title: Season-dependent associations of circadian rhythm-regulating loci (CRY1, CRY2 and MTNR1B) and glucose homeostasis: the GLACIER Study.
abstract: OBJECTIVE
  The association of single nucleotide polymorphisms (SNPs) proximal to CRY2 and MTNR1B with fasting glucose is well established. CRY1/2 and MTNR1B encode proteins that regulate circadian rhythmicity and influence energy metabolism. Here we tested whether season modified the relationship of these loci with blood glucose concentration.
  
  
  METHODS
  SNPs rs8192440 (CRY1), rs11605924 (CRY2) and rs10830963 (MTNR1B) were genotyped in a prospective cohort study from northern Sweden (n = 16,499). The number of hours of daylight exposure during the year ranged from 4.5 to 22 h daily. Owing to the non-linear distribution of daylight throughout the year, season was dichotomised based on the vernal and autumnal equinoxes. Effect modification was assessed using linear regression models fitted with a SNP × season interaction term, marginal effect terms and putative confounding variables, with fasting or 2 h glucose concentrations as outcomes.
  
  
  RESULTS
  The rs8192440 (CRY1) variant was only associated with fasting glucose among participants (n = 2,318) examined during the light season (β = -0.04 mmol/l per A allele, 95% CI -0.08, -0.01, p = 0.02, p interaction = 0.01). In addition to the established association with fasting glucose, the rs11605924 (CRY2) and rs10830963 (MTNR1B) loci were associated with 2 h glucose concentrations (β = 0.07 mmol/l per A allele, 95% CI 0.03, 0.12, p = 0.0008, n = 9,605, and β = -0.11 mmol/l per G allele, 95% CI -0.15, -0.06, p < 0.0001, n = 9,517, respectively), but only in participants examined during the dark season (p interaction = 0.006 and 0.04, respectively). Repeated measures analyses including data collected 10 years after baseline (n = 3,500) confirmed the results for the CRY1 locus (p interaction = 0.01).
  
  
  CONCLUSIONS
  In summary, these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis.
authors.affiliation: Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Clinical Research Center Building 91, Level 10, Jan Waldenströms gata 35, SE-205 02, Malmö, Sweden, frida.renstrom@med.lu.se.
authors.forename: Frida
authors.initials: F
authors.lastname: Renström
authors.forename: Robert W
authors.initials: RW
authors.lastname: Koivula
authors.forename: Tibor V
authors.initials: TV
authors.lastname: Varga
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
mesh_terms: D000328:Adult; D000483:Alleles; D001786:Blood Glucose / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D056931:Cryptochromes / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D005838:Genotype; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D044123:Receptor, Melatonin, MT2 / Q000235:genetics*; D012621:Seasons
chemical_list: D001786:Blood Glucose; C538963:CRY1 protein, human; C538966:CRY2 protein, human; D056931:Cryptochromes; C573871:MTNR1B protein, human; D044123:Receptor, Melatonin, MT2