title: TRIB1 constitutes a molecular link between regulation of sleep and lipid metabolism in humans.
abstract: Epidemiological studies show association between sleep duration and lipid metabolism. In addition, inactivation of circadian genes induces insulin resistance and hyperlipidemia. We hypothesized that sleep length and lipid metabolism are partially controlled by the same genes. We studied the association of total sleep time (TST) with 60 genetic variants that had previously been associated with lipids. The analyses were performed in a Finnish population-based sample (N = 6334) and replicated in 2189 twins. Finally, RNA expression from mononuclear leucocytes was measured in 10 healthy volunteers before and after sleep restriction. The genetic analysis identified two variants near TRIB1 gene that independently contributed to both blood lipid levels and to TST (rs17321515, P = 8.92(*)10(-5), Bonferroni corrected P = 0.0053, β = 0.081 h per allele; rs2954029, P = 0.00025, corrected P = 0.015, β = 0.076; P<0.001 for both variants after adjusting for blood lipid levels or body mass index). The finding was replicated in the twin sample (rs17321515, P = 0.022, β = 0.063; meta-analysis of both samples P = 8.1(*)10(-6), β = 0.073). After the experimentally induced sleep restriction period TRIB1 expression increased 1.6-fold and decreased in recovery phase (P = 0.006). In addition, a negative correlation between TRIB1 expression and slow wave sleep was observed in recovery from sleep restriction. These results show that allelic variants of TRIB1 are independently involved in regulation of lipid metabolism and sleep. The findings give evidence for the pleiotropic nature of TRIB1 and may reflect the shared roots of sleep and metabolism. The shared genetic background may at least partially explain the mechanism behind the well-established connection between diseases with disrupted metabolism and sleep.
authors: Public Health Genomics Unit and Institute for Molecular Medicine FIMM, National Institute for Health and Welfare, Helsinki, Finland.
authors: H M
authors: HM
authors: Ollila
authors: S
authors: S
authors: Utge
authors: E
authors: E
authors: Kronholm
authors: V
authors: V
authors: Aho
authors: W
authors: W
authors: Van Leeuwen
authors: K
authors: K
authors: Silander
authors: T
authors: T
authors: Partonen
authors: M
authors: M
authors: Perola
authors: J
authors: J
authors: Kaprio
authors: V
authors: V
authors: Salomaa
authors: M
authors: M
authors: Sallinen
authors: M
authors: M
authors: Härmä
authors: T
authors: T
authors: Porkka-Heiskanen
authors: T
authors: T
authors: Paunio
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL; D015331:Cohort Studies; D006970:Disorders of Excessive Somnolence / Q000097:blood / Q000235:genetics; D005260:Female; D005387:Finland; D015870:Gene Expression / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D012890:Sleep / Q000235:genetics*; D012892:Sleep Deprivation / Q000097:blood / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D014427:Twins / Q000235:genetics
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D047908:Intracellular Signaling Peptides and Proteins; C493170:TRIB1 protein, human; D014280:Triglycerides; D017346:Protein Serine-Threonine Kinases