Original ArticleSleep disruption and duration are associated with variants in genes involved in energy homeostasis in adults with HIV/AIDS
Introduction
Sleep disturbance is a common symptom in chronic illness populations, and it is estimated that up to 75% of adults with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) experience sleep problems [1]. Their most common sleep complaints are difficulty staying asleep [[2], [3], [4]] and short sleep duration [3,5]. Energy metabolism has a reciprocal relationship with circadian clocks [6,7], has been linked to poor sleep in animal models and humans [[8], [9], [10], [11], [12]], and is elevated in HIV-infected individuals [13,14]. A genome-wide association study has also identified body mass index (BMI) relationships with self-reported long and short sleep duration [15]. However, research is limited on relationships between sleep parameters specifically using objective measures, and genes related to energy metabolism and energy balance in adults with HIV.
White adipose tissue (WAT) is the body's primary tissue for energy storage and has a major role in energy homeostasis. WAT secretes adiponectin, a peptide hormone involved in maintaining energy balance and regulating insulin sensitivity in liver and muscle. The expression of the adiponectin gene (ADIPOQ) is inversely associated with total WAT mass and food intake (and therefore obesity). Insulin resistance, obesity, and type 2 diabetes are key components of metabolic syndrome, which we previously showed to be prevalent in the HIV/AIDS cohort also evaluated herein [16]. Leptin and ghrelin are also important peptide hormones involved in energy homeostasis. Like adiponectin, leptin is secreted by WAT and suppresses appetite, and therefore affects energy equilibrium. Ghrelin is secreted mainly in the gut and acts on the central nervous system to regulate appetite and energy balance. In humans, sleep duration is an important factor influencing leptin and ghrelin levels, and chronic short sleep duration is associated with low leptin and high ghrelin levels [10,11,17].
Two key transcriptional factors that regulate genes in fat metabolism are in the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors [18]. While PPAR-alpha (PPARα) is expressed chiefly in the liver, it is expressed at lower levels throughout the body [18]. PPAR-gamma (PPARγ) is expressed mainly in WAT to control triglyceride storage and adipocyte differentiation and is associated with insulin sensitivity [18].
Variations in levels of adiponectin [19], ghrelin, leptin [20], PPARα [21,22] and PPARγ [19] have been reported in relation to sleep in animal models [19,22] and humans [20]. Similarly, variations in levels of adiponectin [23], ghrelin [24], leptin [25], PPARα [26], and PPARγ [27] have been reported in HIV-infected adults. Leptin [25], adiponectin [28], PPARα and PPARγ [29] gene polymorphisms have also been associated with metabolic abnormalities in HIV-infected individuals. Similarly, gene polymorphisms in adiponectin [30], leptin [31], ghrelin [32], and PPARγ [33] have been associated with sleep-related phenotypes such as sleep duration or sleep apnea in other populations. However, no research to date has evaluated variations in biomarkers (ie, single nucleotide polymorphisms, plasma levels) of these genes and objective sleep measures in the context of HIV infection, where sleep disturbance is prevalent and multi-factorial.
The purpose of this study was to determine whether objectively measured sleep disruption and duration, in a sample of adults with HIV infection, are associated with single nucleotide polymorphisms (SNPs) in five select genes related to energy homeostasis (ie, adiponectin [ADIPOQ], ghrelin [GHRL], leptin [LEP], PPARα [PPARA], PPARγ [PPARG]) previously identified to be associated with sleep and HIV in other studies. We describe the relative contributions of variations in each gene to the variance in sleep disruption and duration. Finally, circulating levels of adiponectin, ghrelin, and leptin were evaluated to determine their relationships with sleep parameters and variations in energy homeostasis genes.
Section snippets
Participants and setting
The Symptom and Genetic Study was a longitudinal study aimed at identifying biomarkers (ie, genetic, protein) of symptom experience among HIV-infected adults [34]. We previously reported the impact of circadian regulation and cytokine biomarkers on sleep and fatigue in adults with HIV [[35], [36], [37], [38], [39]]. This analysis focuses on a cross-sectional evaluation of genetic and plasma biomarkers of energy homeostasis and relationships to sleep outcomes at the initial visit, which was
Sample characteristics
A convenience sample of 350 adults with HIV was enrolled in the study, and 61 participants were excluded prior to analysis due to screening positive for illicit drugs (n = 31), unable to submit a urine or blood sample (n = 2), and having incomplete or invalid actigraphy data (n = 28), An additional 12 participants were missing valid actigraphy data for the initial visit, and actigraphy data were used from a subsequent visit. Sample characteristics for the 289 participants are in Table 1. The
Discussion
In this study of adults with HIV, 17 SNPs from five genes (ADIPOQ, GHRL, LEP, PPARA, PPARG) were associated with sleep disruption or duration after adjusting for genomic estimates of ancestry, self-reported race/ethnicity, and other relevant covariates. Of these 17 SNPs, six were associated with both WASO and TST. These findings are consistent with prior studies reporting associations between plasma biomarkers of energy homeostasis and self-reported measures of sleep quality and duration [12].
CRediT authorship contribution statement
Bradley E. Aouizerat: Conceptualization, Methodology, Investigation, Formal analysis, Writing - original draft. Eeeseung Byun: Investigation, Writing - review & editing. Clive R. Pullinger: Investigation, Writing - review & editing. Caryl Gay: Investigation, Formal analysis, Project administration, Visualization, Writing - review & editing. Anners Lerdal: Investigation, Writing - review & editing. Kathryn A. Lee: Conceptualization, Methodology, Investigation, Formal analysis, Supervision,
Acknowledgments
This research was supported by a grant from the National Institute of Mental Health (NIMH, 5 R01 MH074358). Data collection was supported by the General Clinical Research Center in the UCSF CTSA (1 UL RR024131). The authors gratefully acknowledge the funding for Eeeseung Byun by the National Institutes of Health/National Institute of Nursing Research (T32 NR007088, K23 NR017404) and the Academic Senate at UCSF.
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