Season-dependent associations of circadian rhythm-regulating loci (CRY1, CRY2 and MTNR1B) and glucose homeostasis: the GLACIER Study

Abstract

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.

CRY1 and CRY2 genetic variants in seasonality: A longitudinal and cross-sectional study

“…In addition, the minor alleles of the CRY2 SNPs rs11605924, rs10838524 and rs7933420 all revealed increases in fasting glucose in a sample of non-diabetic individuals with the family history of type 2 diabetes (Machicao et al, 2016). Furthermore, the A-allele of CRY2 SNP rs11605924 was confirmed to associate with fasting glucose, and shown to associate with the 2-hour glucose levels after the 75-gram oral glucose tolerance test if administered during the winter, but not if administered in the summer (Renstrom et al, 2015). On the other hand, the minor C-allele of CRY1 SNP rs2287161 was shown to interact with the level of carbohydrate intake, that is both a susceptibility factor to type 2 diabetes and a characteristic of seasonal affective disorder, to modulate fasting insulin and insulin resistance (Dashti et al, 2014).…”

Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes

“…This association has subsequently been confirmed in other populations (Jonsson et al, 2013;Renströ m et al, 2015;Rö nn et al, 2009). Despite the very robust genetic association, a molecular understanding of why melatonin signaling is involved in the pathogenesis of T2D has still not been reached.…”

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

“…Interest in MT in the pathogenesis of T2DM derived initially from three independent genome-wide association studies that led to the identification of several frequent polymorphisms located near the MTNR1B gene that were associated with increased fasting plasma glucose, a reduction of early insulin response to glucose, and ultimately an increased risk of developing T2DM (Bouatia-Naji et Lyssenko et al, 2009). This genetic association is very robust and was subsequently replicated by several groups in other populations (Ronn et al, 2009;Renström et al, 2015). Surprisingly, the influence of MT on insulin secretion is still debated, with conflicting results generated in vitro using rodent and human islets (Lyssenko et al, 2009;Costes et al, 2015).…”