Abstract
Increased risk of developing metabolic syndrome (MetS) has been associated with the circadian clock genes. In this study, we assessed whether 29 circadian clock-related genes (including ADCYAP1, ARNTL, ARNTL2, BHLHE40, CLOCK, CRY1, CRY2, CSNK1D, CSNK1E, GSK3B, HCRTR2, KLF10, NFIL3, NPAS2, NR1D1, NR1D2, PER1, PER2, PER3, REV1, RORA, RORB, RORC, SENP3, SERPINE1, TIMELESS, TIPIN, VIP, and VIPR2) are associated with MetS and its individual components independently and/or through complex interactions in a Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing MetS and its individual components. A total of 3,000 Taiwanese subjects from the Taiwan Biobank were assessed in this study. Metabolic traits such as waist circumference, triglyceride, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and fasting glucose were measured. Our data showed a nominal association of MetS with several single nucleotide polymorphisms (SNPs) in five key circadian clock genes including ARNTL, GSK3B, PER3, RORA, and RORB; but none of these SNPs persisted significantly after performing Bonferroni correction. Moreover, we identified the effect of GSK3B rs2199503 on high fasting glucose (P = 0.0002). Additionally, we found interactions among the ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, RORA rs8034880, and RORB rs972902 SNPs influenced MetS (P < 0.001 ~ P = 0.002). Finally, we investigated the influence of interactions between ARNTL rs10832020, GSK3B rs2199503, PER3 rs10746473, and RORB rs972902 with environmental factors such as alcohol consumption, smoking status, and physical activity on MetS and its individual components (P < 0.001 ~ P = 0.002). Our study indicates that circadian clock genes such as ARNTL, GSK3B, PER3, RORA, and RORB genes may contribute to the risk of MetS independently as well as through gene-gene and gene-environment interactions.
Highlights
Circadian rhythms are naturally recurring cycles that regulate the timing of biological events such as the sleep-wake cycle and energy metabolism [1]
It has been suggested that circadian clock genes such as aryl hydrocarbon receptor nuclear translocator like (ARNTL), CRY1, and period circadian clock 2 (PER2) are expressed in human adipose tissue, and their gene expressions were related to the individual components of metabolic syndrome (MetS) such as waist circumference [11]
Several animal studies indicated that metabolic complications such as MetS, dyslipidemia, glucose intolerance, hypoinsulinaemia, and diabetes can result from deletion of the Arntl, Clock, or Per3 genes, suggesting miscommunication between the circadian clock and metabolic pathways may lead to metabolic disorders [12,13,14]
Summary
Circadian rhythms are naturally recurring cycles that regulate the timing of biological events such as the sleep-wake cycle and energy metabolism [1]. Animal studies showed that a loss-of-function mutation of the circadian clock genes, such as Clock and Arntl, may result in metabolic abnormalities of lipid and glucose homeostasis, hallmarks of MetS [5, 6]. Woon et al found that a three-marker haplotype (rs6486121, rs3789327, and rs969485) of the ARNTL gene was associated with hypertension, an individual component of MetS [9]. Several animal studies indicated that metabolic complications such as MetS, dyslipidemia, glucose intolerance, hypoinsulinaemia, and diabetes can result from deletion of the Arntl, Clock, or Per genes, suggesting miscommunication between the circadian clock and metabolic pathways may lead to metabolic disorders [12,13,14]
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