretin (-909T/
C), (-22C/T), and (-20C/A) polymorphisms16,17 in PD patients with
and without SOS. Hypocretin-1 and hypocretin-2 are neuropeptides processed from a common precursor, preprohypocretin.10
INTRODUCTION
SLEEP DISORDERS AND DAYTIME SLEEPINESS ARE
FREQUENT FINDINGS IN PATIENTS WITH PARKINSON
DISEASE (PD).2-6 THE UNDERLYING CAUSES ARE STILL
controversial. In 1999, “sleep attacks” (termed sudden onset of
sleep [SOS] in this paper) were described in PD patients taking
the nonergoline dopamine-receptor agonists pramipexole and ropinirole.7 SOS is defined by abrupt episodes of unplanned sleep
during activities of daily living in which they are not expected
to occur (eg, speaking, eating, drinking, standing, cooking, and
driving). Since nonergoline dopamine-receptor agonists have a
negligible affinity to the dopamine D1-receptor family (ie, DRD1
and DRD5), we hypothesized that SOS may be associated with
an alteration of dopaminergic transmission involving a member
of the dopamine D2-receptor family.8 Therefore, we performed a
Disclosure Statement
This was not an industry supported study. Dr. Oertel has received research
support from Pfizer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Orion,
and Schwarz Pharma AG. Dr. Geller is an employee for Decode Genetics.
Dr. Stiasny-Kolster is a member of the Advisory Board for Restless Legs
Syndrome, GlaxoSmithKline Germany. Drs. Rissling, Möller, and Körner
have indicated no financial conflicts of interest.
Submitted for publication November 2004
Accepted for publication February 2005
Address correspondence to: Dr. J. C. Möller, Department of Neurology,
Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany, Tel: 49 6421 2865200; Fax: 49 6421 2867055; E-mail: moellerc@staff.
uni-marburg.de
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Sleep Attacks—Rissling et al
PATIENTS AND METHODS
Table 1—Characteristics of Patients With Parkinson Disease
Patients
Total Probands, no.
In 2000, a questionnaire on SOS in PD was sent to 12,000 members of the German Parkinson Association (Deutsche ParkinsonVereinigung), the national patient support group.18 The methods
and results of this survey have been presented elsewhere.18 We
used the data from this survey to collect blood samples from PD
patients with (group A) and without (group B) SOS, matched according to drug therapy, disease duration, sex, and age.1 Patients
were defined as having SOS if they reported unexpected SOS at
least 2 to 4 times per month and a subjectively abrupt transition
from wakefulness to sleep. With the data set that we used, it was
possible to obtain a near-to-perfect matching concerning the criteria type and dosage of dopamine-receptor agonist and levodopa
dosage. The patients were recruited by a semistructured telephone
interview in which the diagnosis of PD was reviewed by questions concerning the disease symptoms and levodopa responsiveness. Subsequently, the patients’ general practitioner collected the
blood samples and sent them to our laboratory. Previously, we investigated the allele and genotype frequencies of several polymorphisms in the DRD2, DRD3, and DRD4 genes in this population.1
Now 264 (n = 132 in each group) of these PD patients receiving a
combination therapy with levodopa, dopamine-receptor agonist,
and other antiparkinsonian drugs were analyzed with respect to
the role of the hypocretin system in the pathogenesis of SOS. All
patients were of Germanic, caucasian origin. The study was performed in accordance with the Declaration of Helsinki and was
approved by the local ethics committee. Written informed consent
was given by all participants.
Patients with sudden onset of sleep, no. (%)
Men (%)
Women (%)
Mean age, y (SD)
Mean self-rated disease severity (SD)
Mean duration of disease, y (SD)
132 (50)
86 (65.2)
46 (34.8)
67 (9.5)
2.9 (0.8)
10.5 (6.1)
Controls without sudden onset of sleep), no. (%)
Men (%)
Women (%)
Mean age, y (SD)
Mean self-rated disease severity (SD)
Mean duration of disease, y (SD)
132 (50)
82 (62.1)
50 (37.9)
64.5 (8.3)
2.3 (1.0)
8.7 (5.2)
Table 2—Distribution of the -909t/C Alleles and Genotypes in Subjects
With (Patients) and Without (Controls) Sudden Onset of Sleep.
