TY - JOUR

T1 - Season-dependent associations of circadian rhythm-regulating loci (CRY1, CRY2 and MTNR1B) and glucose homeostasis

T2 - the GLACIER Study

AU - Renström, Frida

AU - Koivula, Robert W

AU - Varga, Tibor V

AU - Hallmans, Göran

AU - Mulder, Hindrik

AU - Florez, Jose C

AU - Hu, Frank B

AU - Franks, Paul W

PY - 2015/5

Y1 - 2015/5

N2 - AIMS/HYPOTHESIS: 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/INTERPRETATION: In summary, these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis.

AB - AIMS/HYPOTHESIS: 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/INTERPRETATION: In summary, these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis.

KW - Adult

KW - Alleles

KW - Blood Glucose/genetics

KW - Circadian Rhythm/genetics

KW - Cryptochromes/genetics

KW - Female

KW - Gene-Environment Interaction

KW - Genetic Association Studies

KW - Genotype

KW - Homeostasis/genetics

KW - Humans

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Receptor, Melatonin, MT2/genetics

KW - Seasons

U2 - 10.1007/s00125-015-3533-8

DO - 10.1007/s00125-015-3533-8

M3 - Journal article

C2 - 25707907

VL - 58

SP - 997

EP - 1005

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 5

ER -