Delayed sleep phase syndrome (DSPS) is a circadian rhythm disorder where individuals experience difficulty modifying the time they go to sleep and wake up in response to environmental changes. The circadian rhythm itself is regulated by a variety of clock genes, and various other genes (e.g., AA-NAT gene, CKIϵ gene) code for proteins that regulate clock genes. Various polymorphisms of the clock gene influencers have been shown to increase susceptibility to DSPS. This paper seeks to examine how certain cultural characteristics (e.g., napping, timing of meals, exposure to artificial light) and the presence of the AA-NAT gene (G619A polymorphism) and the CKIϵ gene (S408N polymorphism) influence the prevalence of DSPS amongst Japanese and Brazilian populations.
Academic Editor: David Bennett Bennett, Drexel University College of Medicine, USA.
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Copyright © 2020 Abram Estafanous, et al.
The authors have declared that no competing interests exist.
The circadian rhythm is an intrinsic oscillator of physiological function that results in 24-hour day and night cycles1. These cycles allow organisms to adapt to changes in the environment, such as changes in light duration2. Zeitgebers are stimuli that act as time-cues for the circadian rhythm3 and help adjust the duration of sleep to 24 hours3,4. Examples of zeitgebers include the amount of light present during the day2, feeding pattern (breakfast, lunch, and dinner), social/academic commitments, and exercise, with the amount of daylight being the dominant zeitgeber. The center of the circadian rhythm is the suprachiasmatic nucleus (SCN) of the hypothalamus1. SCN neurons receive light from the retina, and this photic information is converted into chemical information that alters gene expression of SCN neurons2. The SCN transmits the rhythmic information it receives, such as the amount of daylight, to cells found elsewhere in the body (e.g., pineal gland) that results in a variety of outputs (e.g., endocrine signals, body temperature changes)2. The SCN induces the pineal gland to secrete melatonin. The expression of melatonin is an important regulator of sleep as it correlates with an increase in sleep propensity5 and decreased sleep onset latency6.
Sleep itself is influenced by a variety of cultural and genetic factors, which affect sleep by influencing the circadian rhythm. An example of a cultural factor found in Brazil is the presence of a late evening dinner7. Studies have shown that mammals alter their circadian rhythm based on food availability. For example, if mammals are presented with food during the second half of the day, they become more active and experience an increase in body temperature a few hours before the food is given8. Thus, the presence of a late evening dinner may decrease sleep onset in Brazilians by increasing physiologic functions such as body temperature. Genes may also influence circadian rhythm. A cluster of genes known as clock genes regulate the circadian rhythm, including cortisol secretion, body temperature, and the actual sleep/wake cycle9. These genes have been demonstrated to be present at different frequencies among different ethnic groups. For example, one study demonstrated that the clock gene polymorphisms PER3 and T3111C were found to be present at a higher frequency among Asian descendants in Brazil, as compared to Caucasian descendants9. The presence of various polymorphisms has been shown to increase susceptibility to sleep disorders. For example, one study demonstrated that a polymorphism of the PER2 gene showed a significant association with delayed sleep phase syndrome (DSPS) in Japanese adults10. This review selected Brazil and Japan as the countries of interest due to the amount of existing literature that focuses on the prevalence of the same types of genes that influence sleep as well as on the different cultural characteristics that may potentially influence sleep trends in both countries.
DSPS is a circadian rhythm disorder where individuals have a sleep schedule that has a considerably later time of sleep onset than is preferred by the individual or is the societal and cultural convention11. As a result, individuals with DSPS experience difficulty falling asleep and difficulty waking up, especially when they have to modify the time they go to sleep to meet environmental changes, such as a new work schedule11. While the cause of DSPS is unknown11, the factors that contribute to DSPS likely include behavioral and biological factors6. One factor that potentially contributes to DSPS is the use of artificial light before falling asleep6. Exposure to artificial light may inhibit the production of melatonin, a hormone that decreases sleep onset latency12. Another potential influence on DSPS may be some genes that have been found to have effects on clock proteins, such as the casein kinase I epsilon (CKIϵ) protein which phosphorylates clock proteins13. These genes that regulate clock proteins have polymorphisms that have been associated with different disorders of the circadian rhythm, such as DSPS.
