A systematic review of variations in circadian rhythm genes and type 2 diabetes.

Background: Type 2 diabetes (T2D) is a chronic disease that has severe individual and 26 societal consequences, which is forecast to worsen in future. A new field of investigation is 27 variations in circadian rhythm (CR) genes, in conjunction with diet and sleep variables, 28 associations with, and effects on, T2D development. 29 Objective: This systematic review aimed to analyse all current literature regarding CR gene 30 variations and T2D, and explore their interplay with diet and sleep variables on T2D 31 outcomes. This review was registered with PROSPERO (CRD42021259682). 32 Methodology: Embase and Pubmed were searched on 6/8/2021 / 11/8/2021 for studies of all 33 designs, including participants from both sexes, all ethnicities, ages, and geographic 34 locations. Participants with risk alleles / genotypes were compared with the wildtype 35 regarding T2D outcomes. Studies risk of bias were scored according to the ROBINS I/E 36 criteria. 37 Results: 31 studies were found (association n=29 / intervention n=2) including >600,000 38 participants from various ethnicities, sexes, and ages. Variations in the melatonin receptor 1b 39 (MTNR1B), brain and muscle arnt-like 1 (BMAL1) and period circadian regulator (PER) 40 genes were consistently associated with T2D outcomes. 41 Conclusions: Individuals with variations in MTNR1B, BMAL1 and PER may be at higher 42 risk of T2D. Further research is needed regarding other CR genes. More longitudinal studies 43 and randomised trials are required before clinical recommendations can be made.