Genotype
Patients (n=132)
Controls (n=132)
Patients (n = 132)
Controls (n = 132)
T/T
T/C
C/C
81(61.36%) 44(33.33%) 7(5.30%) P = .0235*
66(50.00%) 50(37.88%) 16(12.12%)
Allele
T
206(78%)
182(69%)
C
58(22%)
82(31%)
P = .0180†
Allele T: 187 and 108 bp; allele C: 295 bp
*Cochran-Armitage Trend test
† Pearson χ²-test
Genotyping
Genomic DNA was isolated from venous blood samples and
subjected to polymerase chain reactions followed by restriction
enzyme digestion using standard laboratory protocols.19,20 The allele frequency and genotypic distribution of the (–909T/C), the (22C/T), and the (-20C/A) polymorphisms in the preprohypocretin
gene were determined as described elsewhere.17
vs 4.4 mg), bromocriptine (12.9 mg vs 12.8 mg), pergolide (2.24
mg vs 2.30 mg), α-dihydroergocryptine (41.5 mg vs 40.0 mg),
cabergoline (4.63 mg vs 4.44 mg), and lisuride (0.70 mg vs 0.77
mg) were almost identical. Further antiparkinsonian medications
included anticholinergic agents (group A: 50 cases; group B: 58
cases), N-methyl-D-asparate inhibitors (group A: 47 cases; group
B: 49 cases), COMT-inhibitors (group A: 20 cases; group B: 17
cases), and others (group A: 39 cases; group B: 27 cases).
The genotype distribution in patients with SOS and controls
did not differ from Hardy-Weinberg equilibrium. Table 2 shows
the distribution of the (-909T/C) preprohypocretin polymorphism
alleles and genotypes in the 2 groups. The variant allele T of the
(-909T/C) polymorphism was more commonly found in PD patients with SOS as compared with PD patients without SOS. Statistical analysis showed that there were significant differences in
the genotype (P = .024) and allele (P = .018) distribution between
PD patients with SOS and the control group. For heterozygous
and homozygous carriers of allele T, the genotype relative-risk
estimates for the presence of SOS were 2.01 (95% confidence
interval [CI]: 0.76-5.34) and 2.81 (95% CI: 1.09-7.25), respectively. The positive predictive value of allele T carriers was 0.52
(95% CI: 0.45-0.58), and the respective negative predictive value
was 0.70 (95% CI: 0.47-0.87).
We also performed direct sequencing analysis of the hypocretin promoter/exon-1 region in 264 PD patients. In the present
study, we did not find the (-22C/T) polymorphism in any PD pa-
Statistical Analysis
First we tested whether our populations were in Hardy-Weinberg equilibrium. Comparison of genotype and allele frequencies
between the groups was subsequently carried out using CochranArmitage trend tests and Pearson χ² tests, respectively. A P value
of .05 was considered significant. Furthermore, genotype relative
risks and predictive values were estimated for the (-909T/C) polymorphism. Besides, we descriptively compared the expected and
observed genotype frequencies of the Taq IA polymorphism in
the DRD2 gene and the (-909 T/C) polymorphism in the preprohypocretin gene. The statistical analyses were performed using
the programs SAS (SAS Institute, Cary, NC) and SPSS 11 (SPSS,
Inc., Chicago, Ill).
RESULTS
Table 1 shows descriptive statistics of both groups. Ninety-four
percent of all patients were treated with levodopa. The average
daily dosages for levodopa (362.0 mg [group A] versus 371.5 mg
[group B]), pramipexole (1.14 mg vs 1.12 mg), ropinirole (4.0 mg
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Sleep Attacks—Rissling et al
tient with SOS, but we did find it in 1 patient without SOS. Furthermore, we did not identify any patient featuring the (-20C/A)
variant in our population.
Table 3 shows the comparison between the expected and observed genotype frequencies of the Taq IA polymorphism in
the DRD2 gene and the (-909T/C) polymorphism in the preprohypocretin gene. Using descriptive statistics, the expected and
observed genotype combination frequencies of these 2 polymorphisms were quite similar.
