Association study of dopamine D2, D3, D4 receptor and serotonin transporter gene polymorphisms with sleep attacks in Parkinson's disease

Abstract

Sleep attacks are a common yet only recently recognized phenomenon in patients with Parkinson's disease (PD). Initially reported to occur only with particular dopamine agonists, sleep attacks have been observed with all dopaminergic drugs. [1][2][3] In the majority of affected patients, sleep attacks are a stable phenomenon and occur with and without excessive daytime sleepiness. 2 Presence or absence of warning signs preceding a sleep attack have received particular interest, as sleep attacks without warning signs might be especially dangerous.It is conceivable that intrinsic variations of the sleep regulating systems in interaction with dopaminergic drugs may provoke the occurrence of sleep attacks. To test if genetic variants of the different dopamine receptors or the serotonin transporter contribute to the etiology of sleep attacks, we examined four known polymorphisms of the genes for dopamine receptors 2, 3, and 4 (DRD2 141C del/ins; DRD2 TaqIA; DRD3 Ser9Gly; DRD4 48 base pair [bp] repeat), and the 5-HTTLPR polymorphism in the serotonin transporter gene (SERT) in a community based case control study. We found an association between sleep attacks without warning signs and the DRD4*2 (short) allele. METHODSIn a survey of 2,952 German PD patients, we previously identified 177 patients with sleep attacks defined as "an event of falling asleep suddenly, unexpectedly, and irresistibly while engaged in some activity, e.g., during a meal, a telephone call, writing, or driving a car", using a self-rating scale and a structured telephone interview. Details of this study can be found in the June 2003 issue of Movement Disorders. 2 Special emphasis was placed on warning signs such as "yawning, closing of the eyelids, rapid decrease of mental alertness or acute onset of excessive tiredness immediately before falling asleep". 2 PD patients falling asleep while passive (e.g., watching TV or reading) were not considered for this association study. Information on intake of dopaminergic drugs at the time of sleep attacks was collected, and a control group of PD patients without sleep attacks was matched according to type of dopaminergic treatment (no dopa and no dopamine agonist; levodopa (L-dopa) only; dopamine agonist only; L-dopa plus dopamine agonist; L-dopa plus more than one dopamine agonist), disease duration, and age. Rank order for matching was type of treatment, followed by disease duration and age. All patients were of Caucasian ethnicity and gave written informed conDrs. Paus and Seeger contributed equally to this work.

Pharmacogenetics of Antiparkinsonian Drug Treatment: A Systematic Review

“…Associations were found between sleep attacks without warning signs and a DRD4 gene or a HCRT gene polymorphism [60,64]. Others found a positive association with a DRD2 gene or a COMT gene polymorphism [61,62], although the latter could not be replicated [60,63].…”

“…Paus and colleagues studied the association between polymorphisms in the DRD2 gene (141C del/ins and TaqIA), DRD3 gene (Ser9Gly), DRD4 gene (48-bp repeat) and 5-HTTLPR and sleep attacks in patients with PD taking dopaminergic drugs [60]. PD patients with sleep attacks and without sleep attacks were matched for dopaminergic treatment, disease duration and age.…”

Sleep Disorders and Fibromyalgia

“…The serotonin transporter gene regulatory region (5-HTTLPR) is controversially associated with personality trait in fibromyalgia [54,55], and an s-allele of the 5-HTTLPR is frequent in patients suffering from insomnia [56]. The dopamine D4 receptor gene, also associated with personality trait in fibromyalgia [57], has been related with sleep attacks in Parkinson's disease [58]. Furthermore, a functional Val158Met polymorphism (in which substitution of valine [Val] to methionine [Met] at codon 158 results in reduction in the activity of the catechol-O-methyltransferase [COMT] enzyme, which metabolizes catecholamines) is associated with human pain sensitivity [59] in several pain conditions, including fibromyalgia [60].…”

Excessive daytime sleepiness and unintended sleep in Parkinson’s disease

“…Alleles of catechol-O-methyltransferase (a degradative enzyme of dopamine) confer a greater risk for sleepiness [38], as do variants of the D4 dopamine receptor [39] and preprohypocretin polymorphisms [40]. Advanced disease or disease duration are also potential contributing factors [2••, 13,15], as are benzodiazepine use [2••], male sex [11], co-morbid dementia or psychosis [15], and autonomic failure (eg, orthostatic hypotension) [16].…”