While there has been an examination of the genetic influences on the prevalence of DSPS, to the writers’ knowledge, there have been no studies to examine how the sleep trends – a cultural factor – of Brazil and Japan may modify how clock genes influence the prevalence of DSPS. The purpose of this review is to examine how the presence of certain genes that influence clock genes and certain cultural characteristics of Brazil and Japan may play a role in the prevalence of DSPS.
Genetic Influencers on the Prevalence of Delayed Sleep Phase Syndrome
The arylalkylamine N-acetyltransferase (AA-NAT) gene, which is involved in melatonin synthesis, and specifically its G619A polymorphism, has been examined in DSPS and non-DSPS patients14,15. Hohjoh et al. (2002) examined a Japanese DSPS population in Tokyo. The population was diagnosed based on the diagnostic criteria of the International Classification of Sleep Disorders. The study demonstrated that the G619A polymorphism had a higher prevalence (16.0%) among patients with DSPS, compared to their healthy cohorts who had a prevalence of 3.1%. In contrast, Pereira et al. (2007) found a 0% prevalence of the same G619A polymorphism amongst Brazilian DSPS patients, while a 0.2% prevalence was found amongst the non-DSPS group. The study did not specify which diagnostic criteria was used to select the DSPS patients.
The prevalence of the S408N polymorphism of the casein kinase I epsilon (CKIϵ) gene, which is expressed in the SCN and encodes a protein that phosphorylate clock proteins, has also been examined in DSPS and non-DSPS patients. Takano et al. (2004) examined DSPS patients in Japan who were diagnosed based on the International Classification of Sleep Disorders and found that the prevalence of the S408 polymorphism of the CKIϵ gene in their DSPS patients was 6.1%, as compared to 12.3% in non-DSPS patients. Castro et al. (2008) examined the same polymorphism of the CKIϵ gene in a Brazilian DSPS population, which was diagnosed based on the diagnostic criteria of the International Classification of Sleep Disorders. They found a prevalence of 0% among their DSPS patients and 1.5% among their non-DSPS patients13.
A comparison of these studies is presented in Table 1.Table 1. Prevalence of genes associated with DSPS in DSPS and non-DSPS patients
|Hohjoh et al. (2002)||Japan||50 DSPS patients;161 non-DSPS patients||AA-NAT gene(G619A polymorphism)||DSPS patients 16.0%;Non-DSPS patients 3.1%|
|Pereira et al. (2007)||Brazil||17 DSPS patients;372 non-DSPS patients||AA-NAT gene(G619A polymorphism)||DSPS patients 0%;Non-DSPS patients 0.2%|
|Takano et al. (2004)||Japan||196 DSPS patients;276 non-DSPS patients||CKIϵ gene(S408N polymorphism)||DSPS patients 6.1%;Non-DSPS patients 12.3%|
|Castro et al. (2008)||Brazil||16 DSPS patients;195 non-DSPS patients||CKIϵ gene(S408N polymorphism)||DSPS patients 0%;Non-DSPS patients 1.5%|
Intersection of Genetics and the Cultural Characteristics of Brazil and Japan that Influence Sleep on DSPS
The sleep trends found in Brazil and Japan may influence the effect genes have on the prevalence of DSPS in those countries. This may explain why the patients of Pereira et al. (2007) who had DSPS did not have significant prevalence of the AA-NAT gene but still had DSPS. This may also explain why the patients of Takano et al. (2004) and Castro et al. (2008) still had DSPS, despite the fact that they did not have a significant prevalence of the CKIϵ gene. For example, according to Brazilian custom, dinner is served in the late evening, which necessitates a later sleep time7. This may be a risk factor for individuals in Brazil who practice this custom to have a delay in their sleep onset. Another study by Santos-Silva et al. (2009) examined sleep trends in the city of Sao Paulo, Brazil. The study examined a variety of sleep habits and complaints over three decades – in 1987, 1995, and 2007. The study showed that over the last few decades, adults have gone to bed at later times. While the population has also woke up at later times, the total time of sleep duration has decreased. The study also demonstrated that complaints of insomnia have increased over the last three decades17. The study proposed that the reason for this increase in sleep complaints may be due to the frequent exposure to artificial light that comes with living in an industrialized society. This may also explain why the Brazilian population of Pereira et al. (2007) had DSPS even though there was no significant association of the AA-NAT gene with DSPS. A study by Gooley et al. (2011)demonstrated that exposure to room light before bedtime suppresses melatonin production. Because melatonin decreases sleep onset latency, the use of room light in an industrialized society like Sao Paulo, Brazil may predispose the population to DSPS, even though they do not have the G619A polymorphism of the AA-NAT gene.
