Circadian clock genes are critical regulators of energy homeostasis and metabolism. However, whether variation in the circadian genes is associated with metabolic phenotypes in humans remains to be explored. In this study, we systemically genotyped 20 tag single nucleotide polymorphisms (SNPs) in 8 candidate genes involved in circadian clock, including CLOCK, BMAL1(ARNTL), PER1, PER2, CRY1, CRY2, CSNK1E,, and NOC(CCRN4L) in 1,510 non-diabetic Chinese subjects in Taipei and Yunlin populations in Taiwan. Their associations with metabolic phenotypes were analyzed. We found that genetic variation in the NOC gene, rs9684900 was associated with body mass index (BMI) (P = 0.0016, Bonferroni corrected P = 0.032). Another variant, rs135764 in the CSNK1E gene was associated with fasting glucose (P = 0.0023, Bonferroni corrected P = 0.046). These associations were consistent in both Taipei and Yunlin populations. Significant epistatic and joint effects between SNPs on BMI and related phenotypes were observed. Furthermore, NOC mRNA levels in human abdominal adipose tissue were significantly increased in obese subjects compared to non-obese controls. Conclusion Genetic variation in the NOC gene is associated with BMI in Chinese subjects.
References
[1]
Huang W, Ramsey KM, Marcheva B, Bass J (2011) Circadian rhythms, sleep, and metabolism. J Clin Invest 121: 2133–2141.
[2]
Rutter J, Reick M, McKnight SL (2002) Metabolism and the control of circadian rhythms. Annu Rev Biochem 71: 307–331.
[3]
Bass J, Takahashi JS (2010) Circadian integration of metabolism and energetics. Science 330: 1349–1354.
[4]
Stubblefield JJ, Terrien J, Green CB (2012) Nocturnin: at the crossroads of clocks and metabolism. Trends Endocrinol Metab 23: 326–333.
[5]
Buxton OM, Cain SW, O'Connor SP, Porter JH, Duffy JF, et al. (2012) Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci Transl Med 4: 129ra143.
[6]
Gangwisch JE (2009) Epidemiological evidence for the links between sleep, circadian rhythms and metabolism. Obes Rev 10 Suppl 237–45.
[7]
Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, et al. (2005) Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308: 1043–1045.
[8]
Grimaldi B, Bellet MM, Katada S, Astarita G, Hirayama J, et al. (2010) PER2 controls lipid metabolism by direct regulation of PPARgamma. Cell Metab 12: 509–520.
[9]
Green CB, Douris N, Kojima S, Strayer CA, Fogerty J, et al. (2007) Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proc Natl Acad Sci U S A 104: 9888–9893.
[10]
Hee SW, Tsai SH, Chang YC, Chang CJ, Yu IS, et al. (2012) The role of nocturnin in early adipogenesis and modulation of systemic insulin resistance in human. Obesity (Silver Spring) 20: 1558–1565.
[11]
Kawai M, Green CB, Lecka-Czernik B, Douris N, Gilbert MR, et al. (2010) A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-gamma nuclear translocation. Proc Natl Acad Sci U S A 107: 10508–10513.
[12]
Pasula S, Chakraborty S, Choi JH, Kim JH (2010) Role of casein kinase 1 in the glucose sensor-mediated signaling pathway in yeast. BMC Cell Biol 11: 17.
[13]
Moriya H, Johnston M (2004) Glucose sensing and signaling in Saccharomyces cerevisiae through the Rgt2 glucose sensor and casein kinase I. Proc Natl Acad Sci U S A. 101: 1572–1577.
[14]
Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42: 105–116.
[15]
Scott EM, Carter AM, Grant PJ (2008) Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int J Obes (Lond) 32: 658–662.
[16]
Garaulet M, Corbalan MD, Madrid JA, Morales E, Baraza JC, et al. (2010) CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet. Int J Obes (Lond) 34: 516–523.
[17]
Sookoian S, Gemma C, Gianotti TF, Burgueno A, Castano G, et al. (2008) Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity. Am J Clin Nutr 87: 1606–1615.
[18]
Garaulet M, Lee YC, Shen J, Parnell LD, Arnett DK, et al. (2009) CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids. Am J Clin Nutr 90: 1466–1475.
[19]
Garaulet M, Corbalan-Tutau MD, Madrid JA, Baraza JC, Parnell LD, et al. (2010) PERIOD2 variants are associated with abdominal obesity, psycho-behavioral factors, and attrition in the dietary treatment of obesity. J Am Diet Assoc 110: 917–921.
[20]
Englund A, Kovanen L, Saarikoski ST, Haukka J, Reunanen A, et al. (2009) NPAS2 and PER2 are linked to risk factors of the metabolic syndrome. J Circadian Rhythms 7: 5.
[21]
Woon PY, Kaisaki PJ, Braganca J, Bihoreau MT, Levy JC, et al. (2007) Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc Natl Acad Sci U S A 104: 14412–14417.
[22]
Lin JW, Chang YC, Li HY, Chien YF, Wu MY, et al. (2009) Cross-sectional validation of diabetes risk scores for predicting diabetes, metabolic syndrome, and chronic kidney disease in Taiwanese. Diabetes Care 32: 2294–2296.
[23]
Chang YC, Chang TJ, Jiang YD, Kuo SS, Lee KC, et al. (2007) Association study of the genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population. Diabetes 56: 2631–2637.
[24]
Barrett JC (2009) Haploview: Visualization and analysis of SNP genotype data. Cold Spring Harb Protoc 2009: pdb ip71.
[25]
Lou XY, Chen GB, Yan L, Ma JZ, Mangold JE, et al. (2008) A combinatorial approach to detecting gene-gene and gene-environment interactions in family studies. Am J Hum Genet 83: 457–467.
