Chronological age interacts with the circadian melatonin receptor 1B gene variation, determining fasting glucose concentrations in Mediterranean populations. Additional analyses on type-2 diabetes risk

Authors: SORLI, JOSE - University Of Valencia; BARRAGAN, ROCIO - University Of Valencia; COLTELL, OSCAR - Instituto De Salud Carlos Iii; PORTOLES, OLGA - University Of Valencia; PASCUAL, EVA - University Of Valencia; ORTEGA-AZORIN, CAROLINA - University Of Valencia; GONZALEZ, JOSE - University Of Valencia; ESTRUCH, RAMON - Instituto De Salud Carlos Iii; SAIZ, CARMEN - University Of Valencia; PEREZ-FIDALGO, ALEJANDRO - University Of Valencia; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; CORELLA, DOLORES - University Of Valencia

Submitted to: Nutrients
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/24/2020
Publication Date: 10/29/2020
Citation: Sorli, J.V., Barragan, R., Coltell, O., Portoles, O., Pascual, E.C., Ortega-Azorin, C., Gonzalez, J.I., Estruch, R., Saiz, C., Perez-Fidalgo, A., Ordovas, J.M., Corella, D. 2020. Chronological age interacts with the circadian melatonin receptor 1B gene variation, determining fasting glucose concentrations in Mediterranean populations. Additional analyses on type-2 diabetes risk. Nutrients. 12(11):3323. https://doi.org/10.3390/nu12113323.
DOI: https://doi.org/10.3390/nu12113323

Interpretive Summary: Aging is associated with a deterioration of the biological rhythms, including poor sleep. The latter could be mediated by decreased melatonin (a hormone that triggers sleep) production. Melatonin has also been associated with type-2 diabetes. The aim of this study conducted by investigators in Spain and at the HNRCA in Boston was to investigate whether a gene variant in the melatonin receptor gene was associated with glucose levels and whether this association was age-dependent. Three Mediterranean cohorts (n = 2823) were analyzed for this purpose. This study revealed that the genetic variant investigated was associated with glucose levels in an age-dependent manner, having a more significant effect in younger people. Therefore, the early identification of such genetic risk will facilitate the identification of subjects with a greater predisposition to diabetes and implement early prevention with dietary and behavioral approaches.

Technical Abstract: Gene-age interactions have not been systematically investigated on metabolic phenotypes and this modulation will be key for a better understanding of the temporal regulation in nutrigenomics. Taking into account that aging is typically associated with both impairment of the circadian system and a decrease in melatonin secretion, we focused on the melatonin receptor 1B (MTNR1B)-rs10830963 C>G variant that has been associated with fasting glucose concentrations, gestational diabetes, and type-2 diabetes. Therefore, our main aim was to investigate whether the association between the MTNR1B-rs10830963 polymorphism and fasting glucose is age dependent. Our secondary aims were to analyze the polymorphism association with type-2 diabetes and explore the gene-pregnancies interactions on the later type-2 diabetes risk. Three Mediterranean cohorts (n = 2823) were analyzed. First, a cross-sectional study in the discovery cohort consisting of 1378 participants (aged 18 to 80 years; mean age 41 years) from the general population was carried out. To validate and extend the results, two replication cohorts consisting of elderly individuals were studied. In the discovery cohort, we observed a strong gene-age interaction (p = 0.001), determining fasting glucose in such a way that the increasing effect of the risk G-allele was much greater in young (p = 5.9 x 10-10) than in elderly participants (p = 0.805). Consistently, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose concentrations in the two replication cohorts (mean age over 65 years) did not reach statistical significance (p > 0.05 for both). However, in the elderly cohorts, significant associations between the polymorphism and type-2 diabetes at baseline were found. Moreover, in one of the cohorts, we obtained a statistically significant interaction between the MTNR1B polymorphism and the number of pregnancies, retrospectively assessed, on the type-2 diabetes risk. In conclusion, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose is age-dependent, having a greater effect in younger people. However, in elderly subjects, associations of the polymorphism with type-2 diabetes were observed and our exploratory analysis suggested a modulatory effect of the number of past pregnancies on the future type-2 diabetes genetic risk.