The association between clock gene polymorphisms and type 2 diabetes: A systematic review and meta-analysis

Background: Misalignment of the endogenous circadian system may contribute to the risk of type 2 diabetes. This systematic review and meta-analysis examined the association between clock gene polymorphisms and glycemic parameters and type 2 diabetes. Methods: Embase, Medline, and Web of Science databases were searched from inception to August 20, 2024. Empirical studies examining the association between core clock gene polymorphisms and type 2 diabetes and glycemic parameters, and studies examining non-core clock genes with information on environmental factors were included. A multi-level meta-analytical approach was used, and a weighted odds ratio was reported (PROSPERO, CRD42022337706). Results: In total, 37 studies comprising 535,063 participants were included. CRY2 was associated with higher fasting blood glucose (OR: 1.07, 95 % CI: 1.03–1.11) and impaired glucose tolerance (OR: 1.02, CI: 1.00–1.04). Polymorphisms in MTNR1B were associated with a greater risk of type 2 diabetes. CLOCK was associated with lower risk of type 2 diabetes (OR: 0.94, CI: 0.89–1.00), and PER3 was associated with lower fasting insulin (OR: 0.94, CI: 0.91–0.97) and lower risk of insulin resistance (OR: 0.92, CI: 0.88–0.95). These associations reflect pooled variant-level effects within genes, and the effects of certain variants were modified by diet, alcohol consumption, physical activity, sleep, and length of daylight. Conclusions: Specific polymorphisms in circadian genes, including CRY2, MTNR1B, CLOCK, and PER3, were associated with glycemic parameters and type 2 diabetes risk. These associations may be influenced by lifestyle and environmental factors, and interventions targeting circadian alignment could potentially modify diabetes risk, although further research is needed.