Effects of circadian clock genes and health-related behavior on metabolic syndrome in a Taiwanese population: Evidence from association and interaction analysis

PLoS One. 2017 Mar 15;12(3):e0173861. doi: 10.1371/journal.pone.0173861. eCollection 2017.


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.

MeSH terms

  • Adult
  • Circadian Clocks / genetics*
  • Female
  • Health Behavior*
  • Humans
  • Male
  • Metabolic Syndrome / genetics*
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Taiwan

Grants and funding

This work was supported by the Ministry of Economic Affairs in Taiwan (http://www.moea.gov.tw/; SBIR Grant S099000280249-154; EL), by Taipei Veterans General Hospital, Taiwan (www.vghtpe.gov.tw/; Grants VGHUST103-G1-4-1, V105C-008, and V105E17-002-MY2-1; SJT), by National Health Research Institutes, Taiwan (www.nhri.org.tw/; Grant NP-105-SP-04; YLL), and by the Ministry of Science and Technology, Taiwan (https://www.most.gov.tw/; Grant MST 102-2314-B-002-117-MY3; PHK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The commercial affiliation, Vita Genomics, Inc., provided support in the form of salary for author EL, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.