In Japan, some individuals practice a daytime nap known as inemuri, which often occurs in public areas18. The presence of inemuri creates a situation where individuals consolidate some of their sleep during the day and the rest of their sleep at night. In the chapter Negotiating sleep patterns in Japan18, Steger describes inemuri as an individual sleeping in a situation where they should not be asleep, such as at work18. The lack of consistent sleep timing with inemuri may create difficulty with sleep onset at night, where the majority of sleep is consolidated in Japan18, which may be a predisposing factor for DSPS. In addition, a study by Liu et al. (2000)examined 4000 adult individuals over age 20 from mostly suburban and urban regions around Japan. The study found that the overall presence of symptoms of insomnia was 21.4%. While the study did not assess the use of artificial light before bedtime, it can be reasonably presumed that many in their surveyed population used artificial room light before bedtime as is common in many industrialized cities. As discussed previously, exposure to artificial light may suppress melatonin production, which may contribute to a predisposition to DSPS.
The results of the four studies examined indicate relationships between the examined genes and the prevalence of DSPS. Based on the four studies examined, the presence of the AA-NAT gene (G619A polymorphism) increased the susceptibility to DSPS among Japanese individuals but not Brazilian individuals. The presence of the CKIϵ gene (S408N polymorphism) did not increase susceptibility to DSPS among Japanese or Brazilian individuals.
Several theories have been proposed as to why there are genetic differences between ethnicities when it comes to genes that potentially predispose to DSPS. One theory relates the impact of human migration out of the continent of Africa and to various geographic latitudes20. These various latitudes present differences in light intensity, temperature, and seasonal changes in the length of a day20. The function of the circadian rhythm biological clock is to provide extrinsic information, such as changes in light intensity or day length, so that an organism can modify their intrinsic physiological and/or extrinsic behavioral response to optimize adaptiveness to a changing environment20. Thus, the different gene polymorphisms found across various ethnicities may be the result of natural selection to optimize adaptiveness based on differing latitudinal environments20. This theory is consistent with the findings of Hohjoh et al. (2002), in which Japanese DSPS patients had a higher prevalence of the AA-NAT gene as compared to the Brazilian DSPS patients studied by Pereira et al. (2007).
One limitation of this review is that other polymorphisms may exist in the samples studied that may contribute to DSPS. The studies that this review examined only looked at two polymorphisms – the G619A polymorphism of the AA-NAT gene and the S408N polymorphism of the CKIϵ gene. Another limitation to this review is the lack of standardized criteria to determine DSPS in patients across all studies examined. Both Hojhoh et al. (2002) and Pereira et al. (2007) examined the prevalence of the AA-NAT gene (G619A polymorphism) in DSPS patients. Hohjoh et al. (2002) mentioned that the criteria used to diagnose DSPS was the International Classification of Sleep Disorders. Pereira et al. (2007) did not mention which diagnostic criteria they used. Thus, this may potentially be a confounding factor, as the two sets of DSPS patients from the studies may not have been diagnosed according to the same criteria. Another limitation is the focus on the countries of Brazil and Japan only. Brazil and Japan were selected due to the amount of existing literature examining the genes of interest – the AA-NAT gene and CKIϵ gene – as well as how specific cultural characteristics potentially affect sleep trends found in both countries. Future studies should examine the same phenomenon in other countries with both similar and different latitudes as well as other genetic polymorphisms that may lead to susceptibility to DSPS.
We reviewed two studies that examined the prevalence of the AA-NAT gene (G619A polymorphism) among DSPS patients in a Brazilian and Japanese population and two studies that examined the prevalence of the CKIϵ gene (S408N polymorphism) in a Brazilian and Japanese population. While the presence of certain polymorphisms contributes to the presence of DSPS as concluded by the individual studies, this review also examined how the sleep trends found in Japan and Brazil – such as exposure to artificial light before bedtime, the presence of the midday nap in Japan (inemuri), and the presence of later dinners in Brazil – may affect the prevalence of DSPS. This review serves to fill a gap in the existing literature by assessing how sleep trends may affect the prevalence of DSPS. Continuing to research in this area would aid clinicians in better understanding the role that sleep habits play in sleep disorders, specifically DSPS, which may in turn facilitate more effective treatment of these conditions.
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