To our knowledge, this is the first study to show an association between sleep duration and the incidence of Hhcy using a nationally representative sample in the United States. These results showed that excessive sleep or sleep deprivation was associated with Hhcy risk, and the associations were U-shaped between sleep duration and the risk of Hhcy. This highlighted the importance of a proper amount of sleep duration for the prevention of Hhcy.

Sleep is a reversible state of rest and recuperation with many critical active processes that comprises approximately one-third of human life. The American Academy of Sleep Medicine reported in 2015 that adults should sleep 7 or more hours per night regularly to promote optimal health [22]. A recent meta-analysis of prospective studies reports that 7–8 h of sleep per day results in the lowest risk of diabetes, with a 9% increased risk of diabetes for every hour of sleep lost [23]. Sleeping less than 7 h per night regularly is associated with adverse health outcomes, including weight gain and obesity, diabetes, hypertension, heart disease, stroke, depression [24], and increased risk of death [25]. Sleeping less than 7 h per night is also associated with impaired immune function, increased pain, impaired performance, increased errors, and greater risk of accidents [26]. Based on the above considerations, reduced sleep duration has been clearly associated with decreased quality of life as well as increased rates of metabolic disease, cardiovascular disease, and mortality [1, 27].

A previous study has demonstrated that a long sleep duration was associated with increased serum-Hcy levels, which were verified in our study, and amplified the genetic susceptibility to higher Hcy [28]. Dietary factors, as an important regulatory factor, play a critical role in the prevention and management of Hhcy. Previous study demonstrated that increased homocysteine levels were related to short sleep duration, and did not take dietary factors into account in the statistical analysis. In our study, we found that the association between sleep duration and the risk of Hhcy was U-shaped after adjusting for a series of dietary factors, which highlighted the importance of dietary factors in the relationship between sleep duration and Hhcy. Previous study has demonstrated that insomnia or hypersomnia is an independent risk factor for Hhcy. Our results are consistent with previous research. In addition, folic acid and vitamin B12 deficiency are closely related to the occurrence and development of Hhcy, and thromboembolic manifestations are relatively frequent in patients with intermediate/severe Hhcy related to inherited disorders and deficiencies in vitamin B12 and folic acid [29]. Therefore, during the statistical analysis, confounders adjusted in logistic regression included two important factors, total dietary folic acid and vitamin B12 intake.

The alteration of circadian patterns could be a key mechanism to explain our observations. The effects of sleep on circadian rhythmicity have already shown that sleep duration could affect circadian perturbance and influence the manifestation of metabolic disorders [30, 31]. Current evidence suggests that circadian rhythm-related metabolic disorders affect cysteine and other synthesis mechanisms in the human body. Indeed, an underlying circadian pattern may influence serum-Hcy concentrations, and previous studies have shown that serum-Hcy levels in adults are circadian, the highest levels occur during the late evening and the lowest levels occur during the morning [32]. Small heterodimer partner (SHP), an important regulator of lipid and bile acid metabolism, is a member of the liver clock and has been shown to play critical roles in metabolic homeostasis [33, 34]. Animal studies have shown that disruption of SHP in mice alters the expression timing of genes that regulate Hcy metabolism and the liver responses to ethanol and Hcy. Moreover, SHP inhibits the transcriptional activation of betaine-homocysteine S-methyltransferase and cystathionine g-lyase required for Hcy metabolism by FOXA1 [34].

The variation in Hcy levels could be influenced by various genetic and nongenetic events. We do understand that the metabolic cycle is likely to be influenced by the biologic clock of an individual and Hcy metabolism follows a circadian rhythm [35, 36]. The day and night cycles in humans have been reported to be regulated by Circadian Locomotor Output Cycle protein Kaput genes [37]. However, controlling the nongenetic events can the genetic factors of Hcy metabolism contributing to the variations in Hcy levels and do these variations have rhythmicity.

Although associations between long sleep duration and elevated inflammatory status have been proven statistically. Sleep and immunity are bidirectionally linked. Immune system activation alters sleep, and sleep affects our body’s defense system in turn [38]. Stimulation of the immune system by microbial challenges triggers an inflammatory response, which can not only induce an increase in sleep duration and intensity but also cause a disruption of sleep depending on its magnitude and time course. In the absence of an infectious challenge, sleep appears to promote inflammatory homeostasis through effects on several inflammatory mediators, such as cytokines. Nonetheless, a recent report has shown that sleeping too long or too short can affect immune status and disrupt immune defenses. Inflammation and immune response may be responsible for both cytokine production and telomeric erosion[39], and another study has highlighted that shortened leukocyte telomere length is associated with increased Hcy levels [40]. As can be seen from the above, sleep duration may play a role in regulating levels of Hcy. This notion is supported by findings that prolonged sleep deficiency (e.g., short sleep duration, sleep disturbance) can lead to chronic, systemic low-grade inflammation and is associated with various diseases that have an inflammatory component, like diabetes, atherosclerosis, Hhcy, and neurodegeneration.

We found that increasing age was a risk factor for Hhcy, consistent with previous epidemiologic findings. A large number of investigations and studies have shown that the prevalence of Hhcy caused by population aging increases with age, the body’s immunity decreases, multiple organs weaken progressively, and the number of hospitalizations and invasive procedures increase, which makes viruses and bacteria more invasive and people more susceptible to infection [38]. The induction of a hormonal constellation that supports immune functions is one likely mechanism underlying the immune-supporting effects of sleep.

To conclude, short sleep duration and oversleeping are related to a variety of diseases, including Hhcy. One of the most distinctive features of this study is we discovered the association between sleep duration and Hhcy risk by performing a large sample quantitative data analysis on the NHANES database. Meanwhile, we adjusted for confounding factors including dietary factors associated with sleep or Hcy at various points in the multivariate logistic regression models. This study still has some limitations and needs to be further improved: First, in this cross-sectional study, sleep duration was evaluated by self-reported questionnaires and serum homocysteine levels were assessed only at one time, which might lead to certain bias and could not make causal inferences. In the following research, it is necessary to further use mendelian randomization method to explore the causal relationship between sleep duration and Hhcy. Further longitudinal investigations concerning the effect of sleep duration on homocysteine alteration might help provide a better understanding of the pathogenesis of Hhcy. Second, some risk factors associated with Hhcy might not be identified in the study, which might lead to result bias. Therefore, when we investigate the causal relationship between sleep duration and Hhcy, confounding factors should be adjusted as comprehensively as possible. Third, there may be a link between chronotype and homocysteine. However, the variables provided by NHANES database were limited, and the chronotype variable was not included in the NHANES database. Therefore, the effect of chronotype on Hhcy was not considered in this study, and this variable would be fully considered in the following mechanism study.