Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Nutrients. 2020 Oct 29;12(11):3323. doi: 10.3390/nu12113323.
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 ( = 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 ( = 0.001), determining fasting glucose in such a way that the increasing effect of the risk G-allele was much greater in young ( = 5.9 × 10) than in elderly participants ( = 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 ( > 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.
基因-年龄相互作用尚未在代谢表型上得到系统研究，这种调节对于更好地理解营养基因组学中的时间调节将是关键。考虑到衰老通常与昼夜节律系统的损害和褪黑素分泌减少有关，我们专注于褪黑素受体 1B (MTNR1B)-rs10830963 C>G 变体，该变体与空腹血糖浓度、妊娠糖尿病和 2 型糖尿病有关。因此，我们的主要目的是研究 MTNR1B-rs10830963 多态性与空腹血糖之间的关联是否依赖于年龄。我们的次要目的是分析该多态性与 2 型糖尿病的关联，并探索基因-妊娠对 2 型糖尿病风险的相互作用。对三个地中海队列（n=2823）进行了分析。首先，在发现队列中进行了一项横断面研究，该队列由来自普通人群的 1378 名参与者（年龄 18 至 80 岁；平均年龄 41 岁）组成。为了验证和扩展结果，研究了两个由老年人组成的复制队列。在发现队列中，我们观察到了强烈的基因-年龄相互作用（p=0.001），使得风险 G 等位基因的增加效应在年轻人（p=5.9×10）中比在老年人（p=0.805）中大得多。一致地，MTNR1B-rs10830963 多态性与两个复制队列（平均年龄超过 65 岁）中的空腹血糖浓度的关联没有达到统计学意义（两者均大于 0.05）。然而，在老年队列中，在基线时发现该多态性与 2 型糖尿病之间存在显著关联。此外，在其中一个队列中，我们获得了一个统计学上显著的交互作用，即 MTNR1B 多态性与回顾性评估的怀孕次数之间的交互作用，对 2 型糖尿病的风险有影响。总之，MTNR1B-rs10830963 多态性与空腹血糖的关联依赖于年龄，在年轻人中影响更大。然而，在老年人群中，观察到该多态性与 2 型糖尿病有关，我们的探索性分析表明，过去怀孕次数对未来 2 型糖尿病遗传风险的调节作用。
