Lin Eugene, Kuo Po-Hsiu, Liu Yu-Li, Yang Albert C, Kao Chung-Feng, Tsai Shih-Jen
Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Vita Genomics, Inc., Taipei, Taiwan.
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.
昼夜节律时钟基因与代谢综合征（MetS）发生风险的增加有关。在本研究中，我们评估了29个与昼夜节律时钟相关的基因（包括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和VIPR2）是否独立地和/或通过复杂的相互作用与台湾人群中的代谢综合征及其各个组分相关。我们还分析了环境因素与这些基因在影响代谢综合征及其各个组分方面的相互作用。本研究评估了来自台湾生物银行的总共3000名台湾受试者。测量了腰围、甘油三酯、高密度脂蛋白胆固醇、收缩压和舒张压以及空腹血糖等代谢特征。我们的数据显示，代谢综合征与五个关键昼夜节律时钟基因（包括ARNTL、GSK3B、PER3、RORA和RORB）中的几个单核苷酸多态性（SNP）存在名义上的关联；但在进行Bonferroni校正后，这些SNP均未显著持续存在。此外，我们确定了GSK3B rs2199503对高空腹血糖的影响（P = 0.0002）。此外，我们发现ARNTL rs10832020、GSK3B rs2199503、PER3 rs10746473、RORA rs8034880和RORB rs972902 SNP之间的相互作用影响了代谢综合征（P < 0.001至P = 0.002）。最后，我们研究了ARNTL rs10832020、GSK3B rs2199503、PER3 rs10746473和RORB rs972902与饮酒、吸烟状况和身体活动等环境因素之间的相互作用对代谢综合征及其各个组分的影响（P < 0.001至P = 0.002）。我们的研究表明，ARNTL、GSK3B、PER3、RORA和RORB等昼夜节律时钟基因可能独立地以及通过基因-基因和基因-环境相互作用导致代谢综合征的风险。