Table 3—Comparison Between Expected and Observed DRD2 Taq
IA 1 and Preprohypocretin (-909T/C) Genotype Frequencies in Subjects With (Patients) and Without (Controls) Sudden Onset of Sleep
Patients (n = 132)
Genotypes
Taq IA
A2/A2
A1/A2
DISCUSSION
A1/A1
Hypocretin and PD
The current study shows that there is a statistically significant
association between the (-909T/C) preprohypocretin variant allele
T and PD patients with SOS. The (-909T/C) polymorphism is a
common C-to-T variant located within an Alu repeat region approximately 3 kb upstream of the start codon.17
The hypocretin-signaling system is important in the regulation
of the sleep-wake cycle and is disturbed in narcolepsy.10 Narcoleptic patients suffer from symptoms such as excessive daytime
sleepiness and shortened latency of sleep. The role of hypocretin
in PD, however, remains controversial. Compared to narcolepsy,
PD has been suggested to be associated with normal CSF levels of hypocretin.21 Furthermore 3 patients with early-stage PD,
who reported excessive daytime sleepiness during dopamine-receptor agonist treatment, had normal hypocretin-1 values in the
CSF.22 In another study, hypocretin-1 concentrations in ventricular CSF in 19 parkinsonian patients were measured and compared
with those of neurologic controls, such as patients with essential
tremor and severe dyskinesia secondary to a midbrain stroke or
multiple sclerosis.23 In patients with PD, hypocretin levels were
negatively correlated with disease severity, as measured by the
Unified Parkinson Disease Rating Scale in an off-treatment period. Hypothalamic cellular loss is usual in PD, with the lateral and
posterior nuclei being the main targets of degenerative process in
this area.24 Accordingly, hypocretin levels in the CSF may reflect
the size of the hypocretin neuron pool,25 and a decrease in hypocretin levels may indicate degeneration of hypocretin neurons
in PD. The greater decrease in HCRT levels in the CSF with increasing disease severity suggests progressive hypocretin neuron
degeneration. The authors of this study proposed that hypocretin
deficiency may occur mainly at the advanced stage of PD, as suggested by the negative correlation between hypocretin levels and
motor disability.23
T/C
27.0
29
15.7
13
1.3
2
C/C
4.3
3
2.5
3
0.2
1
T/T
27.5
27
31.5
32
7
7
T/C
20.8
19
23.9
25
5.3
6
C/C
6.7
9
7.6
6
1.7
1
not associated with human narcolepsy using randomly selected
narcolepsy patients, most of whom were HLA-DQB1*0602 associated and without a family history. Gencik et al16 identified a
(-22C/T) polymorphism in exon-1 of the hypocretin gene in 6 of
178 narcolepsy patients versus 1 of 189 controls and postulated a
significant association. This finding was not confirmed by Hungs
et al.17 Another study examined the same sequence in 72 narcoleptic subjects versus 24 control subjects. In this study, a singlebase-pair change at position -20 (C to A) was observed in a single
patient without HLA-DQB1*0602.13 This polymorphism was observed in a few unaffected Caucasian control subjects, supporting
its likely benign nature.17 The effect of these polymorphisms on
the phenotype, eg, the degree of daytime sleepiness in narcolepsy
patients, has not yet been addressed.
