Daylight exposure may modify the effect of variants at MTNR1B and CRY2 on glucose tolerance: the GLACIER Study. F. Renström1,2, R. Koivula1, T. V. Varga1, G. Hallmans3, F. B. Hu2, J. C. Florez4, H. Mulder5, P. W. Franks1,2,6 1) Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden; 2) Department of Nutrition, Harvard School of Public Health, Boston, USA; 3) Public Health & Clinical Medicine, Section for Nutritional Research, Umeå University Hospital, Umeå, Sweden; 4) Massachusetts General Hospital, Harvard Medical School, Boston, USA; 5) Department of Clinical Sciences, Skåne University Hospital Malmö, Malmö, Sweden; 6) Department of Public Health & Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden.

   Background: MTNR1B and CRY2 are key players in the regulation of the circadian rhythm, both of which control glucose homeostasis. We recently reported novel associations between genetic variants at these two loci and 2-hrs glucose levels following an oral glucose tolerance test (OGTT) (Renström et al., Diabetes, 2011). This study was performed in a population cohort situated ~400km (250 mi) south of the Arctic Circle in Sweden, where annual daylight hours vary between 4.5-22 hrs. Here we aimed to test the hypothesis that variation in daylight exposure modifies the relationship of rs10830963 (MTNR1B) and rs11605924 (CRY2) variation with 2-hr glucose levels. Methods: The rs10830963 (MTNR1B) and rs11605924 (CRY2) loci were genotyped in GLACIER, a prospective cohort study of 16,499 adults from the county of Västerbotten in northern Sweden. Daylight exposure was dichotomized according to the vernal and autumnal equinox. Effect modification by daylight exposure was tested by fitting generalized linear models on 2-hr glucose levels including the product term (SNP × season) along with the marginal effects. All analyses were adjusted for age, sex, fasting time and fasting glucose concentrations.Results: The CRY2 locus was positively associated with 2-hr glucose levels during the darker months ( = 0.07 mmol/l per effect allele, P = 0.002, n = 9,605), whereas no association was observed among participants examined during the lighter months ( = -0.02 mmol/l per effect allele, P = 0.38, n = 6,215; Pinteraction = 0.01). In participants who underwent the OGTT during the dark season, the MTNR1B locus was significantly inversely associated with 2-hr glucose levels ( = -0.10 mmol/l per effect allele, P < 0.0001, n = 9,517), whereas no association was observed among participants examined during the bright season ( = -0.03 mmol/l per effect allele, P = 0.35, n = 6,174; Pinteraction = 0.06). Conclusions: Our study provides novel epidemiological evidence of a biologically plausible interaction between the rs10830963 (MTNR1B) and rs11605924 (CRY2) with daylight exposure on glucose tolerance levels.

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