Dopamine, Hypocretin, and Daytime Sleepiness
The DRD2 gene is located on chromosome 11q22-q23. Most
studies of the Taq IA polymorphism are related to alcohol and
other substance abuse.27-29 Wieczorek et al30 screened gene regions for association with narcolepsy by a microsatellite-based
approach, describing their finding that the most frequent allele
5 of the DRD2 microsatellite was significantly increased in the
patient group. Animal and postmortem studies in humans have
shown that the dopaminergic system is disturbed in narcolepsy,
with special emphasis on the cataplectic aspect of the disorder.31
Recently, Eisensehr et al32 reported that the D2-receptor binding
was elevated in narcolepsy and correlated positively with the frequency of cataplectic and sleep attacks. The authors emphasized
that the human striatal dopaminergic system is altered in vivo in
narcolepsy with cataplexy. Additionally, Dauvilliers et al14 found
a strong effect of a functional polymorphism of COMT activity
on disease severity in narcolepsy. COMT is one of the major enzymes in dopamine metabolism, and different activities of this
enzyme could potentially result in different rates of turnover of
endogenous dopamine or dopamine derived from exogenous
sources, such as levodopa, in subjects with different COMT genotypes.15 The finding that COMT activity is important for the disease severity in narcolepsy makes an involvement of COMT in
the pathogenesis of “sleep attacks” in PD conceivable. Frauscher
et al15 demonstrated an association between a COMT genotype
and subjective daytime sleepiness in PD patients. The authors
speculated that the mechanism of action of COMT on daytime
sleepiness might involve a higher availability of endogenous or
exogenous dopamine at sleepiness-related brain structures, with
dopaminergic binding sites such as the ventral tegmental area or
the mesostriatal system.33 Hypocretin neurons have widespread
Hypocretin Polymorphisms
Polymorphisms in the promoter region of hormone genes have
been implicated in disease susceptibility, most notably in the
HLA-associated autoimmune disorder type I insulin-dependent
diabetes mellitus, in which a variable number of tandem-repeat
polymorphisms upstream of the preproinsulin gene are known to
be associated with increased insulin-dependent diabetes mellitus
susceptibility.26 Peyron et al13 have suggested in previous work
that the 2 hypocretin-receptor genes are not major contributors for
narcolepsy susceptibility, based on the observation that frequent
hypocretin receptor-1 and hypocretin receptor-2 polymorphisms
were not associated with this disorder. Furthermore Hungs et al17
reported that the (-909T/C) preprohypocretin polymorphism was
SLEEP, Vol. 28, No. 7, 2005
(-909T/C) T/T
expected 49.7
observed 49
expected 28.8
observed 31
expected 2.5
observed
1
Controls (n = 132)
873
Sleep Attacks—Rissling et al
projections, with dense excitatory projections to all monoaminergic and cholinergic cell groups.11 The hypocretin transmission is
higher in the active period and is activated by sleep deprivation.34
It has been suggested that hypocretin neurons drive monoaminergic activity to control sleep-wake states.35,36 Reports of sleep
disturbances in dopaminergic disorders such a PD7,33 emphasize
dopamine’s role in sleep regulation. Sleep can be controlled by
D2 or D3 presynaptic receptor modulation of the ventral tegmental
area but not by the activity of the substantia nigra.37 Dopaminergic neurons of the ventral tegmental area, but not the substantia
nigra, are excited by hypocretin.11 Additionally, the existence of
sleep-state dependent dopaminergic neurons in the ventral periaqueductal gray has been demonstrated.38 These findings suggest
that the dopaminergic neurons in the ventral tegmental area and
ventral periaqueductal gray, which are under the control of hypocretin neurons, may be important in regulating wakefulness.11 In
the present work, we did not identify any PD patient with SOS
featuring the (-22C/T) or (-20C/A) preprohypocretin polymorphism. This result suggests that these variants do not contribute
significantly to the pathogenesis of “sleep attacks” in PD. Since
we previously found a significant association between the DRD2
Taq IA polymorphism and SOS in PD,1 we analyzed the distribution of the expected and observed (-909T/C) and DRD2 Taq IA
genotypes in patients with and without SOS. Since these values
were similar, we suggest that—despite the proposed interaction of
the dopaminergic and hypocretinergic system in the regulation of
daytime sleepiness—the (-909T/C) variant allele T and the DRD2
Taq IA variant allele A2 contribute as independent risk factors to
the occurrence of “sleep attacks” in PD. This result indicates that
multiple genetic factors play a role in the pathogenesis of this still
poorly recognized phenomenon.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
17.
18.
19.
SUMMARY
20.
The current study suggests that the T allele of the (-909T/C)
preprohypocretin variant is associated with a significantly increased risk of developing SOS in PD patients. The T allele is
likely not useful as a predictor of SOS in the routine clinical management of PD patients, although C/C homozygotes may be less
susceptible to the development of SOS. Further studies are mandatory to confirm this single association in independent samples.
21.
22.
23.
ACKNOWLEDGMENTS
24.
We would like to thank C. Höft and R. Burmester for expert
technical assistance.
25.
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